# Minimal Residual Disease and Mechanisms of Breast Cancer Recurrence

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $382,375

## Abstract

Project Summary
 Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality
in women, largely due to distant, incurable recurrences arising years, or even decades, after treatment of the
primary tumor. Recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells
(DTCs) that survive primary treatment and persist in the host in a presumed dormant state. Indeed, the
presence of bone marrow DTCs following treatment is independently associated with a substantially increased
risk of recurrence. At present, however, the mechanisms enabling residual tumor cells to maintain dormancy
and ultimately recur are poorly understood, and DTC-directed treatment approaches are non-existent.
Consequently, the ability to therapeutically target survival mechanisms utilized by DTCs would constitute a
transformational new approach to preventing breast cancer recurrence and the mortality associated with it.
 Increasingly, treatment for cancer patients involves targeted therapies. In particular, targeted inhibition of
HER2 in breast cancer patients in the adjuvant setting represents a clear example in which residual tumor cells
can be kept at bay for extended periods of time. Using genetically engineered mouse models that faithfully
recapitulate tumor dormancy and recurrence, we have developed an hypothesis that activation of the c-MET
pathway may be essential for the survival of human and mouse breast cancer cells subjected to chemotherapy
or targeted anti-HER2 therapy. Importantly, whereas c-MET appears to play only a limited role in primary
breast tumorigenesis, our preclinical studies suggest the possibility that activation of the c-MET pathway may
play a critical role in enabling dormant residual tumor cell survival and tumor recurrence.
 We hypothesize that effectively disabling the survival mechanisms by which DTCs persist in breast cancer
patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby
improve survival. Specifically, we hypothesize that c-MET activation contributes to the survival and recurrence
of DTCs, and that these mechanisms are recapitulated in patients. The specific aims of this proposal are to:
(1) Determine the impact of c-MET pathway inhibition on residual disease and recurrence in mice; and (2)
Determine the impact of c-MET inhibition on residual disease and recurrence in patients, by leveraging patient
samples from a novel clinical trial initiated based on findings from the initial study period for this R01
application. These aims will be accomplished using a novel flow cytometry approach to isolate and evaluate c-
MET in DTCs in mouse models and in breast cancer patients, by functionally evaluating the impact of c-MET
pathway inhibition on the survival and recurrence of DTCs following targeted therapy or chemotherapy in
mouse models, and evaluation of primary and metastatic patient samples. Results of the p...

## Key facts

- **NIH application ID:** 10174765
- **Project number:** 5R01CA143296-09
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** LEWIS A CHODOSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,375
- **Award type:** 5
- **Project period:** 2010-06-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174765

## Citation

> US National Institutes of Health, RePORTER application 10174765, Minimal Residual Disease and Mechanisms of Breast Cancer Recurrence (5R01CA143296-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10174765. Licensed CC0.

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