Samir Parekh, MBBS Email Samir Parekh

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.