MCL is a rare and incurable non-Hodgkins lymphoma whose pathogenesis is not clearly understood. The SOX11 transcription factor is overexpressed in the majority of Mantle cell lymphomas. We identified the direct DNA binding targets of SOX11 in several oncogenic pathways using ChIP-sequencing and functional genomics. We have now developed an inducible mouse model of SOX11 overexpression that recapitulates the MCL phenotype. We are developing anti-SOX11 small molecules with structural biologist Dr. Aneel Aggarwal at Mount Sinai that could be applicable in MCL and other SOX11 expressing tumors like lung cancer, ovarian cancer, and glioma.
1) Kuo PY, Jatiani SS, Rahman AH, Edwards D, Jiang Z, Ahr K, Perumal D, Leshchenko VV, Brody J, Shaknovich R, Ye BH, Parekh S. SOX 11 augments BCR signaling to drive MCL-like tumor development. Blood. 2018.
2) 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.
3) Jatiani SS, Christie S, Leshchenko VV, Jain R, Kapoor A, Bisignano P, Lee C, Kaniskan HÜ, Edwards D, Meng F, Laganà A, Youssef Y, Wiestner A, Alinari L, Jin J, Filizola M, Aggarwal AK, Parekh S. SOX11 Inhibitors Are Cytotoxic in Mantle Cell Lymphoma. Clin Cancer Res. 2021 Aug 15.
4) Filizola M, Parekh S, Aggarwal AK, Christie SN, Jatiani SS, inventors; Icahn School of Medicine at Mount Sinai, assignee. SOX11 inhibitors for the treatment of Mantle Cell Lymphoma. United States Patent Application No. 62/376,056. 2016.
5) 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.
6) Parekh S, Weniger MA, Wiestner A. New molecular targets in mantle cell lymphoma. Semin Cancer Biol. 2011.
7) 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.
8) 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
Immune Responses in Cancer Patients with COVID-19
Mount Sinai was the epicenter of the COVID-19 pandemic in New York, with over 5,000 patients admitted during the first wave. I volunteered as an inpatient attending for cancer and non-cancer patients with COVID-19 and saw firsthand the variability to treatment response especially in immunocompromised cancer patients. Our assays for CAR-T cytokine storm were adapted to an institution-wide assay for COVID related cytokine assessment and we have continued efforts in understanding and defining differences between healthy individuals and immunocompromised Multiple Myeloma patients to guide management and treatment guidelines.
1) Van Oekelen O, Parekh S. CD8+ T cells: An ineffective armor against prolonged COVID-19 in cancer patients. Cell Rep Med. 2022
2) Aleman A, van Kesteren M, Zajdman AK, Srivastava K, Cognigni C, Mischka J, Chen LY, Upadhyaya B, Serebryakova K, Nardulli JR, Lyttle N, Kappes K, Jackson H, Gleason CR, Oostenink A, Cai GY, Van Oekelen O; PVI/MM/Seronet Study Group; van Bakel H, Sordillo EM, Cordon-Cardo C, Merad M, Jagannath S, Wajnberg A, Simon V, Parekh S. Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma. EBioMedicine. 2023
3) Aleman A, Upadhyaya B, Tuballes K, Kappes K, Gleason C, Beach K, Agte S, Srivastava K, PVI/Seronet Study Group, Van Oekelen O, Barcessat V, Bhardwaj N, KimSchulze S, Gnjatic S, Brown B, Cordon-Cardo C, Krammer F, Merad M, Jagannath S, Wajnberg A, Simon V, Parekh S. Variable cellular responses to SARS-CoV-2 in fully vaccinated patients with multiple myeloma. Cancer Cell. 2021.
4) Van Oekelen O, Gleason CR, Agte S, Srivastava K, Beach K, Aleman A, Kappes K, Mouhieddine TH, Wang B, Chari A, Cordon-Cardo C, Krammer F, Jagannath S, Simon V, Wajnberg A, Parekh S. Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. Cancer Cell. 2021.
5) Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, Lavin Y, Swartz TH, Madduri D, Stock A, Marron TU, Xie H, Patel M, Tuballes K, Van Oekelen O, Rahman A, Kovatch P, Aberg JA, Schadt E, Jagannath S, Mazumdar M, Charney AW, Firpo-Betancourt A, Mendu DR, Jhang J, Reich D, Sigel K, Cordon-Cardo C, Feldmann M, Parekh S, Merad M, Gnjatic S. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nature Medicine. 2020.
6) Wang B, Van Oekelen O, Mouhieddine TH, Del Valle DM, Richter J, Cho HJ, Richard S, Chari A, Gnjatic S, Merad M, Jagannath S, Parekh S, Madduri D. A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward. Journal of Hematology and Oncology. 2020.
7) Madduri D, Parekh S, Campbell TB, Neumann F, Petrocca F, Jagannath S. Anti-BCMA CAR T administration in a relapsed and refractory multiple myeloma patient after COVID-19 infection: a case report. Journal of Medical Case Reports. 2021.
Mantle Cell Lymphoma (MCL)
Integrative Genomics for Drug Repositioning in Myeloma
With the advent of next-generation sequencing, we have been systematically developing and studying the application of integrative genomics (including methylation, gene expression and exome sequencing) to guide personalized repurposing of FDA approved drugs to overcome chemotherapy resistance in B cell malignancies like non-Hodgkins Lymphoma and Multiple Myeloma. I have an ongoing IRB approved clinical trial for genomic signature guided therapeutic selection in collaboration with Drs. Jagannath and Schadt, Dean for Precision Medicine and the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai.
1) Bhalla S, Melnekoff DT, Keats J, et al. Patient Similarity Network of Multiple Myeloma identifies patient sub-groups with distinct genetic and clinical features. Science Advances. In press. doi:10.1126/sciadv.abg9551.
2) Lagana A, Beno I, Melnekoff D, Leshchenko V, Madduri D, Ramdas D, Niglio S, Perumal D, Kidd B, Miotto R, Shaknovich R, Chari A, Cho HJ, Barlogie B, Jagannath S, Dudley J, Parekh S. Precision Medicine for Relapsed Multiple Myeloma Based on a Multi-Omics Approach. JCO Precis Oncol. 2018.
3) Lagana A, Perumal D, Melnekoff D, Readhead B, Kidd BA, Leshchenko VV, Kuo PY, Keats J, DeRome M, Parekh S, et al. Integrative network analysis identifies novel drivers of pathogenesis and progression in newly diagnosed multiple myeloma. Leukemia. 2018.
4) Kamath GR, Renteria AS, Jagannath S, Gallagher EJ, Parekh S, Bickell NA. Where you live can impact your cancer risk: a look at multiple myeloma in New York City. Ann Epidemiol. 2020.
5) Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. Nat Chem Biol. 2020.