Samir Parekh, MBBS
- ASSOCIATE PROFESSOR | Medicine, Hematology and Medical Oncology
- ASSOCIATE PROFESSOR | Oncological Sciences
Research Topics:Computational Biology, Drug Resistance, Epigenetics, Lymphoma, Transcriptional Activation and Repression
Dr. Parekh's team is studying Mantle Cell Lymphoma (MCL), a rare and usually fatal subtype of non-Hodgkin’s lymphoma, in collaboration with a Phase II clinical trial at the NIH. The specific aims of this project are to (1) Identify aberrantly methylated genes in MCL as compared to normal naïve B cells (2) Identify differentially methylated genes associated with Bortezomib resistance in MCL (3) Construct a multi-platform model predictive for patient outcomes in MCL. These correlative studies are likely to improve our molecular understanding of pathways involved in lymphoma pathogenesis, and identify signatures useful for better selection of patients for epigenetic therapy in future prospective trials. So far, results using array based methylation and gene expression analysis of primary MCL have demonstrated (a) Widespread genomic hypomethylation in comparison to Naïve B cells which are the cell of origin for these lymphomas. (2) Silencing of tumor suppressor genes including MLF1, CDKN2B and PCDH8 that are amenable to therapeutic induction by epigenetic drugs (c) Novel hypomethylated genes e.g. CD37 are over-expressed and amenable to therapeutic targeting witha novel agents. (See publications section below) Currently, they are adopting a massively parallel sequencing approach with a view toward developing a comprehensive methylation map in order to identify prognostic signatures in MCL patients and examine the precise contribution of aberrantly methylated genes e.g. SOX11, NOXA to MCL pathogenesis and drug resistance.
Diffuse Large B Cell Lymphoma (DLBCL) drug resistance and AIDS-DLBCL epigenomics: MTOR inhibitors are emerging as active drugs in Non-Hodgkin’s lymphomas; however, response rates still remain under 50% and mechanisms of resistance are poorly understood. Using an approach combining high throughput genomic analysis and in-silico drug discovery, Dr. Parekh's lab has identified and validated a strategy combining rapalogs with inhibitors of the AKT pathway (such as MK-2206), which could be rapidly translated to clinical trials in lymphoma and other non-hematological malignancies. Recently, they have also demonstrated that the antiviral protease inhibitor Nelfinavir is highly effective in Rapamycin resistant cell line models, and potentially useful in AIDS-associated lymphoma, which is particularly prevalent in the minority population served by the AECC. (See publications section below). DLBCL occurs more frequently in AIDS patients and has inferior outcomes to DLBCL in patients not infected with HIV. There is an urgent unmet need for new therapeutics for relapsed AIDS-DLBCL. In collaboration with Dr. Greally and Center for Epigenomics (AECOM) Dr. Parekh's lab is currently studying genome-wide DNA methylation and RNA expression changes in AIDS-DLBCL to identify novel therapeutic targets for patients with this disease.
Multiple Myeloma: Multiple Myeloma (MM) is a fatal proliferation of plasma cells that primarily affects elderly individuals, afflicting over 21,000 patients and accounting for over 10,000 deaths in the US each year. Most patients with MM relapse and ultimately become refractory to chemotherapy. Molecular and cytogenetic stratification of patients canidentify patients at high risk of relapse, who have a particularly poor survival. Even though gene expression profiling (GEP) has been shown to be better than standard criteria and leads to better treatment stratification, a notable proportion of patients with high-risk gene expression signature can also achieve very good long-term survival, whereas some patients with low-risk gene expression signature myeloma (MM) can experience early relapse. Thus, newer molecular markers are needed for better risk stratification and most importantly newer therapeutic targets are desperately needed for patients with high-risk and relapsed disease. Widespread, novel, stage specific genomic and epigenomic changes can be seen during myelomagenesis and are distinct in high-risk and relapsed patients. Based on these data we hypothesize that integrative genomic analysis can define biologically and clinically distinct forms of myeloma beyond what can be gleaned by gene expression profiling alone, and by bringing together multiple types of molecular measures and understanding their relationships, we can reveal a more complete picture of multiple myeloma pathology and therapeutic opportunities. We are performing high-resolution genome-wide genomic and epigenomic characterization of primary MM using next-generation sequencing and correlating these data with survival outcomes in a well-annotated cohort of patients treated at Mt. Sinai. We expect our results to yield novel insights into pathogenesis of relapsed MM, improved prognostic models and new therapeutic targets not identified by current technologies, and to identify approved therapies that could be repurposed for improving the treatment of relapsed MM. These studies will identify the functional roles of epigenetic dysregulation in high-risk myeloma and relapsed myeloma and identify novel pathways and targets. We will then use computational techniques in collaboration with the Mount Sinai Institute of Genomics and Multiscale Biology to screen thousands of drugs against the identified MM targets and pathways to identify novel therapeutics for high risk MM, including compounds approved for other diseases that may be repurposed for treating MM.
To read more about Dr. Parekh's research, please visit the Parekh Laboratory website.
American Board of Internal Medicine
- Multiple Myeloma
Multi-Disciplinary Training AreasBiophysics and Systems Pharmacology [BSP], Cancer Biology [CAB], Genetics and Genomic Sciences [GGS]
MBBS, K J Somaiya Medical College
Residency, Internal Medicine, Cook County Hospital
Fellowship, Hematology & Onc., Montefiore Medical Center /Albert Einstein College of Medicine
Young Investigator Award
First Overall and Highest Rank in General Internal Medicine
Young Investigator Travel Award
Petrich AM, Leshchenko V, Kuo PY, Xia B, Thirukonda VK, Ulahannan N, Gordon S, Fazzari MJ, Ye BH, Sparano JA, Parekh S. Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2012 May; 18(9).
Wetzler M, Thomas DA, Wang ES, Shepard R, Ford LA, Heffner TL, Parekh S, Andreeff M, O'Brien S, Kantarjian HM. Phase I/II trial of nanomolecular liposomal annamycin in adult patients with relapsed/refractory acute lymphoblastic leukemia. Clinical lymphoma, myeloma & leukemia 2013 Aug; 13(4).
Heuck CJ, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, Chrysofakis G, Schinke C, Tariman J, Vickrey E, Pulliam N, Nischal S, Zhou L, Bhattacharyya S, Meagher R, Hu C, Maqbool S, Suzuki M, Parekh S, Reu F, Steidl U, Greally J, Verma A, Singhal SB. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. Journal of immunology (Baltimore, Md. : 1950) 2013 Mar; 190(6).
Thirukonda V, Petrich A, Parekh S. Classical Hodgkin lymphoma and spontaneous regression. Clinical advances in hematology & oncology : H&O 2012 Nov; 10(11).
Levine AM, Noy A, Lee JY, Tam W, Ramos JC, Henry DH, Parekh S, Reid EG, Mitsuyasu R, Cooley T, Dezube BJ, Ratner L, Cesarman E, Tulpule A. Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013 Jan; 31(1).
Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R, Yu Y, Bhagat TD, Bhattacharyya S, Barreyro L, Heuck C, Mo Y, Parekh S, McMahon C, Pellagatti A, Boultwood J, Montagna C, Silverman L, Maciejewski J, Greally JM, Ye BH, List AF, Steidl C, Steidl U, Verma A. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 2012 Sep; 120(10).
Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, Ben-Neriah S, Montagna C, Parekh S, Pellagatti A, Boultwood J, Paietta E, Ketterling RP, Cripe L, Fernandez HF, Greenberg PL, Tallman MS, Steidl C, Mitsiades CS, Verma A, Steidl U. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood 2012 Aug; 120(6).
Petrich AM, Sparano JA, Parekh S. Paradigms and Controversies in the Treatment of HIV-Related Burkitt Lymphoma. Advances in hematology 2012; 2012.
Parekh S. Taking it up a notch in MCL. Blood 2012 Mar; 119(9).
Parekh S, Weniger MA, Wiestner A. New molecular targets in mantle cell lymphoma. Seminars in cancer biology 2011 Nov; 21(5).
Kalac M, Scotto L, Marchi E, Amengual J, Seshan VE, Bhagat G, Ulahannan N, Leshchenko VV, Temkin AM, Parekh S, Tycko B, O'Connor OA. HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL. Blood 2011 Nov; 118(20).
Schindler J, Gajavelli S, Ravandi F, Shen Y, Parekh S, Braunchweig I, Barta S, Ghetie V, Vitetta E, Verma A. A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia. British journal of haematology 2011 Aug; 154(4).
Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, Yu Y, Remache Y, Weniger MA, Rafiq S, Suh KS, Goy A, Wilson W, Verma A, Braunschweig I, Muthusamy N, Kahl BS, Byrd JC, Wiestner A, Melnick A, Parekh S. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 2010 Aug; 116(7).
Alencar C, Abramowtiz M, Parekh S, Braunshweig I, Jacobson M, Silverman L, Verma A. Atypical presentations of Sweet's syndrome in patients with MDS/AML receiving combinations of hypomethylating agents with histone deacetylase inhibitors. American journal of hematology 2009 Oct; 84(10).
Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood 2009 Oct; 114(18).
Parekh S, Privé G, Melnick A. Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas. Leukemia & lymphoma 2008 May; 49(5).
Hussain S, Browne R, Chen J, Parekh S. Lenalidomide-induced severe hepatotoxicity. Blood 2007 Nov; 110(10).
Parekh S, Polo JM, Shaknovich R, Juszczynski P, Lev P, Ranuncolo SM, Yin Y, Klein U, Cattoretti G, Dalla Favera R, Shipp MA, Melnick A. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 2007 Sep; 110(6).
Parekh S, Perez A, Yang XY, Billett H. Chronic parvovirus infection and G6PD deficiency masquerading as Diamond-Blackfan anemia. American journal of hematology 2005 May; 79(1).
Parekh S, Hebert T, Ratech H, Sparano J. Variable problems in lymphomas: CASE 3. Spontaneous regression of HIV-associated Burkitt's lymphoma of the cecum. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2005 Nov; 23(31).
Koduri PR, Parekh S. Zidovudine-related anemia with reticulocytosis. Annals of hematology 2003 Mar; 82(3).
Parekh S, Koduri PR. Spontaneous regression of HIV-associated Hodgkin's disease. American journal of hematology 2003 Feb; 72(2).
Parekh S, Ratech H, Sparano JA. Human immunodeficiency virus-associated lymphoma. Clinical advances in hematology & oncology : H&O 2003 May; 1(5).
Parekh S, Iyer R, Sequeira W. Transient renal dysfunction with Raynaud's phenomenon: is there a connection?. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 2003 Apr; 9(2).
Parekh S, Pisaneschi M, Sequeira W. A case of acute swelling of the left shoulder. Postgraduate medical journal 2002 Jun; 78(920).
Leshchenko VV, Kuo PY, Jiang Z, Weniger MA, Overbey J, Dunleavy K, Wilson WH, Wiestner A, Parekh S. Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma. Oncotarget 2015 Feb;.
Veluswamy RR, Ward SC, Yum K, Abramovitz RB, Isola LM, Jagannath S, Parekh S. Adverse drug reaction: pomalidomide-induced liver injury. Lancet 2014 Jun; 383(9935).
Kuo PY, Leshchenko VV, Fazzari MJ, Perumal D, Gellen T, He T, Iqbal J, Baumgartner-Wennerholm S, Nygren L, Zhang F, Zhang W, Suh KS, Goy A, Yang DT, Chan WC, Kahl BS, Verma AK, Gascoyne RD, Kimby E, Sander B, Ye BH, Melnick AM, Parekh S. High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma. Oncogene 2015 Mar; 34(10).
Leshchenko VV, Kuo PY, Jiang Z, Thirukonda VK, Parekh S. Integrative genomic analysis of temozolomide resistance in diffuse large B-cell lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2014 Jan; 20(2).