# Survival and Recurrence of Dormant Cancer Cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $368,288

## Abstract

Recurrent breast cancer is typically an incurable disease. Consequently, the tendency of breast cancers
to recur following treatment is the most important determinant of clinical outcome. Recurrent tumors invariably
arise from the reservoir of residual tumor cells (RTCs) that can persist in patients in a presumed dormant state
for many years after treatment of their primary tumor. As such, minimal residual disease, tumor dormancy, and
recurrence constitute fundamental manifestations of tumor progression that collectively are responsible for the
vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast
cancer progression, however, the mechanisms underlying them are largely unknown. Consequently,
understanding the biology of RTCs and elucidating the molecular pathways that contribute to tumor dormancy
and recurrence is a critical priority in cancer research.
 We propose that disabling the survival mechanisms by which dormant RTCs persist in breast cancer
patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby
improve survival. Using genetically engineered mouse models that faithfully recapitulate tumor dormancy and
recurrence, we have determined that uPAR and its binding partner, α5 integrin, are markedly down-regulated
in dormant RTCs, but are subsequently up-regulated, along with FAK activity, in spontaneous recurrent tumors
that arise with a stochastic latency period. When taken together with the observations that elevated uPAR and
α5 integrin expression are each strongly associated with an increased risk of recurrence in women with breast
cancer, we hypothesize that down-regulation of uPAR and α5β1 integrin are required for entrance into the
dormant state following therapy, and that subsequent up-regulation of uPAR/α5β1/FAK signaling promotes
mammary tumor recurrence by inducing the re-entry of dormant RTCs into the cell cycle.
 The specific aims of this proposal are to: (1) Define uPAR/α5β1/FAK pathway status in residual disease in
mice and in patients. uPAR/α5β1/FAK pathway activation will be evaluated in primary tumors, recurrent
tumors, RTC in the mammary gland, and DTC in the BM and lungs in GEM models following targeted therapy
or chemotherapy. Companion studies will evaluate the uPAR/α5β1/FAK pathway in BM DTCs, as well as
primary and recurrent metastatic tumor cells in breast cancer patients; and (2) Determine the impact of
uPAR/α5β1/ FAK pathway modulation on residual disease and recurrence.
 By probing the biology of RTCs and the pathways that contribute to tumor recurrence, the proposed
studies will advance the therapeutic goals of maintaining tumor cells in a dormant state, inducing their death by
targeting their survival mechanisms, or blocking preferred pathways of recurrence. We anticipate that this
knowledge will facilitate the development of more effective therapeutic approaches to recurrence that could
improve the treatme...

## Key facts

- **NIH application ID:** 9829098
- **Project number:** 5R01CA148774-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** LEWIS A CHODOSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,288
- **Award type:** 5
- **Project period:** 2010-09-22 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829098

## Citation

> US National Institutes of Health, RePORTER application 9829098, Survival and Recurrence of Dormant Cancer Cells (5R01CA148774-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9829098. Licensed CC0.

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