# Functional characterization of novel oncogenic loci driving progression and immune response in gastrointestinal cancer

> **NIH NIH K99** · STANFORD UNIVERSITY · 2022 · $171,720

## Abstract

PROJECT SUMMARY/ABSTRACT
 Gastric cancer (GC) is one of the most common and lethal cancers worldwide. GC surgery is highly morbid,
and responses to the limited array of treatment options are poor. There is hope that recent genomic sequencing
data can be leveraged to develop newer, improved molecular therapies for GC, but rigorous mechanistic testing
is still needed to validate the therapeutic potential of targeting any newly proposed oncogenes.
 Immunotherapy is an exciting new therapy that has revolutionized oncology and shows tremendous
potential. In contrast to cytotoxic chemotherapies, which exhibit fractional killing invariably leading to resistance,
immune cells can infiltrate almost all anatomic sites to recognize and completely eliminate malignant cells in
primary and wide-spread metastatic disease. However, the immune system’s full anti-tumor killing potential can
be restricted by evasive measures by the tumor and/or intrinsic immunosuppressive mechanisms that limit
collateral damage to normal tissues during anti-tumor inflammatory reactions. In GC, little is known about how
cancer cells evade the system, and studies investigating the molecular mechanisms underlying tumor-
immune interactions have been limited by a lack of physiologically relevant in vitro human systems
where state-of-the-art genetic approaches can be applied. These mechanisms are important because they
would be essential to our understanding of GC tumorigenesis and the regulation of immunotherapeutic
responses. Such mechanistic insight on the immune system to GC is fundamental and significant to advance
and improve GC therapies. In this proposal, we utilize a series of CRISPR/Cas9 genome editing tools to create
novel forward genetically engineered models of the four major GC subtypes as defined by The Cancer Genome
Atlas project, including chromosomal instability (CIN), genomic stability (GS), microsatellite instability (MSI) and
Epstein-Barr virus-associated (EBV) in primary 3D human gastric organoids (Aim1 and Aim2). In a parallel
translational aim, we propose to use a second-generation patient-derived organoid model that allows tumor and
stroma to be preserved alongside each other to study interactions between tumor cells and their veritable
ecosystem of cohabiting immune cells in primary human gastric cancer (Aim 3). The overall goal of this project
is to investigate how genetic alterations contribute to gastric tumorigenesis and immunotherapeutic responses
using synergistic next-generation in vivo and in vitro models. Collectively, the results of this project will provide
new insights into fundamental aspects of the molecular mechanisms underlying the tumor-immune interaction
and enhance current GC immunotherapies.
 A team of expert mentors, advisors and collaborators will train Dr. Lo in new methods that are critical to
the success of this research. The combination of mentoring support, skills, and data obtained in the K99 phase
will provide Dr. Lo a springboard t...

## Key facts

- **NIH application ID:** 10450179
- **Project number:** 5K99CA263014-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yuan-Hung Lo
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $171,720
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450179

## Citation

> US National Institutes of Health, RePORTER application 10450179, Functional characterization of novel oncogenic loci driving progression and immune response in gastrointestinal cancer (5K99CA263014-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450179. Licensed CC0.

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