The Gulhati lab is focused on basic and translational research in gastrointestinal cancers. Ongoing projects in the lab are focused on:
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy that will soon be the second leading cause of cancer death and remains remarkably resistant to all forms of therapy. There is a pressing need to gain a deeper understanding of the fundamental biology underlying this recalcitrant disease and uncover novel treatment strategies with sustained therapeutic efficacy.
Novel bedside remedies are invariably built upon a comprehensive understanding of cellular and molecular mechanisms underlying disease pathogenesis. Our lab is dissecting the fundamental principles governing pancreatic cancer initiation, metastasis and therapeutic resistance with an emphasis on the functional contribution of the tumor microenvironment. We take an integrated genomics and biological systems-based approach employing a diverse array of experimental models and cutting-edge techniques to conduct mechanistic and translational studies. Our overarching goal is to identify new vulnerabilities and novel treatments that can be translated to the clinic.
Pancreatic tumors demonstrate a marked desmoplastic response as well as an influx of immune cells. Recent work from our lab has focused on understanding the recalcitrance to currently available immunotherapies in pancreatic cancer, using genetically engineered mouse models and human biospecimens. To this end, we have identified a novel combinatorial immunotherapy regimen with remarkable efficacy in shrinking PDAC tumors and curing mice of their disease. Current projects in the lab are exploring: i) signaling pathways downstream of KRAS that mediate cross-talk between pancreatic cancer cells and the stromal microenvironment including immune cells and fibroblasts; ii) the immunosuppressive microenvironment in pancreatic tumors and identification of novel therapeutic targets to increase efficacy of immune checkpoint therapy and chemotherapy; iii) identification and functional validation of novel genes and pathways driving pancreatic cancer initiation, metastasis and therapeutic resistance.
Small Intestine Cancer
Small bowel adenocarcinoma (SBA) is a rare, yet highly lethal cancer. The absence of representative model systems and limited knowledge of the molecular alterations driving this cancer have hindered design of disease-specific therapeutic strategies. Prospective trials evaluating treatments for this disease are rare, and the majority of treatments for SBA are extrapolated from colorectal cancer (CRC). The mainstay of treatment for advanced disease is chemotherapy with fluorouracil-based regimens, however chemotherapy benefit is modest and transient. Recent clinical and translational studies from our group and others have uncovered distinct differences in the underlying biology and response to targeted therapies between SBA and CRC demonstrating that SBA represents a unique molecular entity. These molecular differences underscore the critical need for tumor-specific models to facilitate identification of novel therapeutic strategies in this orphan disease. Current projects in the lab are exploring: i) development of novel patient-derived model systems, including cell lines, organoids and PDXs, which encompass the full spectrum of disease incorporating genotypic and anatomic heterogeneity; ii) identification and functional validation of novel oncogenic drivers; iii) interrogating signaling pathways that promote intrinsic or adaptive resistance to targeted therapy.