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2023 Grantee: Julien Dilly, MS
Dana-Farber Cancer Institute
Research Project: Understanding mechanisms of response and resistance to RAS-pathway inhibition in pancreatic cancer
Award: 2023 Pancreatic Cancer Action Network Fellowship, funded by the Francois Wallace Monahan Fund in loving memory of Michael Insel
Award Period: July 1, 2023 – June 30, 2025
Amount: $150,000
Biographical Highlights
Julien Dilly is a PhD student in the Biological and Biomedical program at Harvard University. He is conducting his graduate work in the laboratory of Dr. Andrew Aguirre at Dana-Farber Cancer Institute and the Broad Institute. He joined Dr. Aguirre’s lab as a master’s student research fellow after training under the mentorship of fellow PanCAN grantee Dr. Channing Der at the University of North Carolina at Chapel Hill. After completing his master’s work, Mr. Dilly pursued his research as a technician in Dr. Aguirre’s laboratory before starting his PhD training at Harvard University. His research aims to understand response and resistance to RAS-targeted therapies in pancreatic cancer by leveraging multi-omics approaches on patient specimens, genetically engineered mouse models and in vitro preclinical models.
Project Overview
KRAS is the most frequently mutated gene in pancreatic cancers – occurring in approximately 90% of cases – and the protein KRAS had long been thought of as “undruggable.” However, recent advances in the field have led to two FDA-approved inhibitors of a specific mutation within KRAS, known as G12C. Although KRAS G12C is found in a very small subset of pancreatic cancer cases, development of inhibitors selective for one or multiple more frequent mutations found in this disease have been proven promising in the lab.
Studies of these various drugs in models of pancreatic cancer have identified potential mechanisms by which cancer cells develop resistance. For his Fellowship, funded by the Francois Wallace Monahan Fund in loving memory of Michael Insel, Mr. Dilly will continue to explore and characterize the features of response and resistance to KRAS inhibitors in pancreatic cancer.
First, he will focus on defining how pancreatic cancer cells adapt to KRAS inhibition, using genetically engineered mouse models. These mice are programmed to develop pancreatic cancer that is driven by KRAS G12D, the most common KRAS mutation in human pancreatic cancer. Mr. Dilly will leverage techniques allowing the characterization of genetic material at single cell level, enabling him to study cellular adaptation and plasticity in response to KRAS inhibition. Through this work, he will identify features from the cancer cells and the surrounding tumor microenvironment emerging during resistance to KRAS inhibition and that may be therapeutically targetable.
For his second specific aim, Mr. Dilly will interrogate therapeutic cross-resistance to KRAS inhibitors and chemotherapy. Looking at patient-derived organoids, 3D models of pancreatic tumors and their microenvironment grown in the lab, the team has observed a greater therapeutic potential on models derived from patients who have not received chemotherapy compared to models from patients whose tumor has been exposed to chemotherapy. This finding suggests that chemotherapy may induce a drug-resistant state that limits the effectiveness of RAS-pathway inhibition. Using paired organoids derived from the same patient before and after chemotherapy treatment, Mr. Dilly will define mechanisms of drug cross-resistance. Overall, these studies aim to elucidate new biomarkers (biological clues) and combination therapy strategies that will guide utilization of KRAS inhibitors in clinical setting.
