# Analysis of tumor-stroma signaling that mediates HER2-therapy resistance in breast cancer

> **NIH NIH R00** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $232,845

## Abstract

Project abstract
Analysis of tumor-stroma signaling that mediates HER2-therapy resistance in breast cancer
Drug resistance remains a great concern in HER2+ breast cancer, and a significant portion of patients (40-75%)
will ultimately not respond to therapy. A better understanding of the causes of HER2-therapy resistance is
therefore needed, in order to improve patient outcomes. To date, investigations on mechanisms contributing to
HER2-therapy resistance have focused on tumor cell intrinsic factors that promote cell growth and survival. The
role of extrinsic signals stemming from the tumor microenvironment (i.e. stroma), however, remains unclear.
 The goal of this proposal is to investigate the role of tumor-stroma interactions in HER2-therapy
resistance and develop new strategies to re-sensitize tumor cells to therapy by (1) evaluating whether sensitivity
to lapatinib correlates with stroma-rich niches in a panel of HER2+ breast cancer models ex vivo and in vivo
(Aim 1), (2) examining tumor cell apoptotic priming as a tumor cell survival mechanism in HER2+ breast
cancer patient-derived xenografts and patient samples from the clinical trial TRIO-US-B07 (Aim 2), (3)
investigating additional tumor cell survival mechanisms by an unbiased mass-spectrometry analysis and
developing and optimizing novel combination-therapies using computational modeling and in vivo studies with
patient-derived xenograft models (Aim 3). The results from the proposed studies will lead to the identification
of microenvironmental niches and associated tumor cell signaling pathways that could serve as biomarkers for
patient stratification and provide important information for the design of rational combination therapies that will
re-sensitize tumors to treatment.
 This proposal draws on my bioengineering background and postdoctoral training in cancer biology,
however in order to ensure completion of the goals and successful transition to independence, I have also
devised a detailed training plan, under the guidance of my mentor Dr. Brugge and my advisory team Dr. Letai,
Dr. Michor and Dr. Sorger. During the mentored phase I plan to acquire new skills in (1) systems analysis and
modeling of high-dimensional proteomic datasets to elucidate tumor-stroma signaling, (2) development of
predictive mathematical models for designing effective drug combinations, (3) multiplexed
immunofluorescence to profile in situ molecular markers in tumor and stroma cells and (4) analysis of
predictive biomarkers in samples from clinical trials. The environment at Harvard Medical School presents an
excellent opportunity for training in quantitative cancer biology and maximizing the translational potential of
my research. I will also mentor students and further develop my grantsmanship and lab management skills. The
proposed research plan combined with the career development training will significantly aid me to become an
independent investigator in the field of tumor microenvironment bioengineering...

## Key facts

- **NIH application ID:** 10229397
- **Project number:** 5R00CA222554-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ioannis Zervantonakis
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,845
- **Award type:** 5
- **Project period:** 2019-09-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229397

## Citation

> US National Institutes of Health, RePORTER application 10229397, Analysis of tumor-stroma signaling that mediates HER2-therapy resistance in breast cancer (5R00CA222554-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229397. Licensed CC0.

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