PROJECT SUMMARY/ABSTRACT
Patients with gastrointestinal (GI) metastases in the peritoneal cavity suffer high morbidity,
chemotherapy resistance, and decreased overall survival. The molecular mechanism and phenotypic features
that facilitate peritoneal metastasis are poorly understood, although mucin-expressing tumors exhibit especially
high predilection for peritoneal spread. Preliminary analyses determined in a pan-cancer patient cohort that
mucinous GI tumors are highly enriched in a specific mutation in GNAS that leads to pathogenic gain-of-
function in the encoded G protein alpha subunit (GNAS). GNAS mutations are associated with pancreatic and
small cell lung tumor development, yet the pathogenic mechanism mobilized by GNAS to facilitate metastasis
is unknown. Preliminary data demonstrates that patients with GNAS-mutated GI cancers exhibit increased
burden of peritoneal metastases, decreased response to first-line chemotherapy, and poor overall survival.
Analysis of tumor DNA and RNA from independent groups of patient tumors shows that mutated GNAS may
operate within a distinct gene-regulatory network that activates PI3K and MAPK signaling. The PI and
collaborators established GNAS-mutated, patient-derived-organoids (PDOs) and a peritoneal metastasis
mouse model to evaluate the hypothesis that GNAS is a key molecular driver that governs the signaling
pathway involved in metastatic peritoneal seeding and growth.
To test this hypothesis, the study will (1) define the GNAS-induced gene regulatory networks and
phenotypic features that facilitate tumor progression in patient peritoneal metastasis and CRISPR-Cas9 gene-
edited PDOs and (2) determine the impact of GNAS modulation on metastasis distribution and pathogenicity in
vivo using xenograft metastatic models. Investigations will integrate multi-omic analyses with PDO
experimental validation to improve the fundamental understanding of metastasis and validate GNAS signaling
as a therapeutically-relevant target. The applicant, Dr. Michael Foote, is a rising Assistant Attending in the GI
Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Foote has defined a 5-year plan
to integrate his background in targeted drug development and computational bioinformatics with new expertise
in experimental modeling and molecular biology. Dr. Foote will be mentored by a complementary advisory
committee led by Dr. Luis Diaz, an international expert in genomics with a strong background in training
successful independent physician scientists. Dr. Foote’s development plan includes supportive workshops and
mentoring from an advisory committee of experts in molecular biology, cell signaling, and bioinformatics at
MSKCC, a world-renowned translational center of excellence. Completion of the project goals will facilitate new
therapeutic approaches for treating metastatic GI cancer and Dr. Foote’s development into an independent
physician scientist and expert leader in GI metastasis.