# Project 4 - Characterizing and Overcoming Resistance to ERBB2 Directed Therapy in Metastatic Gastric and Esophageal Adenocarcinoma

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2022 · $370,216

## Abstract

Project Summary 
ERBB2 is amplified in ~20% of Gastric and esophageal adenocarcinomas (GEAs) and 
metastatic ERBB2+ GEAs are treated with a combination of chemotherapy and the antibody 
Trastuzumab. However, Trastuzumab is only modestly effective in GEA, and all other targeted 
agents in ERBB2+ breast cancer have failed in GEA clinical trials. We propose to directly 
address the two primary factors that we hypothesize to mediate failure of ERBB2 therapy in 
GEA: adaptive resistance and genetic complexity. To perform these studies, our team of 
investigators with complementary skill sets will both perform detailed assessment of optimal 
approaches to stably inhibit ERBB2 using an array of patient-derived model systems. 
Furthermore, we will perform a prospective clinical collection spanning multiple large academic 
medical centers in which we evaluate the genetic evolution of ERBB2+ GEAs during therapy, 
define genetic alterations that accompany resistance and then functionally validate mechanisms 
of resistance and optimal combination therapy. We will also explore the role of cell-free (cf)DNA 
genomic profiling to guide therapy in the face of genomic evolution of the disease during 
therapy. The overall goal will be to validate candidate resistance mechanisms and seek to 
define optimal combination therapies that can overcome them. We therefore propose the 
following Specific Aims: Aim 1: To define mechanisms of adaptive resistance to ERBB2 
therapy in GEA patient samples and to develop optimal targeted combinations to stably inhibit 
ERBB2 activity in GEA model systems. Aim 2: To evaluate genetic etiologies of resistance by 
determining how frequently resistance results from ERBB2-negative subclones or from 
secondary genomic alterations in ERBB2+ tumor cells. Aim 3: To validate mechanistically the 
capacity of secondary genomic alterations to promote Trastuzumab resistance and to test 
combination therapies to overcome resistance. In summary, we will define genetic and non- 
genetic mechanisms of resistance to ERBB2 therapy. Ideally, our studies will lead to the 
development of active/optimal candidate therapies that work well in first-line therapy as well as 
in in tumors marked by acquired resistance to current therapy.

## Key facts

- **NIH application ID:** 10456161
- **Project number:** 5P50CA127003-14
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Sandra Ryeom
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,216
- **Award type:** 5
- **Project period:** 2007-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456161

## Citation

> US National Institutes of Health, RePORTER application 10456161, Project 4 - Characterizing and Overcoming Resistance to ERBB2 Directed Therapy in Metastatic Gastric and Esophageal Adenocarcinoma (5P50CA127003-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10456161. Licensed CC0.

---

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