Setsuko K Chambers

Interests

Research

BASIC RESEARCH INTERESTS: Defining RNA binding proteins, miRNAs, RNA epigenetics, and convergent transcription in regulation of CSF-1/CSF-1R expression. Androgens and neoplastic transformation of normal ovarian/tubal epithelium.TRANSLATIONAL RESEARCH INTERESTS: Circulating and tissue miRNA profiling and pathway identification in women at high risk for ovarian cancerCLINICAL RESEARCH: I am the team leader for gynecologic oncology trials at the Cancer Center and have designed/implemented clinical trials on several aspects within the cancer spectrum. We actively accrue to therapeutic trials as well as those that focus on early detection or biomarker identification. I am active in cooperative group (NRG, SWOG, ECOG/ACRIN), industry-sponsored and investigator-initiated trials. I am co-PI of our primary NRG site and serve as a NRG Phase 1 committee member. I was site-PI of an ETCTN phase 1 trial via EDDOP. I also serve as a member of the Early Phase Clinical Trials Program at the Cancer Center.

Courses

No activities entered.

Scholarly Contributions

Chapters

• Chambers, S. K. (2019). Ovarian Cancer Prevention. In Alberts, Hess (Eds), Fundamentals of Cancer Prevention, Third Edition. Springer-Verlag: Heidelberg.

Journals/Publications

• Vulsteke, C., Chambers, S. K., Pérez, M. J., Chan, J. K., Raaschou-Jensen, N., Zhuo, Y., Lorusso, D., Herzog, T. J., de la Motte Rouge, T., Thomes Pepin, J. A., Braicu, E. I., Chen, L. M., Levy, T., Barter, J. F., Pilar Barretina-Ginesta, M., Joosens, E., York, W., Malinowska, I. A., González-Martín, A., & Monk, B. J. (2024). Tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy. European journal of cancer (Oxford, England : 1990), 208, 114157.
  More info

  To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016).
• Wang, X., Woo, H. H., Wei, M., Gibson, S., Miranda, M., Rush, D., Cragun, J., Zheng, W., Yao, G., & Chambers, S. K. (2024). Antiandrogen Flutamide-Induced Restoration of miR-449 Expression Mitigates Functional Biomarkers Associated with Ovarian Cancer Risk. medRxiv : the preprint server for health sciences.
  More info

  The involvement of the androgen and androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. We examined the effects of flutamide on the miRNA expression profile found in women at high risk (HR) for ovarian cancer.
• Wang, X., Woo, H. H., Wei, M., Gibson, S., Miranda, M., Rush, D., Cragun, J., Zheng, W., Yao, G., & Chambers, S. K. (2024). miR-449, identified through antiandrogen exposure, mitigates functional biomarkers associated with ovarian cancer risk. Scientific reports, 14(1), 29937.
  More info

  The involvement of the androgen receptor (AR) pathway in developing epithelial ovarian cancer is increasingly acknowledged. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. This study was initiated by investigating the impact of flutamide on miRNA expression in women at high risk (HR) for ovarian cancer. Ovarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women as well as low-risk (LR) women controls. We performed miRNA sequencing on these 3 sample cohorts and observed that flutamide normalized miRNA levels in HR tissues, notably upregulating the miR-449 family to levels seen in LR tissues. In subsequent tests in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey), flutamide also increased miR-449a and miR-449b-5p levels. Introducing mimics of these miRNAs reduced the mRNA and protein levels of AR and colony-stimulating factor 1 receptor (CSF1R, also known as c-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. Ovarian cancer cell migration was inhibited upon introducing miR-449a and miR-449b-5p mimics. Together, our study suggests a novel dual-inhibitory mechanism of flutamide on the AR pathway (AR expression suppression in addition to direct androgen antagonism) and supports its chemopreventive potential in ovarian cancer, especially for HR patients with low miR-449 expression.
• Anandhan, A., Dodson, M., Shakya, A., Chen, J., Liu, P., Wei, Y., Tan, H., Wang, Q., Jiang, Z., Yang, K., Garcia, J. G., Chambers, S. K., Chapman, E., Ooi, A., Yang-Hartwich, Y., Stockwell, B. R., & Zhang, D. D. (2023). NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Science Advances, 9(5), eade9585.
  More info

  Enhancing the intracellular labile iron pool (LIP) represents a powerful, yet untapped strategy for driving ferroptotic death of cancer cells. Here, we show that NRF2 maintains iron homeostasis by controlling HERC2 (E3 ubiquitin ligase for NCOA4 and FBXL5) and VAMP8 (mediates autophagosome-lysosome fusion). knockout cells have low expression, leading to a simultaneous increase in ferritin and NCOA4 and recruitment of apoferritin into the autophagosome. knockout cells also have low expression, which leads to ferritinophagy blockage. Therefore, deletion of results in apoferritin accumulation in the autophagosome, an elevated LIP, and enhanced sensitivity to ferroptosis. Concordantly, NRF2 levels correlate with HERC2 and VAMP8 in human ovarian cancer tissues, as well as ferroptosis resistance in a panel of ovarian cancer cell lines. Last, the feasibility of inhibiting NRF2 to increase the LIP and kill cancer cells via ferroptosis was demonstrated in preclinical models, signifying the impact of NRF2 inhibition in cancer treatment.
• Holloway, R. W., Thaker, P., Mendivil, A. A., Ahmad, S., Al-Niaimi, A. N., Barter, J., Beck, T., Chambers, S. K., Coleman, R. L., Crafton, S. M., Crane, E., Ramez, E., Ghamande, S., Graybill, W., Herzog, T., Indermaur, M. D., John, V. S., Landrum, L., Lim, P. C., , Lucci, J. A., et al. (2023). A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 33(9), 1458-1463.
  More info

  Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer.
• Tanyi, J. L., Randall, L. M., Chambers, S. K., Butler, K. A., Winer, I. S., Langstraat, C. L., Han, E. S., Vahrmeijer, A. L., Chon, H. S., Morgan, M. A., Powell, M. A., Tseng, J. H., Lopez, A. S., & Wenham, R. M. (2023). A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor-Positive Ovarian Cancer (Study 006). Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 41(2), 276-284.
  More info

  The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor-positive ovarian cancer.
• Chambers, S. K. (2022). Advances in Chemotherapy and Targeted Therapies in Endometrial Cancer. Cancers, 14(20).
  More info

  Endometrial cancer is now recognized to be several diseases with differing biology and responses to treatment. Improved molecular characterization has furthered the development and testing of targeted therapies in the different cohorts of endometrial cancer. Lessons are being learned from other cancers that share similar molecular typing, and hence, potentially similar tumor behavior. This commentary serves as a broad overview of the types of advances to which our patients now have access.
• Moore, K. N., Chambers, S. K., Hamilton, E. P., Chen, L. M., Oza, A. M., Ghamande, S. A., Konecny, G. E., Plaxe, S. C., Spitz, D. L., Geenen, J. J., Troso-Sandoval, T. A., Cragun, J. M., Rodrigo Imedio, E., Kumar, S., Mugundu, G. M., Lai, Z., Chmielecki, J., Jones, S. F., Spigel, D. R., & Cadoo, K. A. (2022). Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: an Open-Label, Four-Arm, Phase II Study. Clinical cancer research : an official journal of the American Association for Cancer Research.
  More info

  This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, Phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade {greater than or equal to}3 adverse events across all cohorts were neutropenia (45/94 [47.9%] patients), anemia (31/94 [33.0%]), thrombocytopenia (30/94 [31.9%]), and diarrhea and vomiting (10/94 [10.6%] each). Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1-3, 8-10, and 15-17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
• Tanyi, J. L., Randall, L. M., Chambers, S. K., Butler, K. A., Winer, I. S., Langstraat, C. L., Han, E. S., Vahrmeijer, A. L., Chon, H. S., Morgan, M. A., Powell, M. A., Tseng, J. H., Lopez, A., & Wenham, R. M. (2021). A Randomized Phase 3 Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor Positive Ovarian Cancer. Lancet Oncology.
• Tanyi, J. L., Randall, L. M., Chambers, S. K., Butler, K. A., Winer, I. S., Langstraat, C. L., Han, E. S., Vahrmeijer, A. L., Chon, H. S., Morgon, M. A., Powell, M. A., Tseng, J. H., Lopez, A. S., & Wenham, R. M. (2022). A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor-Positive Ovarian Cancer (Study 006). . J Clin Oncology.
• Yu, X., Lin, W., Spirtos, A., Wang, Y., Chen, H., Ye, J., Parker, J., Liu, C. C., Wang, Y., Quinn, G., Zhou, F., Chambers, S. K., Lewis, C., Lea, J., Li, B., & Zheng, W. (2022). Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution. . BMC Medicine.
• Yu, X., Lin, W., Spirtos, A., Wang, Y., Chen, H., Ye, J., Parker, J., Liu, C. C., Wang, Y., Quinn, G., Zhou, F., Chambers, S. K., Lewis, C., Lea, J., Li, B., & Zheng, W. (2022). Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution. BMC medicine, 20(1), 283.
  More info

  High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown.
• Swisher, E. M., Kwan, T. T., Oza, A. M., Tinker, A. V., Ray-Coquard, I., Oaknin, A., Coleman, R. L., Aghajanian, C., Konecny, G. E., O'Malley, D. M., Leary, A., Provencher, D., Welch, S., Chen, L. M., Wahner Hendrickson, A. E., Ma, L., Ghatage, P., Kristeleit, R. S., Dorigo, O., , Musafer, A., et al. (2021). Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nature communications, 12(1), 2487.
  More info

  ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.
• Woo, H. H., & Chambers, S. K. (2021). Regulation of closely juxtaposed proto-oncogene and gene expression by mRNA 3' end polymorphism in breast cancer cells. RNA (New York, N.Y.), 27(9), 1068-1081.
  More info

  Sense-antisense mRNA pairs generated by convergent transcription is a way of gene regulation. gene is closely juxtaposed to the gene in the opposite orientation, in chromosome 5. The intergenic region (IR) between and genes is 162 bp. We found that a small portion (∼4.18%) of mRNA is transcribed further downstream, including the end of the gene generating antisense mRNA against mRNA. Similarly, a small portion (∼1.1%) of mRNA is transcribed further downstream, including the end of the gene generating antisense mRNA against the mRNA. Insertion of the strong poly(A) signal sequence in the IR results in decreased and antisense mRNAs, resulting in up-regulation of both and mRNA expression. miR-324-5p targets mRNA 3' UTR, and as a result, regulates mRNA expression. HuR stabilizes mRNA, and as a result, down-regulates mRNA expression. UALCAN analysis indicates that the expression pattern between and HMGXB3 proteins are opposite in vivo in breast cancer tissues. Together, our results indicate that the mRNA encoded by the gene can influence the expression of adjacent mRNA, or vice versa.
• Fader, A., Roque, D., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A., Havrilesky, A., O'Malley, D., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahw, K., Bellone, S., Azodi, M., Lithouhi, B., , Ratner, B., et al. (2020). Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress her2/neu. Updated survival analysis. Clinical Cancer Research.
• Sawyer, T. W., Koevary, J. W., Howard, C. C., Austin, O. J., Rice, P. F., Hutchens, G. V., Chambers, S. K., Connolly, D. C., & Barton, J. K. (2020). Fluorescence and Multiphoton Imaging for Tissue Characterization of a Model of Postmenopausal Ovarian Cancer. Lasers in surgery and medicine, 52(10), 993-1009.
  More info

  To determine the efficacy of targeted fluorescent biomarkers and multiphoton imaging to characterize early changes in ovarian tissue with the onset of cancer.
• Tao, T., Lin, W., Wang, Y., Zhang, J., Chambers, S. K., Li, B., Lea, J., Wang, Y., Wang, Y., & Zheng, W. (2020). Loss of tubal ciliated cells as a risk for "ovarian" or pelvic serous carcinoma. American journal of cancer research, 10(11), 3815-3827.
  More info

  Recent advances suggest the fallopian tube as the main anatomic site for high-grade ovarian or pelvic serous carcinoma (O/PSC). Many studies on the biologic role of tubal secretory cells in O/PSC development has been performed in the last decade. However, the role of tubal ciliated cells in this regard has rarely been explored. The purpose of this study was to determine if the change of the tubal ciliated cells is associated with serous neoplasia within the female pelvis. This study included 3 groups (low-risk or benign control, high-risk, and O/PSC) of patients and they were age-matched. Age of patients ranged from 20 to 85 and the age-associated data was stratified by 10-year intervals. The number of tubal ciliated cells was determined by microscopy and by tubulin immunohistochemical staining. The data was then professionally analyzed. The results showed that the absolute number of tubal ciliated cells decreased significantly with age within each age group. A reduction in ciliated cell counts within the tubal segments remained a significant risk factor for the development of serous cancers within the female pelvis after age adjustment. A dramatic decrease of tubal ciliated cells was identified in patients with high-risk and with O/PSC compared to those in the benign control or low-risk group ( < 0.001). Further, within the tubal fimbria, the number of ciliated cells reduction was more prominent in the high-risk group when compared to those of O/PSC patients. Our findings suggest that a decreased number of ciliated cells within women's fallopian tubes represents another histologic hallmark for early serous carcinogenesis. There is a relationship between loss of tubal ciliated cells and aging, the presence of high-risk factors for tubal-ovarian cancer, and co-existing O/PSCs. This represents an initial study identifying the role of tubal ciliated cells in the development of high-grade serous carcinoma in women's pelvis.
• Woo, H. H., & Chambers, S. K. (2020). The alternative spliced 3'-UTR mediated differential secretion of macrophage colony stimulating factor in breast cancer cells. Biochemical and biophysical research communications, 525(4), 1004-1010.
  More info

  CSF-1 mRNA 3'UTR variants (var) are generated from alternative splicing. CSF-1 protein encoded by var-1 mRNA with long 3'UTR derived from exon-10 is rapidly secreted compared to the CSF-1 protein encoded by var-4 mRNA with short 3'UTR derived from exon-9. Secretion kinetics indicates that HuR, which binds the CSF-1 var-1 mRNA, but not var-4 mRNA, accelerates the secretion of CSF-1 protein. HuR overexpression increases the secretion rate of CSF-1 protein. In contrast, silencing of HuR does not have such an effect, suggesting other compensatory mechanisms. Effect of the CSF-1 mRNA variant 3'UTRs on cellular phenotype shows both CSF-1 var-1 or -4 mRNA is involved in the enhanced rates of migration and invasion observed by both in vitro in breast cancer cells. Our study indicates that the alternative splicing of CSF-1 mRNA 3'UTR can regulate differential secretion of CSF-1 protein.
• Garcia, A., Frahm, C., Jeter, J. M., Abraham, I., Chambers, S. K., Cragun, J. M., & McBride, A. (2019). Incidence of Hypersensitivity Reactions to Carboplatin in Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer with or without BRCA1 or BRCA2 Mutations. J Adv Pract Oncol, 10(5), 428-439.
• Hoyer, P. B., Rice, P. F., Howard, C. C., Koevary, J. W., Dominguez Cooks, J. P., Hutchens, G. V., Chambers, S. K., Craig, Z. R., Connolly, D. C., & Barton, J. K. (2019). Comparison of Reproductive Function in Female Transgenic and Wildtype C57BL/6 Mice. Comparative medicine, 69(1), 16-21.
  More info

  Transgenic (TAg) mice express the oncogenic virus SV40 in Mullerian epithelial cells. Female TAg mice spontaneously develop epithelial ovarian carcinoma, the most common type of ovarian cancer in women. Female TAg mice are infertile, but the reason has not been determined. We therefore investigated whether female TAg mice undergo puberty, demonstrate follicular development, maintain regular cycles, and ovulate. Ovarian cancers in women commonly develop after menopause. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) accelerates follicle degeneration in the ovaries of rats and mice, causing early ovarian failure. We therefore used VCD dosing of mice to develop an animal model for menopause. The purpose of this study was to characterize reproductive parameters in female TAg mice and to investigate whether the onset of ovarian failure due VCD dosing differed between female TAg and WT C57BL/6 mice. As in WT female mice, TAg female mice underwent puberty (vaginal opening) and developed cyclicity in patterns that were similar between the groups. Vehicle-only TAg mice had fewer ovulations (numbers of corpora lutea) than WT animals. VCD exposure delayed the onset of puberty (day of first estrus) in TAg as compared with WT mice. Morphologic evaluation of ovaries revealed many more degenerating follicles in TAg mice than WT mice, and more VCD-dosed TAg mice were in ovarian failure than VCD-dosed WT mice. These results suggest that despite showing similar onset of sexual maturation, TAg mice have increased follicular degeneration and fewer ovulations than WT. These features may contribute to the inability of female TAg mice to reproduce.
• Pandey, R., Woo, H. H., Varghese, F., Zhou, M., & Chambers, S. K. (2019). Circulating miRNA Profiling of Women at High Risk for Ovarian Cancer. Translational oncology, 12(5), 714-725.
  More info

  Survival of epithelial ovarian cancer patients remains poor without significant change over many decades. There is a need to better identify women at high risk (HR) for ovarian cancer. We propose that miRNA dysregulation may play critical roles in the early stages of ovarian cancer development. Circulating miRNAs may represent an important biomarker in this context, and miRNA profiling of serum in women at HR compared to those at low risk (LR) may give insights in tumor initiation pathways. There is also rationale for a specific focus on regulation of the androgen and its related hypoxia pathways in tumor initiation. We hypothesized that subsets of these pathway related miRNAs may be downregulated in the HR state. Serum from four HR and five LR women were sequenced and analyzed for 2083 miRNAs. We found 137 miRNAs dysregulated between the HR and LR groups, of which 36 miRNAs were overexpressed in HR and the vast majority (101 miRNAs or 74%) downregulated in the HR, when compared to LR serum. mRNA targets for the differentially expressed miRNAs were analyzed from three different miRNA-mRNA interaction resources. Functional association analysis of hypoxia and androgen pathway mRNA targets of dysregulated miRNAs in HR serum revealed that all but one of the miRNAs that target 52 hypoxia genes were downregulated in HR compared to LR serum. Androgen pathway analysis also had a similar expression pattern where all but one of the miRNAs that target these 135 identified genes were downregulated in HR serum. Overall, there were 91 differentially expressed miRNA-mRNA pairings in the hypoxia analysis. In the androgen-related analysis, overall, there were 429 differentially expressed miRNA-mRNA pairs. Our pilot study suggests that almost all miRNAs that are conserved and/or validated are downregulated in the HR compared to LR serum. This study, which requires validation, suggests that, via miRNA dysregulation, involvement of both hypoxia and its related androgen pathways may contribute to the HR state. This pilot study is the first report to our knowledge that studies circulating miRNA profiling of HR and LR women.
• Woo, H. H., & Chambers, S. K. (2019). Human ALKBH3-induced mA demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. Biochimica et biophysica acta. Gene regulatory mechanisms, 1862(1), 35-46.
  More info

  In ovarian and breast cancers, the actions of the cytokine CSF-1 lead to poor prognosis. CSF-1 expression can be regulated post-transcriptionally. RNA methylation is another layer of posttranscriptional regulation. The methylation of N atom of adenine (mA) results in a conformational change of RNA which regulates translational efficiency. Our study indicates that the mA is also involved in the CSF-1 mRNA decay. The alteration of ALKBH3 expression, an mA demethylase, regulates the CSF-1 mRNA stability. Demethylation of mA by ALKBH3 increases the half-life of CSF-1 mRNA without affecting the translation efficiency. The mA in CSF-1 mRNA is mapped in the 5'UTR near the translation initiation site. YTHDF2, a known mA reader which interacts with the CCR4-NOT deadenylation complex, is not the reader of mA-containing CSF-1 mRNA. Overexpression of ALKBH3 increases CSF-1 expression and the degree of cancer cell invasiveness without affecting cell proliferation or migration. Collectively, we showed that CSF-1 mRNA decay can be regulated at an epigenetic level, and that alteration of the N‑methylation status leads to phenotypic changes in cancer cell behavior.
• Fader, A. N., Roque, D. M., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A. A., Havrilesky, L., O'Malley, D. M., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahwi, K. S., Celano, P., Bellone, S., Azodi, M., , Litkouhi, B., et al. (2018). Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36(20), 2044-2051.
  More info

  Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.
• Fader, A., Roque, D., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A., Havrilesky, A., O'Malley, D., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahw, K., Bellone, S., Azodi, M., Lithouhi, B., , Ratner, B., et al. (2018). Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress her2/neu. (PRESENTATION/ABSTRACT). Society of Gynecologic Oncology.
• Fader, A., Roque, D., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A., Havrilesky, A., O'Malley, D., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahw, K., Bellone, S., Azodi, M., Lithouhi, B., , Ratner, B., et al. (2018). Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress her2/neu.. J Clin Oncol, 36, 2044-2051. doi:10.1200/JCO.2017.76.5966
• Garcia, A., Abraham, I., Chambers, S. K., Cragun, J. M., Jeter, J. M., & McBride, A. (2018). Incidence of Hypersensitivity Reactions to Carboplatin in Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer with or without BRCA1 or BRCA2 Mutations (ABSTRACT). ASCO.
• Garcia, A., Abraham, I., Chambers, S. K., Cragun, J. M., Jeter, J. M., & McBride, A. (2018). Incidence of Hypersensitivity Reactions to Carboplatin in Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer with or without BRCA1 or BRCA2 Mutations. J Am College Pharmacol.
• Hoyer, P. B., Rice, P. F., Howard, C., Watson, K. J., Dominguez, J. C., Hutchens, G., Chambers, S. K., Craig, Z. R., Connoly, D. C., & Barton, J. K. (2017). Comparison of markers of reproductive function in female C57BI/6 versus TgMISIIR-TAg transgenic mice: effect of VCD exposure on ovarian failure. Comparative Medicine.
• Lin, K. K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L. T., Mann, E., Isaacson, J. D., Maloney, L., O'Malley, D. M., Chambers, S. K., Kaufmann, S. H., Scott, C. L., Konecny, G. E., Coleman, R. L., , Sun, J. X., et al. (2018). BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discovery.
• Woo, H. H., Lee, S. C., Stoffer, J. B., Rush, D., & Chambers, S. K. (2018). Phenotype of vigilin expressing breast cancer cells binding to the 69 nt 3'UTR element in CSF-1R mRNA [epub ahead of print 10/3/2018]. Translational Oncology, 12(1), 106-115.
• Woo, H., & Chambers, S. K. (2018). ALKBH3-Induced m1A Demethylation Increases the CSF-1 mRNA Stability in Breast and Ovarian Cancer Cells (epub 2018 Oct 17). Biochim Biophys Acta Gene Regul Mech, 62(1), 35-46. doi:10.1016/j.bbagrm.2018.10.008
• Cragun, J. M., TenEyk, C., Cui, H., & Chambers, S. K. (2017). The association of miR-let-7i with platinum resistance of a sensitive/resistant ovarian cancer parent/daughter cell line. American Journal of Clinical and Experimental Obstetrics and Gynecology, 4(1), 1-10.
• Harb, W. A., Edelman, M. J., Chambers, S. K., Garland, L., Armour, A., Klein, P., Rao, S., Parker, N., Naumann, R. W., Wang, D., Goss, G., Sachdev, J., & Fu, S. (2017). Phase 1 dose escalation study of the folate receptor-targeted small molecule drug conjugate EC1456 (abstract). EMSO, Madrid Spain.
• Jones, K. M., Randtke, E. A., Yoshimaru, E., Howison, C. M., Chalasani, P., Klein, R. R., Chambers, S. K., Kuo, P. H., & Pagel, M. D. (2017). Clinical translation of tumor acidosis measurements with acidoCEST MRI (abstract). International Society for Magnetic Resonance in Medicine.
• Koevary, J. W., Howard, C., Dominguez Cooks, J., Chambers, S. K., Connolly, D., Hoyer, P., & Barton, J. K. (2017). Optical detection of folate receptor expression in a transgenic model of ovarian cancer (abstract). Biiomedical Engineering Society, Phoenix, AZ.
• Moore, K. N., Cadoo, K. A., Chambers, S. K., Ghamande, S. A., Konecny, G. E., Oza, A. M., Chen, L., Konstantinopoulos, P. A., Lea, J., Spitz, D. L., Uyar, D., Mogundu, G., Laing, N., Strickland, D. K., Jones, S. F., Burriss, H. A., Spigel, D. R., & Hamilton, E. P. (2017). A multicentre phase II study of AZD1775 plus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (abstract). EMSO, Madrid, Spain.
• Woo, H. H., Lee, S. C., Gibson, S. J., & Chambers, S. K. (2017). Expression of the cytoplasmic nucleolin for post-transcriptional regulation of macrophage colony-stimulating factor mRNA in ovarian and breast cancer cells. Biochimica et biophysica acta, 1860(3), 337-348.
  More info

  The formation of the mRNP complex is a critical component of translational regulation and mRNA decay. Both the 5' and 3'UTRs of CSF-1 mRNA are involved in post-transcriptional regulation. In CSF-1 mRNA, a small hairpin loop structure is predicted to form at the extreme 5' end (2-21nt) of the 5'UTR. Nucleolin binds the hairpin loop structure in the 5'UTR of CSF-1 mRNA and enhances translation, while removal of this hairpin loop nucleolin binding element dramatically represses translation. Thus in CSF-1 mRNA, the hairpin loop nucleolin binding element is critical for translational regulation. In addition, nucleolin interacts with the 3'UTR of CSF-1 mRNA and facilitates the miRISC formation which results in poly (A) tail shortening. The overexpression of nucleolin increases the association of CSF-1 mRNA containing short poly (A)n≤26, with polyribosomes. Nucleolin both forms an mRNP complex with the eIF4G and CSF-1 mRNA, and is co-localized with the eIF4G in the cytoplasm further supporting nucleolin's role in translational regulation. The distinct foci formation of nucleolin in the cytoplasm of ovarian and breast cancer cells implicates the translational promoting role of nucleolin in these cancers.
• Chen, H., Klein, R., Arnold, S., Chambers, S., & Zheng, W. (2016). Cytologic studies of the fallopian tube in patients undergoing salpingo-oophorectomy. Cancer cell international, 16, 78.
  More info

  Mounting evidence suggests the fallopian tube as the origin for ovarian high grade serous carcinoma (HGSC). We attempted to identify the tubal cytological features that allow us to distinguish malignant from benign conditions.
• Jones, K. M., Randtke, E. A., Yoshimaru, E. S., Howison, C. M., Chalasani, P., Klein, R. R., Chambers, S. K., Kuo, P. H., & Pagel, M. D. (2016). Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.
  More info

  We optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis.
• Jones, K. M., Randtke, E. A., Yoshimaru, E., Howison, C. M., Chambers, S. K., Klein, R. R., Kuo, P. H., & Pagel, M. D. (2016). Imaging tumor acidosis with acidoCEST MRI: clinical translation from mouse to man (abstract). World Molecular Imaging Congress.
• Risi, M. D., Rouse, A. R., Chambers, S. K., Hatch, K. D., Zheng, W., & Gmitro, A. F. (2016). Pilot Clinical Evaluation of a Confocal Microlaparoscope for Ovarian Cancer Detection. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 26(2), 248-54.
  More info

  The aim of this study is to evaluate the performance of a confocal fluorescence microlaparoscope for in vivo detection of ovarian cancer.
• Santin, A. D., Nickles-Fader, A., Siegel, E., Abdelghany, O., Silasi, D. A., Chambers, S. K., Havrilesky, L., O'Malley, D. O., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahwi, K., Roque, D., & Schwartz, P. (2016). Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-trastuzumab (CP-T) in advanced (Stage III-IV) or recurrent uterine serous carcinoma: results of interim analysis (abstract). International Gynecologic Cancer Society.
• Sinharay, S., Randtke, E. A., Jones, K. M., Howison, C. M., Chambers, S. K., Kobayashi, H., & Pagel, M. D. (2016). Noninvasive detection of enzyme activity in tumor models of human ovarian cancer using catalyCEST MRI. Magnetic resonance in medicine.
  More info

  We proposed to detect the in vivo enzyme activity of γ-glutamyl transferase (GGT) within mouse models of human ovarian cancers using catalyCEST MRI with a diamagnetic CEST agent.
• Sinharay, S., Randtke, E. A., Jones, K. M., Howison, C. M., Chambers, S. K., Kobayashi, H., Ignatenko, N., & Pagel, M. D. (2016). Detection of enzyme activity, enzyme inhibition, and early therapy response using in vivo catalyCEST MRI (abstract). World Molecular Imaging Congress.
• Tate, T. H., Baggett, B., Rice, P. F., Koevary, J. W., Orsinger, G. V., Nymeyer, A. C., Welge, W. A., Saboda, K., Roe, D. J., Hatch, K. D., Chambers, S. K., Utzinger, U., & Barton, J. K. (2016). Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early-stage cancer detection. Journal of biomedical optics, 21(5), 56005.
• Wang, X., Li, L., Cragun, J. M., Chambers, S. K., Hatch, K. D., & Zheng, W. (2016). Assessment of the Role of Intraoperative Frozen Section in Guiding Surgical Staging for Endometrial Cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 26(5), 918-23.
  More info

  The aim of this study was to assess the role of intraoperative frozen section (FS) in guiding decision making for surgical staging of endometrioid endometrial cancer (EC).
• Wang, Y., Wang, Y., Zhang, Z., Park, J. Y., Guo, D., Liao, H., Yi, X., Zheng, Y., Zhang, D., Chambers, S. K., & Zheng, W. (2016). Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway. Oncotarget, 7(9), 10363-72.
  More info

  Progestin resistance is a main obstacle for endometrial precancer/cancer conservative therapy. Therefore, biomarkers to predict progestin resistance and studies to gain a more detailed understanding of the mechanism are needed. The antioxidant Nrf2-AKR1C1 signal pathway exerts chemopreventive activity. However whether it plays a role in progestin resistance has not been explored. In this study, elevated levels of AKR1C1 and Nrf2 were found in progestin-resistant endometrial epithelia, but not in responsive endometrial glands. Exogenous overexpression of Nrf2/AKR1C1 resulted in progestin resistance. Inversely, silencing of Nrf2 or AKR1C1 rendered endometrial cancer cells more susceptible to progestin treatment. Moreover, medroxyprogesterone acetate withdrawal resulted in suppression of Nrf2/AKR1C1 expression accompanied by a reduction of cellular proliferative activity. In addition, brusatol and metformin overcame progestin resistance by down-regulating Nrf2/AKR1C1 expression. Our findings suggest that overexpression of Nrf2 and AKR1C1 in endometrial precancer/cancer may be part of the molecular mechanisms underlying progestin resistance. If validated in a larger cohort, overexpression of Nrf2 and AKR1C1 may prove to be useful biomarkers to predict progestin resistance. Targeting the Nrf2/AKR1C1 pathway may represent a new therapeutic strategy for treatment of endometrial hyperplasia/cancer.
• Baker, A. F., Malm, S. W., Pandey, R., Laughren, C., Cui, H., Roe, D., & Chambers, S. K. (2015). Evaluation of a hypoxia regulated gene panel in ovarian cancer. Cancer microenvironment : official journal of the International Cancer Microenvironment Society, 8(1), 45-56.
  More info

  A panel of nine hypoxia regulated genes, selected from a previously published fifty gene panel, was investigated for its ability to predict hypoxic ovarian cancer phenotypes. All nine genes including vascular endothelial growth factor A, glucose transporter 1, phosphoglycerate mutase 1, lactate dehydrogenase A, prolyl 4-hydroxylase, alpha-polypeptide 1, adrenomedullin, N-myc downstream regulated 1, aldolase A, and carbonic anhydrase 9 were upregulated in the HEY and OVCAR-3 human ovarian cell lines cultured in vitro under hypoxic compared to normoxic conditions as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The gene panel was also elevated in HEY xenograft tumor tissue compared to HEY cells cultured in normoxia. The HEY xenograft tissue demonstrated heterogeneous positive immunohistochemical staining for the exogenous hypoxia biomarker pimonidazole, and the hypoxia regulated protein carbonic anhydrase IX. A quantitative nuclease protection assay (qNPA) was developed which included the nine hypoxia regulated genes. The qNPA assay provided similar results to those obtained using qRT-PCR for cultured cell lines. The qNPA assay was also evaluated using paraffin embedded fixed tissues including a set of five patient matched primary and metastatic serous cancers and four normal ovaries. In this small sample set the average gene expression was higher in primary and metastatic cancer tissue compared to normal ovaries for the majority of genes investigated. This study supports further evaluation by qNPA of this gene panel as an alternative or complimentary method to existing protein biomarkers to identify ovarian cancers with a hypoxic phenotype.
• Chambers, S. K., Oza, A., Vergote, I., Gilbert, L., Ghatage, P., Lisyankaya, A., Ghamande, S., Arranz, J. A., Provencher, D., Bessette, P., Matulonis, U., Shapira-Frommer, R., Amit, A., Clark, R., Symanowski, J. T., Penson, R., & Naumann, R. W. (2015). A randomized double-blind phase 3 trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD in participants with platinum-resistant ovarian cancer (PROCEED) (abstract). Accepted for Presentation at : Society of Gynecologic Oncologists.
• Chambers, S. K., Rouse, A. R., Hatch, K. D., Gmitro, A. F., & Risi, M. D. (2015). Clinical experience with a confocal microlaparoscope for ovarian cancer detection (abstract). Accepted for Presentation at: SPIE BIOS: Endoscopic Microscopy X.
• Ferguson, D. C., Han, L. M., Wang, Y., Cragun, J. M., Hatch, K. D., Chambers, S. K., & Zheng, W. (2015). The role of the fallopian tube in ovarian serous carcinogenesis; biologic mechanisms and clinical impacts. American Journal of Clinical and Experimental Obstetrics and Gynecology, 2(1), 1-13.
• Hess, L. M., Huang, H. Q., Hanlon, A. L., Robinson, W. R., Johnson, R., Chambers, S. K., Mannel, R. S., Puls, L., Davidson, S. A., Method, M., Lele, S., Havrilesky, L., Nelson, T., & Alberts, D. S. (2015). Cognitive function during and six months following chemotherapy for front-line treatment of ovarian, primary peritoneal or fallopian tube cancer: An NRG oncology/gynecologic oncology group study. Gynecologic oncology, 139(3), 541-5.
  More info

  Changes in cognitive function have been identified in and reported by many cancer survivors. These changes have the potential to impact patient quality of life and functional ability. This prospective longitudinal study was designed to quantify the incidence of change in cognitive function in newly diagnosed ovarian cancer patients throughout and following primary chemotherapy.
• MacKerricher, W., Wang, Y., Klein, R. R., Cragun, J. M., Hatch, K. D., Chambers, S. K., & Zheng, W. (2015). Association of microscopic findings of ovarian high-grade serous carcinoma (HGSC) and status of BRCA mutation (abstract). Accepted for Presentation at: US and Canadian Academy of Pathology.
• Sinharay, S., Jones, K., Randtke, E. A., Howison, C., Kobayashi, H., Pagel, M. D., & Chambers, S. K. (2015). In vivo detection of GGT enzyme activity with catalyCEST MRI (abstract). Accepted for Presentation at: World Molecular Imaging Congress.
• Tate, T., Baggett, B., Watson, J., Orsinger, G., Keenan, M., Hatch, K. D., Chambers, S. K., Black, J. F., Barton, J. K., & Utzinger, U. (2015). Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early stage cancer detection (abstract). Accepted for Presentation at: SPIE BIOS: Advanced Biomedical and Clinical Diagnostic and Surgical Guidance Systems XIII.
• Gruessner, C., Gruessner, A., Glaser, K., AbuShahin, N., Zhou, Y., Laughren, C., Wright, H., Pinkerton, S., Yi, X., Stoffer, J., Azodi, M., Zheng, W., & Chambers, S. K. (2014). Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence. Cancer prevention research (Philadelphia, Pa.), 7(9), 896-905.
  More info

  We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day × 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P ≤ 0.0006) and ovarian endosalpingiosis (P ≤ 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers.
• Gruessner, C., Gruessner, A., Glaser, K., Abushahin, N., Laughren, C., Zheng, W., & Chambers, S. K. (2014). Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma. American journal of cancer research, 4(1), 61-72.
  More info

  BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways.
• Jeffery, J. J., Lux, K., Vogel, J. S., Herrera, W. D., Greco, S., Woo, H. H., AbuShahin, N., Pagel, M. D., & Chambers, S. K. (2014). Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging. Experimental biology and medicine (Maywood, N.J.), 239(4), 404-13.
  More info

  Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.
• Baker, A. F., Roe, D. J., Laughren, C., Cohen, J. L., Wright, H. M., Clouser, M. C., Cui, H., Alberts, D. S., & Chambers, S. K. (2013). Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer. Investigational new drugs, 31(1), 160-6.
  More info

  We investigated the safety and efficacy of 90 mg/m(2) bendamustine HCL, administered intravenously on days 1 and 2 every 28 days in 10 women with platinum and taxane resistant epithelial ovarian cancer. There were no objective tumor responses observed; 2 patients had stable disease. Plasma samples collected at pre-treatment and end of cycle one were analyzed for changes in circulating total cytokeratin 18 and caspase cleaved cytokeratin 18 as exploratory early biomarkers of bendamustine-induced tumor cell death. All patients had measureable levels of both total and cleaved caspase 3 cytokeratin 18, but no relationship with response was possible due to the lack of clinical benefit in treated patients. Due to the high incidence of adverse events and absence of objective responses, only ten patients were treated as predefined by the Simon Two-Stage Design in the protocol. Overall, the regimen was not well tolerated and was associated with fatigue and a greater number of gastrointestinal side effects as compared to previously reported experiences in different patient populations. However, our study subjects did experience less bone marrow suppression. The lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens (median of 5) received by the patients participating in this study.
• Chen, C., Li, J., Yao, G., Chambers, S. K., & Zheng, W. (2013). Tubal origin of ovarian low-grade serous carcinoma. American journal of clinical and experimental obstetrics and gynecology, 1(1), 13-36.
• Nelson-Moseke, A. C., Jeter, J. M., Cui, H., Roe, D. J., Chambers, S. K., & Laukaitis, C. M. (2013). An unusual BRCA mutation distribution in a high risk cancer genetics clinic. Familial cancer, 12(1), 83-7.
  More info

  The Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 outnumber those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients' electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without a diagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona's unique ethnic heritage.
• Woo, H. H., Baker, T., Laszlo, C., & Chambers, S. K. (2013). Nucleolin mediates microRNA-directed CSF-1 mRNA deadenylation but increases translation of CSF-1 mRNA. Molecular & cellular proteomics : MCP, 12(6), 1661-77.
  More info

  CSF-1 mRNA 3'UTR contains multiple unique motifs, including a common microRNA (miRNA) target in close proximity to a noncanonical G-quadruplex and AU-rich elements (AREs). Using a luciferase reporter system fused to CSF-1 mRNA 3'UTR, disruption of the miRNA target region, G-quadruplex, and AREs together dramatically increased reporter RNA levels, suggesting important roles for these cis-acting regulatory elements in the down-regulation of CSF-1 mRNA. We find that nucleolin, which binds both G-quadruplex and AREs, enhances deadenylation of CSF-1 mRNA, promoting CSF-1 mRNA decay, while having the capacity to increase translation of CSF-1 mRNA. Through interaction with the CSF-1 3'UTR miRNA common target, we find that miR-130a and miR-301a inhibit CSF-1 expression by enhancing mRNA decay. Silencing of nucleolin prevents the miRNA-directed mRNA decay, indicating a requirement for nucleolin in miRNA activity on CSF-1 mRNA. Downstream effects followed by miR-130a and miR-301a inhibition of directed cellular motility of ovarian cancer cells were found to be dependent on nucleolin. The paradoxical effects of nucleolin on miRNA-directed CSF-1 mRNA deadenylation and on translational activation were explored further. The nucleolin protein contains four acidic stretches, four RNA recognition motifs (RRMs), and nine RGG repeats. All three domains in nucleolin regulate CSF-1 mRNA and protein levels. RRMs increase CSF-1 mRNA, whereas the acidic and RGG domains decrease CSF-1 protein levels. This suggests that nucleolin has the capacity to differentially regulate both CSF-1 RNA and protein levels. Our finding that nucleolin interacts with Ago2 indirectly via RNA and with poly(A)-binding protein C (PABPC) directly suggests a nucleolin-Ago2-PABPC complex formation on mRNA. This complex is in keeping with our suggestion that nucleolin may work with PABPC as a double-edged sword on both mRNA deadenylation and translational activation. Our findings underscore the complexity of nucleolin's actions on CSF-1 mRNA and describe the dependence of miR-130a- and miR-301a-directed CSF-1 mRNA decay and inhibition of ovarian cancer cell motility on nucleolin.
• Karlan, B. Y., Oza, A. M., Richardson, G. E., Provencher, D. M., Hansen, V. L., Buck, M., Chambers, S. K., Ghatage, P., Pippitt, C. H., Brown, J. V., Covens, A., Nagarkar, R. V., Davy, M., Leath, C. A., Nguyen, H., Stepan, D. E., Weinreich, D. M., Tassoudji, M., Sun, Y., & Vergote, I. B. (2012). Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 30(4), 362-71.
  More info

  To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer.
• Woo, H. H., László, C. F., Greco, S., & Chambers, S. K. (2012). Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Molecular cancer, 11, 58.
  More info

  Colony stimulating factor-1 (CSF-1) plays an important role in ovarian cancer biology and as a prognostic factor in ovarian cancer. Elevated levels of CSF-1 promote progression of ovarian cancer, by binding to CSF-1R (the tyrosine kinase receptor encoded by c-fms proto-oncogene).Post-transcriptional regulation of CSF-1 mRNA by its 3' untranslated region (3'UTR) has been studied previously. Several cis-acting elements in 3'UTR are involved in post-transcriptional regulation of CSF-1 mRNA. These include conserved protein-binding motifs as well as miRNA targets. miRNAs are 21-23nt single strand RNA which bind the complementary sequences in mRNAs, suppressing translation and enhancing mRNA degradation.
• Toy, E. P., Lamb, T., Azodi, M., Roy, W. J., Woo, H. H., & Chambers, S. K. (2011). Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells. Breast cancer research and treatment, 129(2), 411-9.
  More info

  The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose-response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.
• Woo, H. H., Yi, X., Lamb, T., Menzl, I., Baker, T., Shapiro, D. J., & Chambers, S. K. (2011). Posttranscriptional suppression of proto-oncogene c-fms expression by vigilin in breast cancer. Molecular and cellular biology, 31(1), 215-25.
  More info

  cis-acting elements found in 3'-untranslated regions (UTRs) are regulatory signals determining mRNA stability and translational efficiency. By binding a novel non-AU-rich 69-nucleotide (nt) c-fms 3' UTR sequence, we previously identified HuR as a promoter of c-fms proto-oncogene mRNA. We now identify the 69-nt c-fms mRNA 3' UTR sequence as a cellular vigilin target through which vigilin inhibits the expression of c-fms mRNA and protein. Altering association of either vigilin or HuR with c-fms mRNA in vivo reciprocally affected mRNA association with the other protein. Mechanistic studies show that vigilin decreased c-fms mRNA stability. Furthermore, vigilin inhibited c-fms translation. Vigilin suppresses while HuR encourages cellular motility and invasion of breast cancer cells. In summary, we identified a competition for binding the 69-nt sequence, through which vigilin and HuR exert opposing effects on c-fms expression, suggesting a role for vigilin in suppression of breast cancer progression.
• Toy, E. P., Azodi, M., Folk, N. L., Zito, C. M., Zeiss, C. J., & Chambers, S. K. (2009). Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor. Neoplasia (New York, N.Y.), 11(2), 136-44.
  More info

  Coexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) in metastatic ovarian cancer specimens is a predictor of poor outcome in epithelial ovarian cancer. This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype. Our current work sought to validate this autocrine stimulation model using stable transfection of a 4-kb CSF-1 construct into otherwise nonvirulent Bix3 ovarian cancer cells. A representative clone, Bix3T8.2, produced a 72-fold increase in CSF-1 gene transcription rate (by nuclear run-off assays) and a 57-fold increase in secreted CSF-1 protein (by sandwich ELISA), compared to parent cells. Comparison of Bix3T8.2 invasion, adhesion, and motility in vitro and metastasis in vivo were made to parental and transfectant controls. Up to 12-fold higher invasiveness was seen with Bix3T8.2 and 2- and 6-fold higher adhesion and motility, respectively, over controls in vitro. In nude mice, i.p. injection of Bix3T8.2 produced a wide array of visceral, nodal, and distant metastasis with a degree of enhanced tumor burden not seen in any of the 10 mice inoculated with transfectant control cells. Complete absence of tumor take distinguished 40% of mice implanted with transfectant control cells. Disruption of this autocrine loop using antisense oligomer therapy against CSF-1R and 3' untranslated region knockdown of CSF-1 protein resulted in reversal of in vitro and in vivo tumor phenotypes. This CSF-1 feedback loop offers a model by which novel biologic therapies can potentially target multiple levels of this pathway.
• Woo, H. H., Zhou, Y., Yi, X., David, C. L., Zheng, W., Gilmore-Hebert, M., Kluger, H. M., Ulukus, E. C., Baker, T., Stoffer, J. B., & Chambers, S. K. (2009). Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer. Oncogene, 28(9), 1176-86.
  More info

  The role of RNA-binding proteins in cancer biology is recognized increasingly. The nucleocytoplasmic shuttling and AU-rich RNA-binding protein HuR stabilizes several cancer-related target mRNAs. The proto-oncogene c-fms, whose 3'untranslated region (3'UTR) is not AU-rich, is associated with poor prognosis in breast cancer. Using a large breast-cancer tissue array (N=670), we found nuclear HuR expression to be associated with nodal metastasis and independently with poor survival (P=0.03, RR 1.45), as well as to be co-expressed with c-fms in the breast tumors (P=0.0007). We described c-fms mRNA as a direct target of HuR in vivo, and that HuR bound specifically to a 69-nt region containing 'CUU' motifs in 3'UTR c-fms RNA. Overexpressing or silencing HuR significantly up- or down-regulated c-fms RNA expression, respectively. We also found that known glucocorticoid stimulation of c-fms RNA and protein is largely dependent on the presence of HuR. HuR, by binding to the 69-nt wild type, but not mutant, c-fms sequence can regulate reporter gene expression post-transcriptionally. We are the first to describe that HuR can regulate gene expression by binding non-AU-rich sequences in 3'UTR c-fms RNA. Collectively, our findings suggest that HuR plays a supportive role for c-fms in breast cancer progression by binding a 69-nt element in its 3'UTR, thus regulating its expression.
• Cracchiolo, B. M., Hanauske-Abel, H. M., Schwartz, P. E., Chambers, J. T., Holland, B., & Chambers, S. K. (2002). Procollagen-derived biomarkers in malignant ascites of ovarian cancer. Independent prognosticators for progression-free interval and survival. Gynecologic oncology, 87(1), 24-33.
  More info

  Matrix formation is a hallmark of solid tumor biology. Circulating antigens of structural matrix proteins should reflect this fact, yet are subject to systemic variables. We propose that if measured regionally, in a cancer-induced extravascular fluid pool such as malignant ascites of ovarian cancer, the same antigens retain their conceptual advantage as surrogate markers for tumor biology.
• Toy, E. P., Chambers, J. T., Kacinski, B. M., Flick, M. B., & Chambers, S. K. (2001). The activated macrophage colony-stimulating factor (CSF-1) receptor as a predictor of poor outcome in advanced epithelial ovarian carcinoma. Gynecologic oncology, 80(2), 194-200.
  More info

  We have previously shown that the macrophage colony-stimulating factor receptor (CSF-1R) and its ligand, CSF-1, together predict poor prognosis in epithelial ovarian carcinoma. The activated or phosphorylated form of CSF-1R (CSF-1Rphos) has been associated with enhanced invasive and metastatic potential. Our goal is to correlate CSF-1Rphos with known prognostic factors and to determine its role in predicting outcome in advanced ovarian cancer.
• Turner, B. C., Knisely, J. P., Kacinski, B. M., Haffty, B. G., Gumbs, A. A., Roberts, K. B., Frank, A. H., Peschel, R. E., Rutherford, T. J., Edraki, B., Kohorn, E. I., Chambers, S. K., Schwartz, P. E., & Wilson, L. D. (1998). Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy. International journal of radiation oncology, biology, physics, 40(1), 77-84.
  More info

  Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC.
• Fishman, D. A., Roberts, K. B., Chambers, J. T., Kohorn, E. I., Schwartz, P. E., & Chambers, S. K. (1996). Radiation therapy as exclusive treatment for medically inoperable patients with stage I and II endometrioid carcinoma with endometrium. Gynecologic oncology, 61(2), 189-96.
  More info

  From 1975 to 1992, 54 patients with clinical Stage I and II endometrioid carcinoma of the endometrium, representing 3.5% of all such patients, were deemed medically inoperable and exclusively received radiation therapy. A cohort of 108 operable patients adjusted for age, clinical stage, and grade served as a control group. The 5-year actuarial cancer-specific survivals for patients with Stage I inoperable, Stage 11 inoperable, Stage I operable, and Stage II operable disease were 80, 85, 98, and 100%. The corresponding 5-year overall survival rates were 30, 24, 88, and 85%. Inoperable patients had a median disease-free interval of 36 months for clinical Stage I and 50 months for Stage II disease versus 74.5 and 77 months for the operable patients (P = 0.001). Inoperable patients with Stage I disease had a median survival of 37 months versus 50 months for Stage II (P = NS), with only 7 (13%) of these patients dying with endometrial cancer. Operable patients had a median survival of 75 and 79 months in Stage I and II, respectively, with 14 patients dying with endometrial carcinoma (13%). Stage I and II inoperable patients had significantly shorter survival than operable patients (P < 0.0001). More deaths from intercurrent disease occurred within the inoperable Stage I group than with the operable group (28 of 32 vs 3 of 15, P < 0.0001). Inoperable patients had a significantly shorter overall survival and more deaths due to intercurrent disease than operable patients (P < 0.0001). However, inoperable patients who did not die from intercurrent disease had a median 5-year survival which approaches that of operable patients. Our study demonstrates that exclusive radiation therapy is a well-tolerated and effective treatment for medically inoperable patients.
• Resnik, E., Chambers, S. K., Carcangiu, M. L., Kohorn, E. I., Schwartz, P. E., & Chambers, I. T. (1996). Malignant uterine smooth muscle tumors: role of etoposide, cisplatin, and doxorubicin (EPA) chemotherapy. Journal of surgical oncology, 63(3), 145-7.
  More info

  Nearly 80% of patients with malignant uterine smooth muscle tumor will suffer local relapse and/or distant metastases after initial surgical resection. There is no convincing evidence that the addition of pelvic radiation improves the outcome. However, adjuvant chemotherapy might be an appropriate therapeutic modality.
• Fishman, D. A., Chambers, S. K., Schwartz, P. E., Kohorn, E. I., & Chambers, J. T. (1995). Extramammary Paget's disease of the vulva. Gynecologic oncology, 56(2), 266-70.
  More info

  Fourteen patients with extramammary Paget's disease of the vulva treated at Yale-New Haven Medical Center from 1982 through 1993 were reviewed to evaluate the accuracy of methods used to delineate surgical margins and to determine if radical operations or surgical margin status was associated with likelihood of recurrence. These 14 patients underwent at total of 25 operations for extramammary Paget's disease. In 8 operations, a total of 44 separate frozen-section biopsies were performed to determine extent of disease with a mean of 5.5 biopsies per patient. Visual judgment alone was used to determine margin status in 17 operations. The ability to delineate free surgical margins on permanent sections was not different, whether judged visually or by frozen-section analysis. Frozen-section analysis was misleading in 3/8 (37.5%) cases, while visual judgment was in error in 6/17 (35%) cases. Moreover, permanent margin status was not found to be predictive of disease recurrence. Two of 5 (40%) patients with positive margins recurred after initial surgery compared with 3 of 9 (33%) patients with negative margins. Of the 14 primary operations, there were 8 wide local excisions, 3 simple vulvectomies, and 3 modified radical vulvectomies. The radicality of the operation as initial treatment did not statistically correlate with disease recurrence.
• Resnik, E., Chambers, S. K., Carcangiu, M. L., Kohorn, E. I., Schwartz, P. E., & Chambers, J. T. (1995). A phase II study of etoposide, cisplatin, and doxorubicin chemotherapy in mixed müllerian tumors (MMT) of the uterus. Gynecologic oncology, 56(3), 370-5.
  More info

  Mixed Müllerian tumors (MMT) of the uterus are aggressive entities that result in a very poor prognosis even for patients in whom the disease is limited to the uterus. This phase II trial was undertaken in an attempt to improve overall survival as well as progression-free survival of these patients. Forty-two consecutive patients were treated with a combination chemotherapy containing etoposide 100 mg/m2 on Days 1 and 2, cisplatin 50 mg/m2 on Day 1, and doxorubicin 50 mg/m2 on Day 1, repeated every 28 days. There were 23 patients with early-stage disease (stages I and II) and 19 patients with advanced (stages III and IV) or recurrent disease. In the early-stage group, the number of cycles ranged from 2 to 9 (5.2 +/- 1.9). The median follow-up was 32 months (range 11-93). There were five recurrences: three patients died of disease at 11, 36, and 51 months, and two patients are still alive with disease at 12 and 19 months. Two-year overall survival was 92%. In the advanced disease group, the number of cycles ranged from 1 to 11 (5.9 +/- 2.4). The median follow-up for this group was 20 months (range 5-62). The median overall survival was 18 months. Two-year overall survival was 33%. Two-year progression-free survival was 20%. Four patients were evaluable for response. There were two complete responses (duration 15-33 months) and two partial responses (duration 6-10 months). The responders were patients whose adenocarcinoma component was of the papillary serous (UPSC) variety. The chemotherapy combination appears to be highly active in early-stage disease. In the advanced uterine MMT it has moderate activity, especially when associated with the UPSC component.
• Kacinski, B. M., Mayer, A. G., King, B. L., Carter, D., & Chambers, S. K. (1992). NEU protein overexpression in benign, borderline, and malignant ovarian neoplasms. Gynecologic oncology, 44(3), 245-53.
  More info

  In situ hybridization (ISH) analysis of 24 benign, borderline, and malignant ovarian tumor specimens revealed NEU transcript expression by epithelial elements in approximately two-thirds of the samples and high-level expression in 3 grade 3 adenocarcinomas. Immunohistochemical staining (IHC) of a total of 86 specimens (including 17 of those studied by ISH) localized NEU antigen expression to epithelial cells in 36 of 86 samples with strong membrane staining observed in 12, including 1 benign, 1 borderline serous carcinoma, 3 clear cell/endometrioid carcinomas, and 7 predominantly papillary serous carcinomas with areas of clear cell/endometrioid histology. Clinical correlation of the IHC results for the 72 Stage I-IV invasively malignant neoplasms revealed no statistically significant association of the intensity of NEU IHC staining with either relapse-free or overall survival. However, more of the patients whose tumors showed strong membrane staining for NEU antigen suffered relapses of disease by 3 and 4 years than did patients whose tumors showed weak or no membrane staining. These results suggest a role for the NEU gene product in the physiology of benign ovarian surface epithelium and the neoplastic epithelium of preinvasive borderline and some invasively malignant adenocarcinomas.
• Mayer, A. R., Chambers, S. K., Graves, E., Holm, C., Tseng, P. C., Nelson, B. E., & Schwartz, P. E. (1992). Ovarian cancer staging: does it require a gynecologic oncologist?. Gynecologic oncology, 47(2), 223-7.
  More info

  Forty-seven patients with presumed Stages I-II invasive ovarian epithelial carcinoma were treated with intravenous 50 mg/m2 cis-platinum, for 2-18 cycles (median, 9), 50 mg/m2 doxorubicin for 2-14 cycles (median, 9), and/or 600 mg/m2 cyclophosphamide for 2-14 cycles (median, 6) after surgical staging by a gynecologic oncologist or a nononcologic surgeon. Mean follow-up is 6.8 years. Cumulative 5-year actuarial survival is 73 +/- 6%; 75 +/- 12% for Stage I and 71 +/- 8% for Stage II disease. When screened for poor prognosticators, only the specialty of the operating surgeon was identified (P < 0.05). Five-year actuarial survival and disease-free survival, respectively, for Stages I-II patients surgically staged by a gynecologic oncologist were 83 +/- 7% and 76 +/- 8%, compared to 59 +/- 11% (P < 0.05) and 39 +/- 11% (P < 0.03) for the group operated upon by a nononcologist.
• Frank, A. H., Tseng, P. C., Haffty, B. G., Papadopoulos, D. P., Kacinski, B. M., Dowling, S. W., Carcangiu, M. L., Kohorn, E. I., Chambers, J. T., & Chambers, S. K. (1991). Adjuvant whole-abdominal radiation therapy in uterine papillary serous carcinoma. Cancer, 68(7), 1516-9.
• Kacinski, B. M., & Chambers, S. K. (1991). Molecular biology of ovarian cancer. Current opinion in oncology, 3(5), 889-900.
  More info

  This minireview, which due to the limitations of space cannot claim to be exhaustive, summarizes major advances in molecular biologic research on ovarian surface epithelial (adeno)carcinomas communicated approximately between the beginning of April 1990 through the end of March 1991. We focus primarily on studies of oncogenes, peptide hormone growth factors and their receptors, steroid hormone receptors, cytogenetics and flow cytometry, and resistance to therapy with cytotoxic agents.
• Kacinski, B. M., Scata, K. A., Carter, D., Yee, L. D., Sapi, E., King, B. L., Chambers, S. K., Jones, M. A., Pirro, M. H., & Stanley, E. R. (1991). FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene, 6(6), 941-52.
  More info

  The expression in vivo of FMS transcripts and antigen by neoplastic epithelial cells was demonstrated immunohistochemically or by in situ hybridization in sixteen of seventeen human breast carcinoma specimens and one case of sclerosing adenosis. Expression of CSF-1 receptor (FMS) transcripts and protein was also observed in vitro in two or three breast carcinoma-derived cell lines and was dramatically increased by dexamethasone, a potent glucocorticoid and inducer of mammary epithelial cell differentiation. Immunohistochemical staining with an anti-CSF-1 antibody identified neoplastic epithelial cell co-expression of fms and CSF-1 antigens in more than one-third of the fms-positive invasive carcinoma specimens. These results suggest that autocrine and paracrine interactions of the lymphohematopoietic cytokine CSF-1 and its receptor may participate in the biology of human mammary neoplasms.
• Kacinski, B. M., Carter, D., Mittal, K., Yee, L. D., Scata, K. A., Donofrio, L., Chambers, S. K., Wang, K. I., Yang-Feng, T., & Rohrschneider, L. R. (1990). Ovarian adenocarcinomas express fms-complementary transcripts and fms antigen, often with coexpression of CSF-1. The American journal of pathology, 137(1), 135-47.
  More info

  In earlier studies of oncogene expression in ovarian and endometrial neoplasms, the authors reported that high tumor levels of fms-complementary transcripts correlate with high histologic grade and advanced clinical stage presentations. In this communication, they pursue these initial clinicopathologic investigations to demonstrate by in situ hybridization and immunohistochemistry that malignant epithelial cells of 14 of 14 invasive adenocarcinomas of the ovary express fms-complementary transcripts. By Northern blotting and by reverse transcription, followed by polymerase chain reaction amplification, the authors also were able to demonstrate fms transcript expression in several ovarian and endometrial carcinoma-derived cell lines. Because about half (6/14) of the invasive adenocarcinoma specimens were shown to coexpress fms and colony-stimulating factor 1, the authors propose that the expression of this lymphohematopoietic cytokine and its receptor by ovarian adenocarcinomas could contribute to their proliferative and invasive characteristics in vivo.
• Kacinski, B. M., Chambers, S. K., Stanley, E. R., Carter, D., Tseng, P., Scata, K. A., Chang, D. H., Pirro, M. H., Nguyen, J. T., & Ariza, A. (1990). The cytokine CSF-1 (M-CSF) expressed by endometrial carcinomas in vivo and in vitro, may also be a circulating tumor marker of neoplastic disease activity in endometrial carcinoma patients. International journal of radiation oncology, biology, physics, 19(3), 619-26.
  More info

  Endometrial epithelial cell expression of CSF-1 and FMS antigens was studied in vivo and in vitro in 24 human endometrial carcinoma and 11 benign endometrial biopsy specimens. Twenty-one of 24 adenocarcinomas and 4 of 11 benign lesions stained positively (by IHC) with rabbit anti-human CSF-1 antibodies, while all 24 carcinomas and 3 out of 11 benign lesions (all secretory endometrial specimens) showed significant IHC staining (1+ or greater) of epithelial elements and tissue macrophages with a mouse anti-FMS (CSF-1 receptor) monoclonal antibody. CSF-1 levels in plasma from endometrial carcinoma patients (85 samples, 24 patients) were also found to be markedly elevated (some greater than 100 ng/ml) in patients with active or recurrent disease. In vitro, several endometrial carcinoma cell lines were shown to express FMS complementary transcripts and FMS antigen which were very similar if not identical to those expressed in choriocarcinoma cell line positive controls. Autocrine and paracrine effects mediated by tumor or stromally produced CSF-1 and a tumor epithelial cell CSF-1 receptor may therefore contribute to the biological behavior of endometrial neoplasms in vivo and in vitro.
• Kacinski, B. M., Carter, D., Kohorn, E. I., Mittal, K., Bloodgood, R. S., Donahue, J., Kramer, C. A., Fischer, D., Edwards, R., & Chambers, S. K. (1989). Oncogene expression in vivo by ovarian adenocarcinomas and mixed-mullerian tumors. The Yale journal of biology and medicine, 62(4), 379-92.
  More info

  Six-micron paraffin sections of paraformaldehyde-fixed specimens of 24 ovarian benign and neoplastic specimens were assayed for tumor cell-specific oncogene expression by a sensitive, quantitative in situ hybridization technique with probes for 17 oncogenes, beta-actin, and E. coli beta-lactamase. In the benign, borderline, and invasive adenocarcinomas, multiple oncogenes, including neu, fes, fms, Ha-ras, trk, c-myc, fos, and PDGF-A chains, were expressed at significant levels relative to a housekeeping gene (beta-actin). In the mixed-Mullerian tumors, a rather different pattern of oncogene expression was observed, characterized primarily by expression of sis (PDGF-B chain). For the adenocarcinomas, statistical analysis demonstrated that expression of several genes (fms, neu, PDGF-A) was closely linked to others (c-fos, c-myc) known to have important roles in the control of cell proliferation, but only one gene, fms, correlated very strongly with clinicopathologic features (high FIGO histologic grade and high FIGO clinical stage) predictive of aggressive clinical behavior and poor outcome. The authors discuss the role that tumor epithelial cell expression of the fms gene product might play in the auto- and paracrine control of growth and dissemination of ovarian adenocarcinomas.
• Kacinski, B. M., Stanley, E. R., Carter, D., Chambers, J. T., Chambers, S. K., Kohorn, E. I., & Schwartz, P. E. (1989). Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasms. International journal of radiation oncology, biology, physics, 17(1), 159-64.
  More info

  We have previously reported our observations of epithelial tumor cell expression of transcripts and protein antigens of CSF-1 and transcripts of a protein closely related--if not identical--to the CSF-1 receptor in ovarian and endometrial neoplasms in vivo and in vitro. In the present communication, we extend these investigations to analyze the clinical utility of determinations of plasma CSF-1 concentrations in 125 samples from 33 patients with ovarian neoplasms and one patient with benign endometriosis. We observed that plasma CSF-1 levels in patients with active and recurrent neoplastic disease were markedly elevated and follow changes in disease status in individual patients. These and other results presented in this communication suggest that not only could CSF-1 be a useful circulating tumor marker in ovarian carcinoma patients, but also that in combination with measurements of other markers--such as CA-125--determinations of plasma CSF-1 levels might actually improve the accuracy of "tumor marker"-based assessments of disease status in patients with malignant ovarian neoplasms.
• Kramer, C., Peschel, R. E., Goldberg, N., Kohorn, E. I., Chambers, J. T., Chambers, S. K., & Schwartz, P. E. (1989). Radiation treatment of FIGO stage IVA carcinoma of the cervix. Gynecologic oncology, 32(3), 323-6.
  More info

  Forty-eight patients with FIGO stage IVA cervix cancer were treated with radiation therapy at the Hunter Radiation Therapy Center, Yale--New Haven Hospital from 1966 to 1985. Nine of the 48 patients are alive without recurrence (NED) and the 5-year actuarial survival rate is 18% (+/- 6%, standard error). There was a substantial difference in outcome based on treatment technique. Thirty-five patients were treated with external beam (EB) plus intracavitary (IC) and 8 of these patients (23%) are NED. None of the 12 patients treated with EB alone are alive. One patient treated with preoperative EB plus exenteration is NED. The severe complication rate was 22% and most complications were vesicovaginal fistulas due to successful treatment for bladder involvement. There was a significant difference in survival for patients with minimal parametrial disease (stage IVA1) versus patients with significant parametrial disease (stage IVA2) which was defined as fixation to one or both pelvic sidewalls or hydronephrosis on IVP. The 5-year survival for stage IVA1 disease was 46% (+/- 14%) versus only 5% (+/- 4%) for stage IVA2 disease. Our results indicate that superior survival for stage IVA cervix cancer patients is associated with two factors: minimal parametrial disease and radiation treatment which combines EB plus IC.

Presentations

• Van Nieuwenhuysen, E., Moore, K., Tillmanns, T., Haygood, C., Chambers, S. K., Priebe, A., Kim, Y., Slomovitz, B., Jonusklene, G., Barretina-Ginesta, M., Csoszi, T., Zagouri, F., Kim, J., Qinglei, G., Mejia, F., De Melo, A., Nishikawa, T., Kowgier, M., Wang, Y., & Westin, S. (2024, November). Durvalumab plus carboplatin/paclitaxel followed by durvalumab with/withoutolaparib for endometrial cancer: mismatch repair deficient and/or microsatelliteinstability-high subpopulation efficacy analyses from the DUO-E trial. International Gynecologic Cancer Society. Cape Town, South Africa.
• tanji, j., morgan, m., chon, h., wenham, r., winer, i., randall, l., Chambers, S. K., butler, k., langstraat, c., han, e., powell, m., & vahrmeijer, a. (2024). Further Analysis of the Phase 3, single-dose, open-label study to investigate the efficacy of pafolacianine sodium injection (OTL38) for intraoperative imaging during cytoreductive surgery of folate receoptor positive ovarian cancer (FOCUSED PLENARY PRESENTATION). Society for Gynecologic Oncology Annual Meeting. San Diego, CA.
• vulsteke, v., Chambers, S. K., rubio perez, m., chan, j., raaschou-jensen, n., zhou, y., lorusso, d., herzog, t., de la Motte, R., bailey, t., braicu, e., chen, l., levy, t., barter, j., barretina-ginesta, m., joosens, e., york, w., malinowska, i., gonzalez-martin, a., & monk, b. (2024). Long-term tolerability of the niraparib individualized starting dose in the PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib first-line maintenance therapy (ABSTRACT). ESGO Annual Meeting 2024.
• Fader, A., Roque, D., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A., Havrilesky, A., O'Malley, D., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahw, K., Bellone, S., Azodi, M., Lithouhi, B., , Ratner, B., et al. (2020, March). Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress her2/neu. Updated survival analysis (PLENARY ORAL SESSION). Society of Gynecologic Oncology. Toronto Canada.
• Chambers, S. K. (2018, November). BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma.. EORTC-NCI-AACR, 2018 Triple Meeeting, Dublin Ireland. Dublin, Ireland: EORTC-NCI-AACR.
• Chen, H., Aly, F. Z., Arnold, S., Klein, R. R., Chambers, S. K., & Zheng, W. (2016, March). Cytological Recognition of Serous Tubal Intraepithelial Carcinoma from Tubal Cytology and Pelvic Washing Samples (abstract). US and Canadian Academy of Pathology. Seattle, WA: USCAP.
• Chambers, S. K. (2015, January). Targeting the CSF-1 receptor to prevent breast cancer bone metastases: Uncovering CSF-1R mRNA regulators. UACC Breast Health Program Retreat. Tucson, AZ.
• Chambers, S. K. (2015, July). Precision Medicine for Ovarian Cancer Patients. Invited plenary session speaker, Ovarian Cancer National Alliance National Conference. San Diego, CA.
• Chambers, S. K. (2015, September). Collaborative Translational Research in Women's Cancers. Seminar, Huntsman Cancer Institute. Salt Lake City, UT.
• Rouse, A. R., Risi, M. D., Chambers, S. K., Hatch, K. D., Zheng, W., & Gmitro, A. F. (2015, February). Clinical experience with a confocal microlaparoscope for ovarian cancer detection. SPIE BIOS: Endoscopic Microscopy X. San Francisco, CA.

Poster Presentations

• Jones, K., Maynard, L., Chambers, S. K., & Ehsani, S. (2024, November). Germline Mutation Spectrum, Demographics, and Outcomes in Patients at the University of Arizona Cancer Center: A Retrospective Analysis [POSTER]. University of Arizona Cancer Center Annual Scientific Retreat.
• holloway, R., thaker, P., Mendivil, A., Ahmad, s., Bell, M., Chambers, S. K., Chan, J., Coleman, R., Crafton, S., Crane, E., Eskander, R., Finklestein, K., Graybill, W., Herzog, T., John, V., Landrum, L., Leiser, A., McHale, M., Miller, R., , Monk, B., et al. (2022, Fall). PHASE 3 STUDY OF EFFICACY & SAFETY OF OLVI-VEC AND PLATINUM-DOUBLET + BEVACIZUMAB COMPARED TO PLATINUM-DOUBLET + BEVACIZUMAB IN PLATINUM-RESISTENT/REFRACTORY OVARIAN CANCER (Poster presentation). IGCS- Annual Global Meeting. New York City, NY.
• trieu, r., alameri, a., alvarez, r., lee, s., maynard, l., schmanski, a., Chambers, S. K., & Melson, J. (2023). Frequency and determinants of missed colonoscopy surveillance in Lynch Syndrome patients in a Screening program with a procedural recall system (ABSTRACT/POSTER). Collaborative Group of Americas on Inherited Gastrointestinal Cancer (CGA-IGC). Las Vegas, NV.
• Anadhan, A., Shakya, A., Dodson, M., Chambers, S. K., & DD, Z. (2021, November). NRF2 inhibition enhances ovarian cancer cell death to ferroptotic cell death (ORAL POSTER PRESENTATION). UACC Retreat.
• Tanji, J. L., Morgan, M. M., Chon, H., Wenham, R. M., Winer, I. S., Randall, L. M., Chambers, S. K., Butler, K. A., Langstraat, C. L., Han, E. S., Powell, M. A., & Vahrmeijer, A. L. (2021, June). Phase 3, Randomized, Single-Dose, Open-Label Study to Investigate the Safety and Efficacy of Pafolacianine Sodium Injection (OTL38) for Intra-Operative Imaging of Folate Receptor Positive Ovarian Cancer (POSTER PRESENTATION). ASCO.
• Woo, H., & Chambers, S. K. (2020, November 13). Regulation of closely juxtaposed c-fms and HMGXB3 gene expression by native antisense RNAs in breast cancer cells (ORAL POSTER PRESENTATION). UACC Retreat: Women’s Cancers II.
• Woo, H., & Chambers, S. K. (2020, Sept 30 2020 - Octo 2 2020). Regulation of closely juxtaposed c-fms and HMGXB3 gene expression by mRNA 3’end polymorphism in breast cancer cells (POSTER). Virtual Keystone Symposium: RNA editing and modifications: from biology to therapy.
• Chambers, S. K., & Cragun, J. M. (2019, Spring 2019). Adavosertib with Chemotherapy in Patients with Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal: An Open-Label, Four-Arm, Phase II Study. ASCO. Chicago, IL: ASCO.
• Siettmann, J., Luiten, R., Garcia, C., Maynard, L., Chambers, S. K., Gasparini, J., & Cianfrocca, M. (2020, Spring 2020). Frequency and Characteristics of Large Deletions in Patients with Muir-Torre Syndrome. American Clinical Genetics Meeting. Seattle, WA.
• Pandey, R., Woo, H., Varghese, F., Zhou, M., & Chambers, S. K. (2018, September). Circulating miRNA profiling of women at high risk for ovarian cancer (POSTER/ABSTRACT). UACC Scientific Retreat.
• Rice, P., Hoyer, P. B., Howard, C. C., Koevary, J. W., Dominguez Cooks, J. P., Hutchens, G. V., Chambers, S. K., Craig, Z. R., Connoly, D. C., & Barton, J. K. (2018, September). Comparison Of Markers of Reproductive Function In Female C57bl/6 Versus Tgmisiir-Tag Transgenic Mice: Effect of Vcd Exposure On Ovarian Failure (ABSTRACT). UACC Scientific Retreat.
• Woo, H., & Chambers, S. K. (2018, June). ALKBH3-Induced m1A Demethylation Increases the CSF-1 mRNA Stability in Breast and Ovarian Cancer Cells (POSTER/ABSTRACT). UACC Scientific Retreat.
• Garcia, A., Frahm, C., Chambers, S. K., Cragun, J. M., Jeter, J., & McBride, A. (2017, Spring). Comparison of Hypersensitivity reaction incidence to carboplatin in ovarian, fallopian tube, or primary peritoneal cancer patients with or without BRCA1 or BRCA2 mutations. Hematology Oncology Pharmacy Association Conference. Anaheim, CA: Hematology Oncology Pharmacy Association.
• Koevary, J. W., Howard, C., Dominguez Cooks, J., Chambers, S. K., Connolly, D., Hoyer, P., & Barton, J. K. (2017, Spring). Optical detection of folate receptor expression in a transgenic model of ovarian cancer. University of Arizona Cancer Center Annual Scientific Retreat. Tucson, AZ: University of Arizona Cancer Center.
• Rivera-Colon, G., Li, L., Zhang, W., Chambers, S. K., Kong, B., & Zheng, W. (2017, Spring). Endometrial serous carcinogenesis in a transgenic mouse model. USCAP Annual Meeting. San Antonio, TX.
• Woo, H., & Chambers, S. K. (2017, Spring). Inhibition of the c-fms proto-oncogene expression by antisense RNA represses motility and invasion of ovarian cancer cells. University of Arizona Cancer Center Annual Scientific Retreat. Tucson, AZ: University of Arizona Cancer Center.
• Eldersveld, J. M., Chen, H., Klein, R. R., Chambers, S. K., Cragun, J. M., & Zheng, W. (2016, September). Mismatch repair protein loss of expression in endometrial hyperplasia. College of American Pathologists. Las Vegas: College of American Pathologists.
• Woo, H., Lee, S., Greco, S., & Chambers, S. K. (2016, April). Nucleolin-enhanced deadenylation-coupled translation of CSF-1 mRNA. University of Arizona Cancer Center Scientific Retreat.
• Aly, F. Z., Chen, H., Arnold, S., Klein, R. R., Chambers, S. K., & Zheng, W. (2015, October). Fallopian Tube cytology in patients undergoing salpingo-oophorectomy. ASCP Annual Meeting. Long Beach, CA.
• Lee, S., Woo, H., & Chambers, S. K. (2015, April). Vigilin, a posttranscriptional regulator of c-fms proto-oncogene, interacts with deadenylation/translation initiation complexes. University of Arizona Cancer Center Scientific Retreat.

Reviews

• Chambers, S. K. (2024. Tracing back primed resistance in cancer via sister cells (INVITED REVIEWER).
• Chambers, S. K. (2016. Invited Reviewer: National Academy of Medicine Report on "Ovarian Cancers: Evolving Paradigms in Research and Care".

Other Teaching Materials

• Chen, H., Klein, R., Arnold, S., Wang, Y., Chambers, S. K., & Zheng, W. (2017. Tubal Cytology of the Fallopian Tube As a Promising Tool for Ovarian Cancer Early Detection (video). Jove Visualized Experiments.

Others

• Chambers, S. K. (2016, January). Invited Perspective: Intraperitoneal chemotherapy for ovarian cancer. HemOnc Today.