- Associate Professor, Medicine
A member of the UA Skin Cancer Institute, Dr. Shaheen received his medical degree from Damascus University in Syria, and completed his fellowship at Indiana University Medical Center, specializing in hematology/oncology. Dr. Shaheen is certified by the American Board of Internal Medicine in hematology and medical oncology. Dr. Shaheen is a Physician-Scientist with clinical and laboratory research efforts. He is specialized in the treatment of melanoma, as well as kidney and bladder tumors.
- M.D. Medicine
- Damascus University, Damascus, Syria, Syrian Arab Republic
- University of Arizona, Tucson, Arizona (2016 - Ongoing)
- University of New Mexico (2015 - 2016)
- University of New Mexico Cancer Center - Department of Medicine - Division of Hematology-Oncology (2009 - 2014)
- Providence Medical Group (2003 - 2009)
Licensure & Certification
- Hematology Board Recertification (2014)
- Oncology Board Recertifiation (2014)
- Oncology Board Certified (2003)
- Medical Licensure Indiana (2000)
- New Mexico Licensure (2009)
- Hematology Board Certified (2003)
- American Board of Internal Medicine (2000)
Dr. Shaheen is a Physician-Scientist with clinical and laboratory research efforts. He is specialized in the treatment of melanoma, as well as kidney and bladder tumors. His clinical trial portfolio includes a spectrum of novel immuno- and targeted therapies. As an example, his team was part of the trial that led to the FDA approval of a powerful immunotherapy combination ( ipilimumab and nivolumab) for the treatment of metastatic melanoma ( NEJM, 2015 May 21;372(21):2006-17)His lab investigates mechanisms of DNA damage response and repair in connection to cancer generation and resistance to therapeutic agents, with an emphasis on the role of the ubiquitin pathway in this process.Homologous Recombination: Is an essential process for the repair of DNA double strand breaks. Dr. Shaheen's lab implicated two ubiqutin proteins (the ubiquitin E3 ligase Pso4, and the deubiquitylase USP20) in this process ( J Biol Chem 2015 May 21;372(21):2006-17, J Biol Chem. 2014 Aug 15;289(33):22739-48). Depletion of these proteins lead to cancer cell sensitivity to radiation and chemotherapy drugs.His lab also investigates the important tumor suppressor deubiquitylase protein (Brca1 associated protein 1 or BAP1) in carcinogenesis. This protein’s function is absent in a significant percentage of cancers including ocular, familial melanoma, renal, and bladder tumors. Understanding BAP1 enigmatic function will be the first step in designing drugs that can help patients with BAP1 pathway mutations.
ResearchCBIO 900 (Fall 2020)
Research ConferenceCBIO 695A (Fall 2020)
Directed ResearchECOL 492 (Spring 2020)
ResearchCBIO 900 (Spring 2020)
Research ConferenceCBIO 695A (Spring 2020)
Research ConferenceCBIO 695A (Fall 2019)
Honors ThesisMCB 498H (Spring 2019)
Directed RsrchMCB 392 (Fall 2018)
Honors ThesisMCB 498H (Fall 2018)
Research ConferenceCBIO 695A (Fall 2018)
Directed ResearchPSIO 492 (Spring 2018)
Directed RsrchMCB 492 (Spring 2018)
- Shaheen, M., & Broxmeyer, H. (2008). Humoral regulation of hematopoiesis. In Basic Principles and Practice 5th edition.
- Shaheen, M., & Broxmeyer, H. (2005). Humoral regulation of hematopoiesis. In Basic Principles and Practice 4th edition.
- Carducci, M., Shaheen, M., Markman, B., Hurvitz, S., Mahadevan, D., Kotasek, D., Goodman, O. B., Rasmussen, E., Chow, V., Juan, G., Friberg, G. R., Gamelin, E., Vogl, F. D., & Desai, J. (2018). A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors. Investigational new drugs, 36(6), 1060-1071.More infoBackground Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.
- Fisher, G. A., Wolin, E. M., Liyanage, N., Lowenthal, S. P., Mirakhur, B., Pommier, R. F., Shaheen, M., Vinik, A. I., & , E. S. (2018). LANREOTIDE THERAPY IN CARCINOID SYNDROME: PROSPECTIVE ANALYSIS OF PATIENT-REPORTED SYMPTOMS IN PATIENTS RESPONSIVE TO PRIOR OCTREOTIDE THERAPY AND PATIENTS NAÏVE TO SOMATOSTATIN ANALOGUE THERAPY IN THE ELECT PHASE 3 STUDY. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 24(3), 243-255.More infoThis ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group).
- Kim, E. S., Kelly, K., Paz-Ares, L. G., Garrido, P., Jalal, S., Mahadevan, D., Gutierrez, M., Provencio, M., Schaefer, E., Shaheen, M., Johnston, E. L., Turner, P. K., Kambhampati, S. R., Beckmann, R., Hossain, A., John, W. J., & Goldman, J. W. (2018). Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase Ib Study. Clinical cancer research : an official journal of the American Association for Cancer Research, 24(22), 5543-5551.More infoAbemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. .
- Fisher, G. A., Wolin, E. M., Liyanage, N., Pitman Lowenthal, S., Mirakhur, B., Pommier, R. F., Shaheen, M., Vinik, A., & , E. S. (2017). Patient-Reported Symptom Control of Diarrhea and Flushing in Patients with Neuroendocrine Tumors Treated with Lanreotide Depot/Autogel: Results from a Randomized, Placebo-Controlled, Double-Blind and 32-Week Open-Label Study. The oncologist.More infoIn the double-blind (DB) ELECT study, lanreotide depot/autogel significantly reduced versus placebo the need for short-acting octreotide for symptomatic carcinoid syndrome (CS) control in neuroendocrine tumor (NET) patients. Here we present patient-reported symptom data during DB and initial open-label (IOL) treatment.
- Infante, J. R., Patnaik, A., Verschraegen, C. F., Olszanski, A. J., Shaheen, M., Burris, H. A., Tolcher, A. W., Papadopoulos, K. P., Beeram, M., Hynes, S. M., Leohr, J., Lin, A. B., Li, L. Q., McGlothlin, A., Farrington, D. L., Westin, E. H., & Cohen, R. B. (2017). Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer. Cancer chemotherapy and pharmacology, 79(2), 315-326.More infoThis first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor.
- Pulluri, B., Kumar, A., Shaheen, M., Jeter, J., & Sundararajan, S. (2017). Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance. Pharmacological research, 123, 95-102.More infoImmunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.
- Sznol, M., Postow, M. A., Davies, M. J., Pavlick, A. C., Plimack, E. R., Shaheen, M., Veloski, C., & Robert, C. (2017). Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer treatment reviews, 58, 70-76.More infoAgents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.
- Amin, A., Lawson, D. H., Salama, A. K., Koon, H. B., Guthrie, T., Thomas, S. S., O'Day, S. J., Shaheen, M. F., Zhang, B., Francis, S., & Hodi, F. S. (2016). Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. Journal for immunotherapy of cancer, 4, 44.More infoIpilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.
- Hodi, F. S., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K. F., McDermott, D. F., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., Shaheen, M., Ernstoff, M. S., Minor, D. R., Salama, A. K., Taylor, M. H., Ott, P. A., Horak, C., Gagnier, P., Jiang, J., , Wolchok, J. D., et al. (2016). Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. The Lancet. Oncology, 17(11), 1558-1568.More infoResults from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.
- Postow, M. A., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K., McDermott, D., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., Shaheen, M., Ernstoff, M. S., Minor, D., Salama, A. K., Taylor, M., Ott, P. A., Rollin, L. M., Horak, C., Gagnier, P., , Wolchok, J. D., et al. (2015). Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. The New England journal of medicine, 372(21), 2006-17.More infoIn a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.
- Abbas, M., Shanmugam, I., Bsaili, M., Hromas, R., & Shaheen, M. (2014). The role of the human psoralen 4 (hPso4) protein complex in replication stress and homologous recombination. The Journal of biological chemistry, 289(20), 14009-19.More infoPsoralen 4 (Pso4) is an evolutionarily conserved protein that has been implicated in a variety of cellular processes including RNA splicing and resistance to agents that cause DNA interstrand cross-links. Here we show that the hPso4 complex is required for timely progression through S phase and transition through the G2/M checkpoint, and it functions in the repair of DNA lesions that arise during replication. Notably, hPso4 depletion results in delayed resumption of DNA replication after hydroxyurea-induced stalling of replication forks, reduced repair of spontaneous and hydroxyurea-induced DNA double strand breaks (DSBs), and increased sensitivity to a poly(ADP-ribose) polymerase inhibitor. Furthermore, we show that hPso4 is involved in the repair of DSBs by homologous recombination, probably by regulating the BRCA1 protein levels and the generation of single strand DNA at DSBs. Together, our results demonstrate that hPso4 participates in cell proliferation and the maintenance of genome stability by regulating homologous recombination. The involvement of hPso4 in the recombinational repair of DSBs provides an explanation for the sensitivity of Pso4-deficient cells to DNA interstrand cross-links.
- Bauman, J., Shaheen, M., Verschraegen, C. F., Belinsky, S. A., Houman Fekrazad, M., Lee, F. C., Rabinowitz, I., Ravindranathan, M., & Jones, D. V. (2014). A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers. Translational oncology.More infoSmokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.
- Shanmugam, I., Abbas, M., Ayoub, F., Mirabal, S., Bsaili, M., Caulder, E. K., Weinstock, D. M., Tomkinson, A. E., Hromas, R., & Shaheen, M. (2014). Ubiquitin-specific peptidase 20 regulates Rad17 stability, checkpoint kinase 1 phosphorylation and DNA repair by homologous recombination. The Journal of biological chemistry, 289(33), 22739-48.More infoRad17 is a subunit of the Rad9-Hus1-Rad1 clamp loader complex, which is required for Chk1 activation after DNA damage. Rad17 has been shown to be regulated by the ubiquitin-proteasome system. We have identified a deubiquitylase, USP20 that is required for Rad17 protein stability in the steady-state and post DNA damage. We demonstrate that USP20 and Rad17 interact, and that this interaction is enhanced by UV exposure. We show that USP20 regulation of Rad17 is at the protein level in a proteasome-dependent manner. USP20 depletion results in poor activation of Chk1 protein by phosphorylation, consistent with Rad17 role in ATR-mediated phosphorylation of Chk1. Similar to other DNA repair proteins, USP20 is phosphorylated post DNA damage, and its depletion sensitizes cancer cells to damaging agents that form blocks ahead of the replication forks. Similar to Chk1 and Rad17, which enhance recombinational repair of collapsed replication forks, we demonstrate that USP20 depletion impairs DNA double strand break repair by homologous recombination. Together, our data establish a new function of USP20 in genome maintenance and DNA repair.
- Verschraegen, C. F., Movva, S., Ji, Y., Schmit, B., Quinn, R. H., Liem, B., Bocklage, T., & Shaheen, M. (2013). A phase I study of the combination of temsirolimus with irinotecan for metastatic sarcoma. Cancers, 5(2), 418-29.More infomTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.
- Williamson, E. A., Boyle, T. J., Raymond, R., Farrington, J., Verschraegen, C., Shaheen, M., & Hromas, R. (2012). Cytotoxic activity of the titanium alkoxide (OPy)(2)Ti(4AP)(2) against cancer colony forming cells. Investigational new drugs, 30(1), 114-20.More infoA novel family of titanium alkoxides with two stable pyridinemethoxide moieties bound to a titanium metal center were synthesized and tested for cytotoxic activity on a variety of cancer cell lines using colony formation assays. One compound, (OPy)(2)Ti(4AP)(2), where OPy is NC(5)H(5)CH(2)O(-), and 4AP is 4-aminophenoxide ((-)OC(6)H(5)(NH(2))-4), demonstrated increased cytotoxicity in breast, colon, and pancreatic cancer cell lines at 100 nanomolar levels with only short exposures. Further, (OPy)(2)Ti(4AP)(2) had activity in colon and pancreatic cancer cell lines that are usually resistant to chemotherapy. This demonstrates that these titanium compounds may have a role in anti-cancer therapy, similar to platinum-based compounds, and the (OPy)(2)Ti(4AP)(2) compound specifically deserves further investigation as an anti-cancer agent in chemo-resistant solid tumors.
- Williamson, E. A., Damiani, L., Leitao, A., Hu, C., Hathaway, H., Oprea, T., Sklar, L., Shaheen, M., Bauman, J., Wang, W., Nickoloff, J. A., Lee, S. H., & Hromas, R. (2012). Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. Cancer research, 72(23), 6200-8.More infoPrevious studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy.
- Fnu, S., Williamson, E. A., De Haro, L. P., Brenneman, M., Wray, J., Shaheen, M., Radhakrishnan, K., Lee, S. H., Nickoloff, J. A., & Hromas, R. (2011). Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proceedings of the National Academy of Sciences of the United States of America, 108(2), 540-5.More infoGiven its significant role in the maintenance of genomic stability, histone methylation has been postulated to regulate DNA repair. Histone methylation mediates localization of 53BP1 to a DNA double-strand break (DSB) during homologous recombination repair, but a role in DSB repair by nonhomologous end-joining (NHEJ) has not been defined. By screening for histone methylation after DSB induction by ionizing radiation we found that generation of dimethyl histone H3 lysine 36 (H3K36me2) was the major event. Using a novel human cell system that rapidly generates a single defined DSB in the vast majority of cells, we found that the DNA repair protein Metnase (also SETMAR), which has a SET histone methylase domain, localized to an induced DSB and directly mediated the formation of H3K36me2 near the induced DSB. This dimethylation of H3K36 improved the association of early DNA repair components, including NBS1 and Ku70, with the induced DSB, and enhanced DSB repair. In addition, expression of JHDM1a (an H3K36me2 demethylase) or histone H3 in which K36 was mutated to A36 or R36 to prevent H3K36me2 formation decreased the association of early NHEJ repair components with an induced DSB and decreased DSB repair. Thus, these experiments define a histone methylation event that enhances DNA DSB repair by NHEJ.
- Shaheen, M., Allen, C., Nickoloff, J. A., & Hromas, R. (2011). Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood, 117(23), 6074-82.More infoBecause cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA double-strand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic double-strand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.
- Shaheen, M., Shanmugam, I., & Hromas, R. (2010). The Role of PCNA Posttranslational Modifications in Translesion Synthesis. Journal of nucleic acids, 2010.More infoOrganisms are predisposed to different types in DNA damage. Multiple mechanisms have evolved to deal with the individual DNA lesions. Translesion synthesis is a special pathway that enables the replication fork to bypass blocking lesions. Proliferative Cell Nuclear Antigen (PCNA), which is an essential component of the fork, undergoes posttranslational modifications, particularly ubiquitylation and sumoylation that are critical for lesion bypass and for filling of DNA gaps which result from this bypass. A special ubiquitylation system, represented by the Rad6 group of ubiquitin conjugating and ligating enzymes, mediates PCNA mono- and polyubiquitylation in response to fork stalling. The E2 SUMO conjugating enzyme Ubc9 and the E3 SUMO ligase Siz1 are responsible for PCNA sumoylation during undisturbed S phase and in response to fork stalling as well. PCNA monoubiquitylation mediated by Rad6/Rad18 recruits special polymerases to bypass the lesion and fill in the DNA gaps. PCNA polyubiquitylation achieved by ubc13-mms2/Rad 5 in yeast mediates an error-free pathway of lesion bypass likely through template switch. PCNA sumoylation appears required for this error-free pathway, and it plays an antirecombinational role during normal replication by recruiting the helicase Srs2 to prevent sister chromatid exchange and hyper-recombination.
- Shaheen, M., Williamson, E., Nickoloff, J., Lee, S. H., & Hromas, R. (2010). Metnase/SETMAR: a domesticated primate transposase that enhances DNA repair, replication, and decatenation. Genetica, 138(5), 559-66.More infoMetnase is a fusion gene comprising a SET histone methyl transferase domain and a transposase domain derived from the Mariner transposase. This fusion gene appeared first in anthropoid primates. Because of its biochemical activities, both histone (protein) methylase and endonuclease, we termed the protein Metnase (also called SETMAR). Metnase methylates histone H3 lysine 36 (H3K36), improves the integration of foreign DNA, and enhances DNA double-strand break (DSB) repair by the non-homologous end joining (NHEJ) pathway, potentially dependent on its interaction with DNA Ligase IV. Metnase interacts with PCNA and enhances replication fork restart after stalling. Metnase also interacts with and stimulates TopoIIalpha-dependent chromosome decatenation and regulates cellular sensitivity to topoisomerase inhibitors used as cancer chemotherapeutics. Metnase has DNA nicking and endonuclease activity that linearizes but does not degrade supercoiled plasmids. Metnase has many but not all of the properties of a transposase, including Terminal Inverted Repeat (TIR) sequence-specific DNA binding, DNA looping, paired end complex formation, and cleavage of the 5' end of a TIR, but it cannot efficiently complete transposition reactions. Interestingly, Metnase suppresses chromosomal translocations. It has been hypothesized that transposase activity would be deleterious in primates because unregulated DNA movement would predispose to malignancy. Metnase may have been selected for in primates because of its DNA repair and translocation suppression activities. Thus, its transposase activities may have been subverted to prevent deleterious DNA movement.
- Wray, J., Williamson, E. A., Royce, M., Shaheen, M., Beck, B. D., Lee, S. H., Nickoloff, J. A., & Hromas, R. (2009). Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells. PloS one, 4(4), e5323.More infoDNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIalpha (Topo IIalpha) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIalpha is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIalpha-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIalpha inhibitors. Here we show that Metnase interacts with Topo IIalpha in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIalpha inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIalpha-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIalpha inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIalpha inhibitors, specifically in anthracycline-resistant breast cancer.
- Shaheen, M., Stender, M. J., McClean, J. W., Look, K. Y., & Einhorn, L. H. (2004). Phase II study of ifosfamide plus daily oral etoposide in previously treated ovarian cancer: a Hoosier Oncology Group (HOG) study. American journal of clinical oncology, 27(3), 229-31.More infoAdvanced epithelial ovarian carcinoma is a chemosensitive tumor to platinum plus paclitaxel combination chemotherapy. However, most patients develop recurrences following their initial platinum-based regimen and are candidates for subsequent chemotherapy. Several chemotherapeutic drugs have been tested as single therapeutic agents or in combination for relapsed epithelial ovarian carcinoma. The response rate has been modest with no obvious advantage to combination chemotherapy versus single agents. Both oral etoposide and ifosfamide have shown activity as single agents in pretreated patients. We completed a phase II study at the Hoosier Oncology Group utilizing oral etoposide plus ifosfamide in patients with relapsed ovarian epithelial carcinoma. Fourteen patients entered the study. Ifosfamide was given intravenously (IV) at a dose of 1.2 g/m2/d on days 1 to 4 with mesna 300 mg/m2 IV 15 minutes prior to and 4 and 8 hours after ifosfamide infusion. Etoposide was administered as 37.5 mg/m2/d orally on days 1 to 14. This regimen was repeated every 28 days until disease progression or for a maximum of 6 cycles. Grade III to IV granulocytopenia occurred in 9 patients (64%), with 2 neutropenic infections, but with no therapy-related deaths. Grade III to IV thrombocytopenia occurred in 3 patients (21%), and grade III to IV nausea and vomiting in 1 patient. No renal, pulmonary, hepatic, cardiac, or serious neurotoxicity was observed. Two patients (14%) achieved partial response, and additional 5 (35%) patients had stable disease. The 1-year survival probability using Kaplan-Meier analysis was 0.8. In this small sample-size trial, we did not demonstrate an advantage to this combination regimen compared to these or other single agents.
- Broxmeyer, H. E., Kohli, L., Kim, C. H., Lee, Y., Mantel, C., Cooper, S., Hangoc, G., Shaheen, M., Li, X., & Clapp, D. W. (2003). Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells. Journal of leukocyte biology, 73(5), 630-8.More infoStromal cell-derived factor-1 (SDF-1/CXCL12) enhances survival of myeloid progenitor cells. The two main questions addressed by us were whether these effects on the progenitors were direct-acting and if SDF-1/CXCL12 enhanced engrafting capability of competitive, repopulating mouse stem cells subjected to short-term ex vivo culture with other growth factors. SDF-1/CXCL12 had survival-enhancing/antiapoptosis effects on human bone marrow (BM) and cord blood (CB) and mouse BM colony-forming units (CFU)-granulocyte macrophage, burst-forming units-erythroid, and CFU-granulocyte-erythroid-macrophage-megakaryocyte with similar dose responses. The survival effects were direct-acting, as assessed on colony formation by single isolated human BM and CB CD34(+++) cells. Effects were mediated through CXCR4 and G(alpha)i proteins. Moreover, SDF-1/CXCL12 greatly enhanced the engrafting capability of mouse long-term, marrow-competitive, repopulating stem cells cultured ex vivo with interleukin-6 and steel factor for 48 h. These results extend information on the survival effects mediated through the SDF-1/CXCL12-CXCR4 axis and may be of relevance for ex vivo expansion and gene-transduction procedures.
- Shaheen, M., Hilgarth, K. A., Hawes, D., Badve, S., & Antony, A. C. (2003). A Mexican man with "too much blood". Lancet (London, England), 362(9386), 806.