I am an Assistant Attending Biologist in the Thoracic Oncology Service, Molecular Pharmacology Program at Memorial Sloan Kettering. My research projects broadly focus on the genetic and epigenetic landscapes of small cell lung cancer (SCLC), therapeutic targeting of the DNA damage response pathways, and identification of improved immunotherapy combinations. In addition to my primary research focus, I currently oversee an active program in patient-derived xenograft model development and characterization at MSK.
My ongoing projects are summarized below:
Targeting DNA damage response vulnerabilities in cancers with enhanced replication stress: Cancer with high genomic instability (like SCLC) rely heavily on the DNA damage response (DDR) to mitigate oncogene-induced replication stress. We demonstrated that major DDR components are overexpressed in SCLC and are targets of small molecule inhibitors in clinical development. We further demonstrated that DDR inhibition stimulates the STING-mediated innate immune pathway to modulate immune responses. This project will uncover the (1) cell-autonomous, and (2) immune-mediated effects of DDR-targeted therapy. We will uncover the novel direct link between DDR inhibition and immune sensing pathways and how that improves immune checkpoint blockade efficacy in otherwise poorly immunogenic SCLCs. My goal is to develop novel immunotherapy approaches for cancers with high replication stress that can be readily translated into the clinic.
Targeting epigenetic modifiers to reactivate antitumor immune response: This project seeks to reverse the immune suppressive phenotype of SCLC by targeting key epigenetic modifiers that have activity in SCLC and regulate immune-related gene expression. Our data suggest that inhibiting these epigenetic modifiers rescues expression of critical mediators of cytotoxic T cell activation which may reestablish tumor immunogenicity. This proposal will examine the mechanisms by which epigenetic modifiers influence the tumor immune microenvironment and ultimately target these pathways to reactive antitumor immunity.
Overcoming primary and acquired resistance to checkpoint blockade therapy: SCLC, the most aggressive form of lung cancer, has a very modest response to immune checkpoint blockade, either as a single agent or in combination. This work is focused on understanding the mechanism of primary and acquired resistance to immunotherapy in this disease. We will further develop therapeutic approaches for enhancing antitumor immunity and the efficacy of anti-PD-1/PD-L1 therapy.
Molecular mechanisms underlying lineage plasticity in lung cancer: Neuroendocrine (NE) transformation in lung adenocarcinoma (LUAD) is a lethal mechanism of resistance that is without effective treatment or prevention options. Due to a lack of cell-level resolution, preclinical models, and the limited availability of clinical specimens, factors underlying this lineage plasticity (LP) from LUAD to more aggressive SCLC are largely unknown. Our preliminary studies showed that several hallmarks of SCLC appear critical to initiate the process of NE transformation, including RB1 and TP53 loss and downregulation of NOTCH signaling. In this project, we aim to systematically uncover core mechanisms facilitating LP in lung cancer. The long-term goal of this project is to develop therapeutic strategies to reverse or prevent LP as a mechanism of acquired resistance.
Developing PDX library of lung cancer: The Rudin lab has developed a robust platform for the routine collection, processing, and engraftment of samples that have been collected as part of multiple clinical trials. We have optimized standard operating procedures and have established over 300 PDX models from various clinical specimens (resection, biopsy, plural effusion, blood, etc.). These models serve as a valuable preclinical platform, co-clinical trials, response to therapies, and identification of biomarkers to targeted therapies. We are working with over 50 laboratories inside and outside of MSK to characterize and utilize this valuable resource.
- 2015: AACR-Women in Cancer Research-Scholar Award, International Conference on Molecular Targets and Cancer Therapeutics, Boston, MA.
- 2016: AACR Scholar-in-Training Award, AACR Special Conference on Tumor Immunology and Immunotherapy, Boston, MA.
- 2015-2018: Jeffrey Lee Cousins Fellowship in Lung Cancer Research, MD Anderson Cancer Center, Houston, TX.
- 2017: Maryanne Rosenstein Family Fellowship in Merkel Cell Carcinoma Research, Houston, TX.
- 2018: Young Investigator Research Award, Immuno-Oncology, Young Investigators’ Forum, Houston, TX.
- 2020: 40 Under 40 Cancer Emerging Leaders Award.
Doctors and faculty members often work with pharmaceutical, device, biotechnology, and life sciences companies, and other organizations outside of MSK, to find safe and effective cancer treatments, to improve patient care, and to educate the health care community.
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Triparna Sen discloses the following relationships and financial interests:
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