Nipun B. Merchant, M.D.
Clinical Professor of Surgery
Description of Research
Pancreatic cancer development is a dynamic in vivo process between tumor cells and the tumor microenvironment. To better understand the microenvironmental response, we use genetically engineered mouse models of pancreatic cancer and patient-derived xenograft models that feature activation of oncogenic Kras and mutations in tumor suppressor genes such as p53, Ink4a and TGFbRII. These mouse models recapitulate key features of human pancreatic adenocarcinomas characterized by extensive remodeling of the surrounding microenvironment. In pancreatic adenocarcinoma, the microenvironmental stroma acts as a barrier to prevent drug delivery to the tumor cells. Dr. Merchant has shown STAT3 inhibitors can remodel the stroma to enhance drug delivery to the tumor and improve therapeutic response. He is interested in understanding the mechanisms involved in the cross-talk between different components of the tumor microenvironment that result in drug resistance. His current research aims to elucidate the cellular and molecular mechanisms of STAT3 signaling in pancreatic cancer cells, and to determine the significance of tumor-stromal interaction in tumor progression and metastatic disease. He has observed that pancreatic cancers cells develop acquired resistance to anti-JAK/STAT3 inhibitors in both in vitro and in vivo. Combinatorial therapeutics targeting primary and resistance pathways are currently being tested for efficacy against pancreatic cancer.
- Dr. Merchant’s studies on activated tyrosine kinase signaling pathways in pancreatic cancer, targeting SRC kinase and epidermal growth factor receptor (EGFR), have established a mechanistic rationale for constitutively activated signal transducer and activator of transcription 3 (STAT3) as a mediator of treatment resistance in pancreatic cancer. He has shown that SRC and EGFR inhibition combined with gemcitabine overcomes STAT3-mediated resistance of pancreatic tumor growth. To overcome the dense desmoplastic reaction associated with lack of drug delivery to pancreas tumors, he has shown that targeting STAT3 with gemcitabine results in inhibition of angiogenesis, remodeling of tumor stroma and “vascular normalization” resulting in enhanced drug delivery to the tumor leading to improved survival in genetic mouse models of pancreas cancer. These results have directly led to a Phase 1 Trial of Dasatinib, Erlotinib and Gemcitabine in patients with Advanced Pancreas Cancer for which he is the PI.
- Using genetic mouse models and orthotopic xenograft models of PDAC, Dr. Merchant has shown that the combination of STAT3 inhibition and gemcitabine enhances drug delivery to the tumor by stromal remodeling, a key strategy that can be utilized to improve therapeutic response. Additionally, he has shown that combination therapies of STAT3 and MEK inhibition and CDK4 and MEK inhibition result in enhanced therapeutic responses by overcoming reciprocal reactivation of redundant oncogenic signaling pathways and altering the PDAC immune microenvironment by decreasing the number of infiltrating MDSCs and tumor promoting macrophages.
- Dr. Merchant has further investigated novel mechanistic insights into ectodomain shedding of EGFR ligands. He has indentified amphiregulin as the primary ligand that regulates EGFR-dependent signaling pathway that mediates the oncogenic effects in gastrointestinal cancers, the targeting of which may enhance therapeutic responses of EGFR inhibitors.
- Due to the significant limitations of randomized trials of pancreas cancer, he has been unable to answer many relevant questions in the management of patients with pancreas cancer. Recognizing these limitations, he founded and directs the Central Pancreas Consortium – a collaborative of eight, high volume pancreas centers that combine their data in an effort to provide meaningful, multi-center, high-volume outcomes data which is more clinically relevant. Dr. Merchant has been able to provide compelling evidence that is now changing the treatment course for patients with pancreas cancer.
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):