Julie Elaine Bauman

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Courses

Scholarly Contributions

Chapters

• Bauman, J. E. (2018). Management of Head and Neck Cancers in the Elderly. In Head and Neck Cancers: Evidence-Based Treatment. Springer Publishing Company.
• Bauman, J. E. (2017). Cancer with Distant Metastases. In Decision-Making in Otolaryngology. Jaypee Brothers Medical Publishers.
• Bauman, J. E. (2017). Chemotherapy of Head and Neck Cancer. In Decision-Making in Otolaryngology. Jaypee Brothers Medical Publishers.
• Bauman, J. E. (2017). Management of Oropharyngeal Squamous Cell Carcinoma. In Textbook of Complex General Surgical Oncology. McGrawl-Hill.
• Bauman, J. E. (2020). Head and Neck Cancer. In Goldman-Cecil Medicine, 26th edition. Elsevier.

Journals/Publications

• Groysman, M., Yi, S. K., Robbins, J. R., Hsu, C. C., Julian, R., Bauman, J. E., Baker, A., Wang, S. J., & Bearelly, S. (2022). The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy. American journal of otolaryngology, 43(1), 103243.
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  To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC).
• Bauman, J. E., Daniel, J. E., Centuori, S. M., Grandis, J. R., Li, H., Daniel, N. P., Zang, Y., Cedars, E. D., & Geiger, J. L. (2021). Clinical trials optimizing investigator and self‐collection of buccal cells for RNA yield. Laryngoscope Investigative Otolaryngology.
• Bauman, J. E., Harris, J., Uppaluri, R., Yao, M., Ferris, R. L., Chen, J., Jordan, R. C., Joshi, N. P., Jujjuvaparu, S., Blakaj, D. M., Henson, C., Sheqwara, J., Mell, L. K., Sen, N., Clump, D. A., Garg, M. K., Yilmaz, E., Torres-Saavedra, P., & Le, Q. T. (2021). NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer. Cancers, 13(12).
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  The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.
• Centuori, S. M., Caulin, C., & Bauman, J. E. (2021). Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention. Current treatment options in oncology, 22(6), 52.
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  To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.
• Geiger, J. L., Cedars, E. D., Zang, Y., Normolle, D. P., Li, H., Grandis, J. R., Centuori, S., Johnson, D. E., & Bauman, J. E. (2021). Clinical trials optimizing investigator and self-collection of buccal cells for RNA yield. Laryngoscope investigative otolaryngology, 6(1), 116-121.
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  Buccal cells are an ideal surrogate tissue for studying biologic effects of carcinogens or drugs, however inherent fragility and salivary RNAses limit RNA yield. We conducted healthy volunteer trials to optimize collection conditions.
• Gutkind, J. S., Molinolo, A. A., Wu, X., Wang, Z., Nachmanson, D., Harismendy, O., Alexandrov, L. B., Wuertz, B. R., Ondrey, F. G., Laronde, D., Rock, L. D., Rosin, M., Coffey, C., Butler, V. D., Bengtson, L., Hsu, C. H., Bauman, J. E., Hewitt, S. M., Cohen, E. E., , Chow, H. S., et al. (2021). Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions. JCI insight, 6(17).
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  BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.
• Jin, N., Keam, B., Cho, J., Lee, M. J., Kim, H. R., Torosyan, H., Jura, N., Ng, P. K., Mills, G. B., Li, H., Zeng, Y., Barbash, Z., Tarcic, G., Kang, H., Bauman, J. E., Kim, M. O., VanLandingham, N. K., Swaney, D. L., Krogan, N. J., , Johnson, D. E., et al. (2021). Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma. The Journal of clinical investigation, 131(22).
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  Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.
• Jones, T. M., Carew, J. S., Bauman, J. E., & Nawrocki, S. T. (2021). Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer. Cancers, 13(13).
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  Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.
• Julian, R., Savani, M., & Bauman, J. E. (2021). Immunotherapy Approaches in HPV-Associated Head and Neck Cancer. Cancers, 13(23).
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  Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.
• Luna, A. J., Sterk, R. T., Griego-Fisher, A. M., Chung, J. Y., Berggren, K. L., Bondu, V., Barraza-Flores, P., Cowan, A. T., Gan, G. N., Yilmaz, E., Cho, H., Kim, J. H., Hewitt, S. M., Bauman, J. E., & Ozbun, M. A. (2021). MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors. PLoS pathogens, 17(1), e1009216.
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  Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.
• Bauman, J. E., Ohr, J., Gooding, W. E., Ferris, R. L., Duvvuri, U., Kim, S., Johnson, J. T., Soloff, A. C., Wallweber, G., Winslow, J., Gaither-Davis, A., Grandis, J. R., & Stabile, L. P. (2020). Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer. Cancers, 12(6).
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  Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8 subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.
• Johnson, D. E., Burtness, B., Leemans, C. R., Lui, V. W., Bauman, J. E., & Grandis, J. R. (2020). Head and neck squamous cell carcinoma. Nature reviews. Disease primers, 6(1), 92.
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  Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
• Kochanny, S. E., Worden, F. P., Adkins, D. R., Lim, D. W., Bauman, J. E., Wagner, S. A., Brisson, R. J., Karrison, T. G., Stadler, W. M., Vokes, E. E., & Seiwert, T. Y. (2020). A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Cancer, 126(10), 2146-2152.
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  MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC.
• Wu, K. Y., Wang, L., Shetty, J., Nishio, M., Murakami, H., Kim, S., Kim, D. W., Karam, S. D., Dennis, P. A., Cho, B. C., Bauman, J. E., & Ahn, M. (2020). 1056P Durvalumab (D) in combination with chemoradiotherapy (CRT) in solid tumours: Phase I CLOVER study. Annals of Oncology, 31. doi:10.1016/j.annonc.2020.08.1176
• Duvvuri, U., George, J., Kim, S., Alvarado, D., Neumeister, V. M., Chenna, A., Gedrich, R., Hawthorne, T., LaVallee, T., Grandis, J. R., & Bauman, J. E. (2019). Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients. Clinical cancer research : an official journal of the American Association for Cancer Research, 25(19), 5752-5758.
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  ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.
• Espinosa-Cotton, M., Fertig, E. J., Stabile, L. P., Gaither-Davis, A., Bauman, J. E., Schmitz, S., Gibson-Corley, K. N., Cheng, Y., Jensen, I. J., Badovinac, V. P., Laux, D., & Simons, A. L. (2019). A preliminary analysis of interleukin-1 ligands as potential predictive biomarkers of response to cetuximab. Biomarker research, 7, 14.
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  The epidermal growth factor receptor (EGFR) monoclonal IgG antibody cetuximab is approved for first-line treatment of recurrent and metastatic (R/M) HNSCC as a part of the standard of care EXTREME regimen (platinum/5-fluorouracil/cetuximab). This regimen has relatively high response and disease control rates but is generally not curative and many patients will experience recurrent disease and/or metastasis. Therefore, there is a great need to identify predictive biomarkers for recurrence and disease progression in cetuximab-treated HNSCC patients to facilitate patient management and allow for treatment modification. The goal of this work is to assess the potential of activating interleukin-1 (IL-1) ligands (IL-1 alpha [IL-1α], IL-1 beta [IL-1β]) as predictive biomarkers of survival outcomes in HNSCC patients treated with cetuximab-based chemotherapy.
• Han, J. E., Yi, S. K., Wang, S., Erman, A., Bearelly, S., Sindhu, S., Robbins, J. R., Bauman, J., & Hsu, C. C. (2019). Neoadjuvant chemotherapy improves survival compared with concurrent chemoradiation alone in nasopharyngeal carcinoma patients with N3 disease. Head & neck, 41(12), 4076-4087.
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  Neoadjuvant chemotherapy (NAC) trials in endemic regions of nasopharyngeal carcinoma (NPC) found improved survival, but studies are lacking in nonendemic regions. We assessed whether adding NAC to concurrent chemoradiation (CRT) improves overall survival (OS), especially in high-risk nonendemic patients.
• Hedberg, M. L., Peyser, N. D., Bauman, J. E., Gooding, W. E., Li, H., Bhola, N. E., Zhu, T. R., Zeng, Y., Brand, T. M., Kim, M. O., Jordan, R. C., VandenBerg, S., Olivas, V., Bivona, T. G., Chiosea, S. I., Wang, L., Mills, G. B., Johnson, J. T., Duvvuri, U., , Ferris, R. L., et al. (2019). Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for -altered head and neck cancer. The Journal of experimental medicine, 216(2), 419-427.
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  is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a -characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0.09-0.62) and overall survival (OS; hazard ratio 0.31, P = 0.0043, 95% CI 0.14-0.69) compared with nonregular NSAID users. For -altered HNSCC, predicted 5-yr DSS was 72% for NSAID users and 25% for nonusers; predicted 5-yr OS was 78% for regular NSAID users and 45% for nonregular users. mutation predicted sensitivity to NSAIDs in preclinical models in association with increased systemic PGE production. These findings uncover a biologically plausible rationale to implement NSAID therapy in -altered HNSCC.
• Hu, L., Li, H., Lee, E. D., Grandis, J. R., Bauman, J. E., & Johnson, D. E. (2019). Gene targets of sulforaphane in head and neck squamous cell carcinoma. Molecular medicine reports, 20(6), 5335-5344.
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  Patients who have undergone curative‑intent therapy for head and neck squamous cell carcinoma (HNSCC) exhibit a high rate of development of second primary tumors (SPTs), which are frequently lethal. A chemoprevention strategy that prevents SPTs would have a major impact on patient outcomes. Sulforaphane, a naturally‑occurring compound derived from cruciferous vegetables exhibits chemopreventive activity against HNSCC in a preclinical model. The effects of sulforaphane are considered to be mediated, in large part, through increased protein expression of the transcription factor nuclear factor erythroid 2‑related factor 2 (NRF2). Development of sulforaphane chemoprevention for HNSCC would benefit from the identification of robust biomarkers of sulforaphane activity in HNSCC cells and normal mucosal epithelial cells. The present study revealed that sulforaphane potently induces multiple oxidative stress‑associated genes at the RNA and protein levels, in HNSCC cells and Het‑1A cells, a non‑tumorigenic mucosal epithelial cell line. In the present analysis, HMOX1 and HSPA1A were identified as the most highly upregulated genes following sulforaphane treatment, suggesting their potential value as biomarkers to guide clinical trials. Sulforaphane induction of HMOX1 and HSPA1A was validated in vivo in murine tissues. Furthermore, the impact of sulforaphane treatment of HNSCC cells on the expression levels of natural killer group 2D (NKG2D) and DNAX accessory molecule‑1 (DNAM‑1) ligands, which are activators of natural killer (NK) cells, was examined. NRF2‑dependent upregulation of the NKG2D ligand MICA/B was observed. However, only one of the six HNSCC cell lines studied exhibited enhanced sensitivity to NK cell‑mediated killing following sulforaphane treatment, suggesting that this may not be a general mechanism of sulforaphane chemopreventive activity in HNSCC. In summary, the present study identified robust biomarkers of sulforaphane activity in HNSCC and normal tissues, supporting their application in the development of sulforaphane chemoprevention approaches for HNSCC.
• Romine, P. E., Martins, R. G., Eaton, K. D., Wood, D. E., Behnia, F., Goulart, B. H., Mulligan, M. S., Wallace, S. G., Kell, E., Bauman, J. E., Patel, S. A., & Vesselle, H. J. (2019). Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome. BMC cancer, 19(1), 70.
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  Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy.
• Sindhu, S. K., & Bauman, J. E. (2019). Current Concepts in Chemotherapy for Head and Neck Cancer. Oral and maxillofacial surgery clinics of North America, 31(1), 145-154.
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  This article highlights the evidence-based data to support systemic treatment options for patients with head and neck squamous cell carcinoma (HNSCC). The discovery of the human papillomavirus epidemic in HNSCC and its favorable prognosis has led to a major focus of research. Patients are stratified into clinical or pathologic risk categories and enrolled in trials comparing standard treatment paradigms with deintensification, in low-risk disease, or to intensification, in intermediate-risk or high-risk disease. Immunotherapy has proven beneficial in second-line palliative therapy and is under investigation in first-line palliative therapy and as a component of definitive, multimodality therapy for high-risk patients.
• Theodoraki, M. N., Yerneni, S., Gooding, W. E., Ohr, J., Clump, D. A., Bauman, J. E., Ferris, R. L., & Whiteside, T. L. (2019). Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT. Oncoimmunology, 8(7), 1593805.
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  : Exosomes, small extracellular vesicles (EVs) derived from the endocytic compartment of their parent cells, are present in plasma of cancer patients and may serve as non-invasive biomarkers of disease outcome. Here, we asked whether tumor-derived (TEX) and/or T-cell derived exosomes can predict outcome in head and neck squamous cell carcinoma (HNSCC) patients treated with oncological therapy. : 18 HNSCC patients enrolled in phase I clinical trial and receiving a combination of cetuximab, ipilimumab and radiation therapy were serially monitored for TEX and T cell-derived exosomes. Exosomes isolated from plasma by size exclusion chromatography were fractionated into TEX and CD3 + T cell-derived exosomes by immunocapture. Exosome-associated proteins were quantified by on-bead flow cytometry. Exosome molecular cargos of patients whose tumors recurred within 2 years (N = 5) were compared to cargos of patients who remained disease free at 2 years (N = 13) after therapy. : The predictive value of the exosome molecular cargo for disease recurrence was evaluated pre-, during and post therapy. In patients whose disease recurred, total exosome proteins, TEX/total exosome ratios, total CD3+, CD3(-)PD-L1+ and CD3 + 15s+ (Treg-derived) exosomes increased from the baseline levels. In patients who remained disease free, total exosome protein and TEX levels decreased, CD3+ and CD3+ CD15s+ exosomes stabilized and CD3+ CTLA4+ exosomes declined after ipilimumab therapy. : TEX and T cell-derived circulating exosomes instead of immune cells were used for monitoring of patients' responses to oncological therapy. The results support the potential role of exosomes as a non-invasive tumor and immune cell biomarkers in cancer.
• Bauman, J. E., Duvvuri, U., Thomas, S., Gooding, W. E., Clump, D. A., Karlovits, B., Wehbe, A., Miller, F. R., Kim, S., Sen, M., Heron, D. E., Grandis, J. R., & Argiris, A. (2018). Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives. Cancer, 124(19), 3881-3889.
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  Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT.
• Brand, T. M., Hartmann, S., Bhola, N. E., Li, H., Zeng, Y., O'Keefe, R. A., Ranall, M. V., Bandyopadhyay, S., Soucheray, M., Krogan, N. J., Kemp, C., Duvvuri, U., LaVallee, T., Johnson, D. E., Ozbun, M. A., Bauman, J. E., & Grandis, J. R. (2018). Cross-talk Signaling between HER3 and HPV16 E6 and E7 Mediates Resistance to PI3K Inhibitors in Head and Neck Cancer. Cancer research, 78(9), 2383-2395.
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  Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the PI3K pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the mAb CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that cross-talk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that cotargeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors. These findings suggest a new therapeutic combination that may improve outcomes in HPV(+) head and neck cancer patients. .
• Ferris, R. L., Saba, N. F., Gitlitz, B. J., Haddad, R., Sukari, A., Neupane, P., Morris, J. C., Misiukiewicz, K., Bauman, J. E., Fenton, M., Jimeno, A., Adkins, D. R., Schneider, C. J., Sacco, A. G., Shirai, K., Bowles, D. W., Gibson, M., Nwizu, T., Gottardo, R., , Manjarrez, K. L., et al. (2018). Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck: The Active8 Randomized Clinical Trial. JAMA oncology, 4(11), 1583-1588.
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  Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity.
• Shayan, G., Kansy, B. A., Gibson, S. P., Srivastava, R. M., Bryan, J. K., Bauman, J. E., Ohr, J., Kim, S., Duvvuri, U., Clump, D. A., Heron, D. E., Johnson, J. T., Hershberg, R. M., & Ferris, R. L. (2018). Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 Stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals. Clinical cancer research : an official journal of the American Association for Cancer Research, 24(1), 62-72.
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  Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti-EGFR-specific priming.Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells.Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed myeloid-derived suppressor cell (MDSC) suppression of T-cell proliferation in vitro These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFβ. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (TCR) clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT.Conclusions: Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC. Clin Cancer Res; 24(1); 62-72. ©2017 AACR.
• Bauman, J. E., Cohen, E., Ferris, R. L., Adelstein, D. J., Brizel, D. M., Ridge, J. A., O'Sullivan, B., Burtness, B. A., Butterfield, L. H., Carson, W. E., Disis, M. L., Fox, B. A., Gajewski, T. F., Gillison, M. L., Hodge, J. W., Le, Q. T., Raben, D., Strome, S. E., Lynn, J., & Malik, S. (2017). Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting. Cancer, 123(7), 1259-1271.
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  Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society.
• Bauman, J. E., Duvvuri, U., Gooding, W. E., Rath, T. J., Gross, N. D., Song, J., Jimeno, A., Yarbrough, W. G., Johnson, F. M., Wang, L., Chiosea, S., Sen, M., Kass, J., Johnson, J. T., Ferris, R. L., Kim, S., Hirsch, F. R., Ellison, K., Flaherty, J. T., , Mills, G. B., et al. (2017). Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. JCI insight, 2(6), e90449.
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  BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.
• Jie, H. B., Srivastava, R. M., Argiris, A., Bauman, J. E., Kane, L. P., & Ferris, R. L. (2017). Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients. Cancer immunology research, 5(5), 408-416.
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  Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TIL) and compared them with those of peripheral blood T lymphocytes (PBL) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared with CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population coexpressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TILs. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. Cancer Immunol Res; 5(5); 408-16. ©2017 AACR.
• Johnson, D. E., & Bauman, J. E. (2017). When the Damage Is Done: Selecting Patients for Head and Neck Cancer Chemoprevention Trials. Cancer prevention research (Philadelphia, Pa.), 10(9), 489-490.
• Marur, S., Li, S., Cmelak, A. J., Gillison, M. L., Zhao, W. J., Ferris, R. L., Westra, W. H., Gilbert, J., Bauman, J. E., Wagner, L. I., Trevarthen, D. R., Balkrishna, J., Murphy, B. A., Agrawal, N., Colevas, A. D., Chung, C. H., & Burtness, B. (2017). E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35(5), 490-497.
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  Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.
• Stabile, L. P., Egloff, A. M., Gibson, M. K., Gooding, W. E., Ohr, J., Zhou, P., Rothenberger, N. J., Wang, L., Geiger, J. L., Flaherty, J. T., Grandis, J. R., & Bauman, J. E. (2017). IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer. Oral oncology, 69, 38-45.
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  Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2016). 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two. Journal for ImmunoTherapy of Cancer, 4(1). doi:10.1186/s40425-016-0173-6
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  ### P189 Rational combinations of intratumoral T cell and myeloid agonists mobilize abscopal responses in prostate cancer #### Casey Ager1, Matthew Reilley2, Courtney Nicholas1, Todd Bartkowiak1, Ashvin Jaiswal1, Michael Curran1 ##### 1Department of Immunology, University of Texas MD Anderson
• Albergotti, W. G., Davis, K. S., Abberbock, S., Bauman, J. E., Ohr, J., Clump, D. A., Heron, D. E., Duvvuri, U., Kim, S., Johnson, J. T., & Ferris, R. L. (2016). Association of pretreatment body mass index and survival in human papillomavirus positive oropharyngeal squamous cell carcinoma. Oral oncology, 60, 55-60.
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  Pretreatment body mass index (BMI) >25kg/m(2) is a positive prognostic factor in patients with head and neck cancer. Previous studies have not been adequately stratified by human papilloma virus (HPV) status or subsite. Our objective is to determine prognostic significance of pretreatment BMI on overall survival in HPV+ oropharyngeal squamous cell carcinoma (OPSCC).
• Argiris, A., Bauman, J. E., Ohr, J., Gooding, W. E., Heron, D. E., Duvvuri, U., Kubicek, G. J., Posluszny, D. M., Vassilakopoulou, M., Kim, S., Grandis, J. R., Johnson, J. T., Gibson, M. K., Clump, D. A., Flaherty, J. T., Chiosea, S. I., Branstetter, B., & Ferris, R. L. (2016). Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer. Annals of oncology : official journal of the European Society for Medical Oncology, 27(8), 1594-600.
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  We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF).
• Bauman, J. E., & Grandis, J. (2016). Oral Cancer Chemoprevention--The End of EPOC, the Beginning of an Epoch of Molecular Selection. JAMA oncology, 2(2), 178-9.
• Bauman, J. E., Zang, Y., Sen, M., Li, C., Wang, L., Egner, P. A., Fahey, J. W., Normolle, D. P., Grandis, J. R., Kensler, T. W., & Johnson, D. E. (2016). Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane. Cancer prevention research (Philadelphia, Pa.), 9(7), 547-57.
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  Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR.
• Chiosea, S. I., Thompson, L. D., Weinreb, I., Bauman, J. E., Mahaffey, A. M., Miller, C., Ferris, R. L., & Gooding, W. E. (2016). Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations. Cancer, 122(20), 3136-3144.
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  The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA).
• Ferris, R. L., Geiger, J. L., Trivedi, S., Schmitt, N. C., Heron, D. E., Johnson, J. T., Kim, S., Duvvuri, U., Clump, D. A., Bauman, J. E., Ohr, J. P., Gooding, W. E., & Argiris, A. (2016). Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer. Annals of oncology : official journal of the European Society for Medical Oncology, 27(12), 2257-2262.
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  Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC.
• Geiger, J. L., Bauman, J. E., Gibson, M. K., Gooding, W. E., Varadarajan, P., Kotsakis, A., Martin, D., Gutkind, J. S., Hedberg, M. L., Grandis, J. R., & Argiris, A. (2016). Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head & neck, 38(12), 1759-1764.
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  Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC.
• Geiger, J. L., Grandis, J. R., & Bauman, J. E. (2016). The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. Oral oncology, 56, 84-92.
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  Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development.
• Hedberg, M. L., Goh, G., Chiosea, S. I., Bauman, J. E., Freilino, M. L., Zeng, Y., Wang, L., Diergaarde, B. B., Gooding, W. E., Lui, V. W., Herbst, R. S., Lifton, R. P., & Grandis, J. R. (2016). Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. The Journal of clinical investigation, 126(1), 169-80.
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  Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.
• Li, H., Wheeler, S., Park, Y., Ju, Z., Thomas, S. M., Fichera, M., Egloff, A. M., Lui, V. W., Duvvuri, U., Bauman, J. E., Mills, G. B., & Grandis, J. R. (2016). Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts. Molecular cancer research : MCR, 14(3), 278-86.
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  Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse-phase protein array and the data was compared with The Cancer Genome Atlas HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared with primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist.
• Ling, D. C., Vargo, J. A., Ferris, R. L., Ohr, J., Clump, D. A., Yau, W. W., Duvvuri, U., Kim, S., Johnson, J. T., Bauman, J. E., Branstetter, B. F., & Heron, D. E. (2016). Risk of Severe Toxicity According to Site of Recurrence in Patients Treated With Stereotactic Body Radiation Therapy for Recurrent Head and Neck Cancer. International journal of radiation oncology, biology, physics, 95(3), 973-980.
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  To report a 10-year update of our institutional experience with stereotactic body radiation therapy (SBRT) for reirradiation of locally recurrent head and neck cancer, focusing on predictors of toxicity.
• Schenker, Y., Arnold, R. M., Bauman, J. E., Heron, D. E., & Johnson, J. T. (2016). An enhanced role for palliative care in the multidisciplinary approach to high-risk head and neck cancer. Cancer, 122(3), 340-3.
• Bauman, J. E., & Ferris, R. L. (2015). Persistent Salivary Human Papillomavirus DNA as a Surveillance Biomarker: Not Just Spitting in the Wind. JAMA oncology, 1(7), 915-7.
• Chiosea, S. I., Williams, L., Griffith, C. C., Thompson, L. D., Weinreb, I., Bauman, J. E., Luvison, A., Roy, S., Seethala, R. R., & Nikiforova, M. N. (2015). Molecular characterization of apocrine salivary duct carcinoma. The American journal of surgical pathology, 39(6), 744-52.
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  Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."
• Clump, D. A., Bauman, J. E., & Ferris, R. L. (2015). Cancer of the oropharynx. Surgical oncology clinics of North America, 24(3), 509-20.
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  The oropharynx has a crucial role in swallowing because of the surrounding constrictor musculature, need for mobility and pliability, and proximity of the base of tongue to the larynx. Human papilloma virus (HPV) infection as a cause of oropharyngeal squamous cell carcinoma has increased dramatically in proportion and overall numbers of oropharyngeal squamous cell carcinoma cases. Better clinical response to therapy and younger age of the HPV+ oropharyngeal squamous cell carcinoma patients have caused functional and quality-of-life considerations to become more important endpoints in evaluating efficacy of therapeutic options; "deintensification" to ameliorate toxicity is under investigation for this population.
• Galloway, T. J., Wirth, L. J., Colevas, A. D., Gilbert, J., Bauman, J. E., Saba, N. F., Raben, D., Mehra, R., Ma, A. W., Atoyan, R., Wang, J., Burtness, B., & Jimeno, A. (2015). A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 21(7), 1566-73.
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  CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC.
• Geiger, J. L., Chiosea, S. I., Challinor, S. M., Nikiforova, M. N., & Bauman, J. E. (2015). Primary RET-mutated lung neuroendocrine carcinoma in MEN2B: response to RET-targeted therapy. Endocrine-related cancer, 22(5), L19-22.
• Jimeno, A., Bauman, J. E., Weissman, C., Adkins, D., Schnadig, I., Beauregard, P., Bowles, D. W., Spira, A., Levy, B., Seetharamu, N., Hausman, D., Walker, L., Rudin, C. M., & Shirai, K. (2015). A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral oncology, 51(4), 383-8.
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  The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC.
• Sheth, S. H., Johnson, D. E., Kensler, T. W., & Bauman, J. E. (2015). Chemoprevention targets for tobacco-related head and neck cancer: past lessons and future directions. Oral oncology, 51(6), 557-64.
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  Progress toward identifying an effective chemopreventive agent to reduce the incidence of head and neck squamous cell carcinoma (HNSCC) has been limited by poor efficacy and intolerable toxicity profiles. In this review, we summarize the biological basis of HNSCC chemoprevention, and outline challenges associated with identifying appropriate high-risk HNSCC populations for chemoprevention studies. We discuss findings and lessons learned from clinical trials that have investigated micronutrient and molecular targeting interventions. Finally, we introduce the concept of green chemoprevention, interventions based upon whole plant foods or simple extracts that may represent a safe and cost-conscious option for the next generation of studies. As our scientific understanding of HNSCC reaches new levels, the field is poised to develop chemoprevention studies based on rigorous biological validation with accessibility to all affected individuals regardless of socioeconomic barriers.
• Van Allen, E. M., Lui, V. W., Egloff, A. M., Goetz, E. M., Li, H., Johnson, J. T., Duvvuri, U., Bauman, J. E., Stransky, N., Zeng, Y., Gilbert, B. R., Pendleton, K. P., Wang, L., Chiosea, S., Sougnez, C., Wagle, N., Zhang, F., Du, Y., Close, D., , Johnston, P. A., et al. (2015). Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma. JAMA oncology, 1(2), 238-44.
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  Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.
• Vargo, J. A., Ferris, R. L., Ohr, J., Clump, D. A., Davis, K. S., Duvvuri, U., Kim, S., Johnson, J. T., Bauman, J. E., Gibson, M. K., Branstetter, B. F., & Heron, D. E. (2015). A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. International journal of radiation oncology, biology, physics, 91(3), 480-8.
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  Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN.
• Bauman, J. E., & Chung, C. H. (2014). CHK it out! Blocking WEE kinase routs TP53 mutant cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 20(16), 4173-5.
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  Mutations in TP53, encoding the master tumor suppressor p53, have posed a developmental therapeutic dilemma due to inability to target loss of function. Inhibition of WEE1 or CHK1 kinase, negative regulators of the G2-M checkpoint, selectively sensitizes p53-deficient cells to exogenous DNA damage, abrogating G2 arrest and precipitating mitotic catastrophe.
• Bauman, J. E., & Ferris, R. L. (2014). Integrating novel therapeutic monoclonal antibodies into the management of head and neck cancer. Cancer, 120(5), 624-32.
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  Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy. Interest in developing novel immunotherapies in HNSCC has been reawakened by the success of cetuximab, a therapeutic monoclonal antibody (mAb) against the epidermal growth factor receptor, which likely relies on immune as well as antisignaling mechanisms. This review focuses on novel therapeutic mAbs in current clinical development against established mechanisms of immune evasion in HNSCC, targeting: 1) tumor antigens, with resultant potential to induce antibody-dependent cell-mediated cytotoxicity and T cell activation; 2) immunosuppressive cytokines; 3) costimulatory tumor necrosis factor-family receptors; and 4) coinhibitory immune checkpoint receptors. Clinical trials of immunotherapeutic mAbs as monotherapy, in combination with cytolytic standard therapies exposing tumor antigens or in combination with other immunomodulatory mAbs, are urgently needed in HNSCC.
• Bauman, J. E., & Grandis, J. R. (2014). Targeting secondary immune responses to cetuximab: CD137 and the outside story. The Journal of clinical investigation, 124(6), 2371-5.
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  Cetuximab is a murine-human chimeric IgG1 mAb directed against the EGFR that is approved for use in patients with colorectal and head and neck carcinomas. While some patients benefit greatly from cetuximab, many do not; therefore, strategies to increase the efficacy of this drug are of great clinical interest. In this issue of the JCI, Kohrt and colleagues report a strategy for enhancing the secondary immune response to cetuximab that involves sequential targeting with an agonist mAb against CD137 expressed on NK and T cells.
• Bauman, J., Shaheen, M., Verschraegen, C. F., Belinsky, S. A., Houman Fekrazad, M., Lee, F. C., Rabinowitz, I., Ravindranathan, M., & Jones, D. V. (2014). A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers. Translational oncology.
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  Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.
• Chang, A. M., Nikiforova, M. N., Johnson, J. T., Bauman, J. E., Perez-Ordonez, B., Seethala, R. R., Krane, J. F., & Chiosea, S. I. (2014). Human papillomavirus-associated adenocarcinoma of the base of tongue: potentially actionable genetic changes. Head and neck pathology, 8(2), 151-6.
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  While human papillomavirus (HPV)-positive squamous and adenosquamous carcinomas of the oropharynx have been well characterized, HPV-associated pure adenocarcinomas are exceptionally rare. Herein we report the clinicopathologic features of one such HPV-associated adenocarcinoma of the base of tongue (BOT). A 70 year-old male presented with a 2.8 cm base of tongue mass and lymphadenopathy. Immunohistochemically, the adenocarcinoma was p63 negative and p16 positive. HPV positivity was shown by in situ hybridization. Features of salivary type tumor or metastasis from a distant primary were absent. IonTorrent™ semiconductor sequencing analysis for 739 cancer-associated mutations in 46 actionable cancer genes was performed and PIK3CA exon 9 (p.E545K) and MET exon 2 (p.E168D) mutations were identified. No PIK3CA or MET amplification was identified by fluorescence in situ hybridization. A re-review of archival HPV-positive oropharyngeal squamous cell carcinomas (n = 89, 1983-2013) showed no additional cases of adenocarcinoma. The clinical follow-up for the three previously reported cases of HPV-associated adenocarcinoma of the BOT was updated. All previously reported cases were tested and were negative for PIK3CA exon 9 and 20 and MET exon 2 mutations. These findings offer a molecular basis for potential therapeutic use of PIK3CA inhibitors in a subset of patients with HPV-associated adenocarcinoma of BOT.
• Griffith, C. C., Thompson, L. D., Assaad, A., Purgina, B. M., Lai, C., Bauman, J. E., Weinreb, I., Seethala, R. R., & Chiosea, S. I. (2014). Salivary duct carcinoma and the concept of early carcinoma ex pleomorphic adenoma. Histopathology, 65(6), 854-60.
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  The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA.
• Gross, N. D., Bauman, J. E., Gooding, W. E., Denq, W., Thomas, S. M., Wang, L., Chiosea, S., Hood, B. L., Flint, M. S., Sun, M., Conrads, T. P., Ferris, R. L., Johnson, J. T., Kim, S., Argiris, A., Wirth, L., Nikiforova, M. N., Siegfried, J. M., & Grandis, J. R. (2014). Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 20(12), 3289-98.
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  The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo.
• Krug, L. M., Wozniak, A. J., Kindler, H. L., Feld, R., Koczywas, M., Morero, J. L., Rodriguez, C. P., Ross, H. J., Bauman, J. E., Orlov, S. V., Ruckdeschel, J. C., Mita, A. C., Fein, L., He, X., Hall, R., Kawabe, T., & Sharma, S. (2014). Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma. Lung cancer (Amsterdam, Netherlands), 85(3), 429-34.
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  CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin.
• Levy, B., Spira, A., Becker, D., Evans, T., Schnadig, I., Camidge, D. R., Bauman, J. E., Hausman, D., Walker, L., Nemunaitis, J., Rudin, C. M., Halmos, B., & Bowles, D. W. (2014). A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 9(7), 1031-5.
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  The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC.
• Libby, E., Garcia, D., Quintana, D., Fekrazad, M. H., Bauman, J., Ebaid, A., Hromas, R., Rabinowitz, I., & Wiggins, C. (2014). Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups. Leukemia & lymphoma, 55(12), 2850-7.
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  This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60-69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.
• Parikh, R. A., Appleman, L. J., Bauman, J. E., Sankunny, M., Lewis, D. W., Vlad, A., & Gollin, S. M. (2014). Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas. Genes, chromosomes & cancer, 53(1), 25-37.
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  The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.
• Yip, L., Wharry, L. I., Armstrong, M. J., Silbermann, A., McCoy, K. L., Stang, M. T., Ohori, N. P., LeBeau, S. O., Coyne, C., Nikiforova, M. N., Bauman, J. E., Johnson, J. T., Tublin, M. E., Hodak, S. P., Nikiforov, Y. E., & Carty, S. E. (2014). A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy. Annals of surgery, 260(1), 163-8.
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  To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate.
• Bauman, J. E., Arias-Pulido, H., Lee, S. J., Fekrazad, M. H., Ozawa, H., Fertig, E., Howard, J., Bishop, J., Wang, H., Olson, G. T., Spafford, M. J., Jones, D. V., & Chung, C. H. (2013). A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral oncology, 49(5), 461-7.
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  The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy.
• Bauman, J. E., Austin, M. C., Schmidt, R., Kurland, B. F., Vaezi, A., Hayes, D. N., Mendez, E., Parvathaneni, U., Chai, X., Sampath, S., & Martins, R. G. (2013). ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial. British journal of cancer, 109(8), 2096-105.
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  Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions.
• Burtness, B., Bauman, J. E., & Galloway, T. (2013). Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition. The Lancet. Oncology, 14(8), e302-9.
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  Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys).
• Gildener-Leapman, N., Ferris, R. L., & Bauman, J. E. (2013). Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral oncology, 49(12), 1089-96.
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  Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA- targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches.
• Martins, R. G., Parvathaneni, U., Bauman, J. E., Sharma, A. K., Raez, L. E., Papagikos, M. A., Yunus, F., Kurland, B. F., Eaton, K. D., Liao, J. J., Mendez, E., Futran, N., Wang, D. X., Chai, X., Wallace, S. G., Austin, M., Schmidt, R., & Hayes, D. N. (2013). Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 31(11), 1415-21.
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  The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy.
• Weickhardt, A. J., Doebele, R. C., Purcell, W. T., Bunn, P. A., Oton, A. B., Rothman, M. S., Wierman, M. E., Mok, T., Popat, S., Bauman, J., Nieva, J., Novello, S., Ou, S. H., & Camidge, D. R. (2013). Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer, 119(13), 2383-90.
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  Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.
• Bauman, J. E., Eaton, K. D., Wallace, S. G., Carr, L. L., Lee, S. J., Jones, D. V., Arias-Pulido, H., Cerilli, L. A., & Martins, R. G. (2012). A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer. BMC cancer, 12, 449.
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  In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR).
• Bauman, J. E., Michel, L. S., & Chung, C. H. (2012). New promising molecular targets in head and neck squamous cell carcinoma. Current opinion in oncology, 24(3), 235-42.
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  Despite advances in multimodality therapy, the overall 5-year survival rate is 40-50% in patients with head and neck squamous cell carcinoma (HNSCC) and current multimodality approaches impart significant toxicities. This review highlights promising targets with the potential to improve clinical outcomes in HNSCC.
• Bauman, J., Verschraegen, C., Belinsky, S., Muller, C., Rutledge, T., Fekrazad, M., Ravindranathan, M., Lee, S. J., & Jones, D. (2012). A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies. Cancer chemotherapy and pharmacology, 69(2), 547-54.
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  The epidermal growth factor receptor (EGFR) is a validated target in malignancy; however, patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy. Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib. This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose (MTD).
• Burtness, B., Marur, S., Bauman, J. E., Golemis, E. A., Mehra, R., & Cohen, S. J. (2012). Comment on "epidermal growth factor receptor is essential for toll-like receptor 3 signaling". Science signaling, 5(254), lc5.
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  Epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) play important roles in tumor growth, which has stimulated efforts toward the design of targeted cancer therapeutics that inhibit their function. A growing body of literature indicates that EGFR and mTOR are also essential to support a functional innate immune response. Hence, although combination therapies that block both EGFR and mTOR may have improved activity against tumors, they may also place patients at risk of fulminant infections. We discuss data supporting this hypothesis.
• Williamson, E. A., Damiani, L., Leitao, A., Hu, C., Hathaway, H., Oprea, T., Sklar, L., Shaheen, M., Bauman, J., Wang, W., Nickoloff, J. A., Lee, S. H., & Hromas, R. (2012). Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. Cancer research, 72(23), 6200-8.
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  Previous studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy.
• Zahn, K. L., Wong, G., Bedrick, E. J., Poston, D. G., Schroeder, T. M., & Bauman, J. E. (2012). Relationship of protein and calorie intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy. Head & neck, 34(5), 655-62.
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  The purpose of this study was to evaluate the relationship of calorie and protein intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy.
• Oprea, T. I., Bauman, J. E., Bologa, C. G., Buranda, T., Chigaev, A., Edwards, B. S., Jarvik, J. W., Gresham, H. D., Haynes, M. K., Hjelle, B., Hromas, R., Hudson, L., Mackenzie, D. A., Muller, C. Y., Reed, J. C., Simons, P. C., Smagley, Y., Strouse, J., Surviladze, Z., , Thompson, T., et al. (2011). Drug Repurposing from an Academic Perspective. Drug discovery today. Therapeutic strategies, 8(3-4), 61-69.
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  Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.
• Carr, L. L., Mankoff, D. A., Goulart, B. H., Eaton, K. D., Capell, P. T., Kell, E. M., Bauman, J. E., & Martins, R. G. (2010). Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clinical cancer research : an official journal of the American Association for Cancer Research, 16(21), 5260-8.
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  We conducted a phase II study to assess the efficacy of continuous dosing of sunitinib in patients with flurodeoxyglucose positron emission tomography (FDG-PET)-avid, iodine-refractory well-differentiated thyroid carcinoma (WDTC) and medullary thyroid cancer (MTC) and to assess for early response per FDG-PET.
• Bauman, J. E., Mulligan, M. S., Martins, R. G., Kurland, B. F., Eaton, K. D., & Wood, D. E. (2008). Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. The Annals of thoracic surgery, 86(5), 1632-8; discussion 1638-9.
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  Isolated local relapse occurs in 24% to 35% of patients after definitive chemoradiation for locally advanced non-small cell lung cancer. Although originally considered inoperable, select patients are referred for surgical salvage. We describe a series of salvage lung resection after curative-intent radiation.
• Bauman, J. E., Eaton, K. D., & Martins, R. G. (2007). Antagonism of platelet-derived growth factor receptor in non small cell lung cancer: rationale and investigations. Clinical cancer research : an official journal of the American Association for Cancer Research, 13(15 Pt 2), s4632-6.
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  Molecules that target growth and survival pathways in cancer cells have revolutionized the treatment of cancer. Imatinib mesylate is one such agent inhibiting the tyrosine kinase that results from the Bcr-Abl translocation. Imatinib is also a potent inhibitor of the platelet-derived growth factor receptor. The platelet-derived growth factor receptor is crucial in the regulation of interstitial fluid pressure, as well as in the function of pericytes. Increased interstitial fluid pressure is a common feature of solid tumors and is thought to impede transcapillary transport of chemotherapy. Preclinical data show that platelet-derived growth factor receptor antagonism decreases interstitial fluid pressure, augments intratumoral concentration of chemotherapy, and impairs tumor growth. Pericytes are important cells in the vascular support structure of tumors regulating endothelial cell survival and directing capillary growth. Preclinical data suggest that dual targeting of pericytes and endothelial cells is a more effective antiangiogenic strategy than antiendothelial monotherapy. Two phase II studies in advanced non-small cell lung cancer are currently under way with imatinib. The first trial evaluates the use of intermittent imatinib and weekly paclitaxel in elderly patients. The second trial evaluates a novel maintenance strategy of imatinib and the antivascular endothelial growth factor antibody bevacizumab after first-line chemotherapy with bevacizumab. These trials should indicate whether encouraging preclinical data can be translated into clinical benefit in non-small cell lung cancer.
• Bauman, J. E., Eaton, K. D., & Martins, R. G. (2007). Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Archives of dermatology, 143(7), 889-92.
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  Squamous cell carcinoma of the skin (SCCS) is rarely encountered by medical oncologists owing to success of local therapies. When advanced SCCS requires systemic palliation, treatment with conventional chemotherapy, such as cisplatin, is often precluded by a patient's age or medical comorbidities. Cetuximab is a human and mouse chimeric antibody against epidermal growth factor receptor, a tyrosine kinase receptor richly expressed by SCCS cells, including lymph node metastases. This drug, approved for treatment of squamous cell carcinoma of the upper aerodigestive tract as well as colorectal cancer, is well tolerated. Toxic effects include acneiform rash and diarrhea. Preclinical data suggest that epidermal growth factor receptor is important in SCCS carcinogenesis.

Poster Presentations

• Centuori, S. M., Bauman, J. E., & Field, M. (2021, June). Implementation and Expansion of Cytek cFluor™ Immunoprofiling Kit, 14 Color to 26 Colors. CYTO. Virtual: ISAC.
• Chow, H., Szabo, E., Wojtowicz, M., Bengtson, L., Ho, E., Garland, L. L., Jose, G., Centuori, S. M., Hsu, C., & Bauman, J. E. (2021, April). Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers. American Association for Cancer Research (AACR),. Virtual Interactive 2021: AACR.
• Bauman, J. E. (2020, December/Winter). Phase 2 study of ADU-S100 in combination with pembrolizumab in adult patients with PD-L1+ recurrent or metastatic HNSCC: Preliminary safety, efficacy and PK/PD results. ESMO Immuno-Oncology Virtual Congress.
• Bauman, J. E. (2020, Fall/September). Durvalumab in combination with chemoradiotherapy in solid tumours: Phase 1 CLOVER study. European Society for Medical Oncology Annual Meeting.
• Bauman, J. E. (2020, May/Summer). Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic head and neck squamous cell carcinoma.. ASCO Annual Meeting / Journal Clinical Oncology.
• Bauman, J. E. (2020, November/Winter). A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603).. Society for Immunotherapy of Cancer.
• Bauman, J. E. (2019, May). CDX3379-04: Phase II evaluation of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC).. Journal of Clinical Oncology.
• Bauman, J. E. (2019, May). NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (Pembrolizumab) in high-risk head and neck squamous cell carcinoma (HNSCC).. Journal of Clinical Oncology.
• Bauman, J. E. (2019, May). Safety of radiotherapy with concurrent and adjuvant MEDI4736 (durvalumab) in patients with locoregionally advanced head and neck cancer with a contraindication to cisplatin: NRG-HN004.. Journal of Clinical Oncology.
• Bauman, J. E. (2018, April). Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma: A Preoperative “Window-of-Opportunity” Study. 2018 AACR Annual Meeting.
• Bauman, J. E. (2018, June). A phase 2, multicenter, open-label study to evaluate the efficacy and safety of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma. 2018 ASCO Annual Meeting.
• Bauman, J. E. (2018, October). Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma. 2018 ESMO Congress.