Project Summary/Abstract: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal
malignancy with few therapeutic options. Tumor transcriptional states are strongly correlated with therapeutic
responses and clinical outcomes in PDAC. However, the mechanisms that regulate PDAC cell states and their
roles in tumor evolution and therapeutic resistance are not well understood. In this proposal, I will investigate
mechanisms regulating PDAC cell state specification, characterize tumor cell plasticity as a potential mechanism
of therapeutic resistance, and identify cell state-specific therapeutic vulnerabilities using genetic and
pharmacologic approaches. In Aim 1, I will investigate how TGF-ß signaling specifies the basal cell state in
organoid models. In Aim 2, I will examine whether TGF-ß-mediated cellular plasticity drives chemo-resistance in
organoid models and serially collected metastatic biopsies analyzed with single-cell RNA-sequencing. In Aim 3,
I will perform compound testing and CRISPR screening in isogenic organoid models induced to adopt either
basal or classical states to identify state-specific therapeutic vulnerabilities. Together, these aims will establish
a rigorous framework for the analysis and modeling of PDAC evolution and will advance our mechanistic
understanding of how microenvironmental factors such as TGF-ß regulate PDAC cell states, plasticity, and drug
resistance, thereby uncovering new avenues for therapeutic development.
I am a medical oncologist with a clinical focus in gastrointestinal cancers and a research background in
cancer biology and biomedical engineering. I am applying for the K08 award with the long-term goal of becoming
an independent laboratory-based investigator with a translational focus in pancreatic and biliary cancers. During
my K08 training, I will perform mentored research in the laboratory of Dr. William Hahn at the Dana-Farber
Cancer Institute (DFCI). Dr. Brian Wolpin will serve as a co-mentor for the translational aspects of my research
and will also act as my clinical mentor. I plan to spend 90% of my time performing research and 10% of my time
on patient care, initially as an inpatient oncology attending but eventually transitioning to the outpatient setting
where I will see patients with gastrointestinal cancers. I have organized an outstanding advisory committee
consisting of faculty from DFCI, Harvard Medical School, the Broad Institute, and MIT to help guide my research
and career development. In addition to Drs. Hahn and Wolpin, my committee members - Drs. Ramesh
Shivdasani, Stuart Schreiber, Alex Shalek, and Stephanie Dougan - are scientific experts in specific areas of my
proposed research, and their insights will prove invaluable to the successful completion of this proposal. The
research environments at DFCI and the Broad Institute are unparalleled and offer numerous opportunities for
scientific advancement and career development. The K08 award along with the aid of my mentors and a focused
training plan will enable me to achieve my goal of becoming an independent physician-scientist.