# Project 1: Molecular Determinants of GIST Pathogenesis

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $467,815

## Abstract

RP1: Molecular Determinants of GIST Pathogenesis
Abstract
Gastrointestinal stromal tumor (GIST) is one of the most prevalent sarcoma subtypes and mesenchymal
neoplasms of the GI tract. Clinically, advanced unresectable and/or metastatic GISTs are rarely curable despite
their initial responses to tyrosine kinase inhibitors. Current risk models (e.g., Miettinen, NIH modified), although
useful to predict patients at high risk of recurrence following surgery, often underestimate recurrence risk in
cases of intermediate size or mitotic count and non-gastric location, and no current risk stratification schemes
consider molecular biomarkers. Discovering, validating, and incorporating molecular determinants of aggressive
and metastatic clinical behavior in GIST clinical care are critical knowledge gaps. Our recent pan-cancer genomic
characterization of metastatic vs. primary tumors and GIST-specific genomic and clinical analysis of a MSK
discovery cohort of >400 untreated patients revealed that biallelic loss of function mutations in MAX or MGA
(each 5%), and MYC amplifications (0.5%), were enriched in untreated metastatic GIST compared to primary
localized GIST. Further, MAX/MGA/MYC genetic alterations and arm-level deletion of 1p were associated with
worse relapse free survival (p<0.001). MAX is the obligative heterodimerization transcriptional activator of MYC
and modulates MYC regulation of cellular function. MAX also interacts with MGA, a core component of the
PRC1.6 complex that regulates cellular differentiation. We hypothesize that genetic perturbations of
MAX/MGA/MYC and arm-level copy number alterations (e.g., -1p) in GIST promote cellular plasticity,
tumorigenesis, and aggressive metastatic behavior through functional inactivation of the PRC1.6 complex and
may represent independent molecular risk biomarkers for GIST relapse and facilitate discovery of rational
pathway targets for metastatic GIST. Here, we propose preclinical and clinical investigations, leveraging
sophisticated and novel multi-omics (e.g., transcriptome, cistrome, epigenome, single cell (sc) and/or single
nuclei (sn) RNA-seq, scATAC-seq coupled with a CellTagging system for clonal tracking) and machine learning
approaches to 1) elucidate the molecular mechanisms of MAX/MGA/MYC perturbations involved in enhanced
cellular plasticity, migration, and metastatic behavior in GIST, and 2) identify and validate molecular biomarkers
predictive of recurrence risk and adjuvant therapy determination in primary GIST after resection, using discovery
and multiple validation GIST patient cohorts to develop a combinatorial pathologic-genomic nomogram to guide
adjuvant imatinib therapy decisions. These studies could change clinical practice in GIST adjuvant treatment
and identify novel therapeutic strategies to target metastases in GIST management.

## Key facts

- **NIH application ID:** 10848814
- **Project number:** 2P50CA217694-06A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ping Chi
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,815
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848814

## Citation

> US National Institutes of Health, RePORTER application 10848814, Project 1: Molecular Determinants of GIST Pathogenesis (2P50CA217694-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10848814. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*