# In Vivo Oncogene-Induced Tumorigenesis and Escape

> **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. These 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 biologically characterize and therapeutically target dormant DTCs
would be a transformational new approach to preventing 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 discovered that tumor cells that survive targeted HER2
inhibition exist in a state of cellular dormancy at both local and distant sites, and retain the ability to resume
growth and give rise to recurrent tumors for the lifetime of the animal. In addition, our preliminary data indicate
that dormant residual tumor cells that survive targeted therapy share multiple features with tumor cells that are
dormant by virtue of being exposed to microenvironmental cues in the bone marrow and other sites.
 We hypothesize that tumor cells surviving targeted therapies exist in a dormant state resembling that
induced by microenvironmental cues, that the mechanisms underlying dormancy at local and distant sites are
related, and that features of dormancy observed in mouse models are recapitulated in patients. The specific
aims of this proposal are to: (1) Determine the functional and phenotypic relationship of tumor dormancy in
DTCs surviving targeted therapy or microenvironmental selection pressures; (2) Determine whether similar
mechanisms regulate tumor dormancy at local and distant sites; and (3) Determine whether bone marrow
DTCs in breast cancer patients in the I-SPY SURMOUNT trial exhibit features of tumor dormancy similar to
those in mouse models. These aims will be accomplished using a novel flow cytometry approach to isolate
and profile DTCs in mouse models and breast cancer patients, and by functionally evaluating mechanisms
regulating dormancy on the survival and recurrence of RTCs at local and distant sites, and in contexts in which
dormancy has been induced by targeted therapy or the microenvironment. Results of the proposed ...

## Key facts

- **NIH application ID:** 10109990
- **Project number:** 5R01CA098371-15
- **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:** 2003-04-18 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109990

## Citation

> US National Institutes of Health, RePORTER application 10109990, In Vivo Oncogene-Induced Tumorigenesis and Escape (5R01CA098371-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10109990. Licensed CC0.

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