# Senescence-Associated Secretory Phenotype (SASP) modulation of the tumor microenvironment as a therapeutic strategy for KRAS-driven tumors

> **NIH NIH R00** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal describes a training program to advance my academic career in the study of the tumor
suppressive barriers that are bypassed during progression to malignancy and how they can be restored for
therapeutic benefit in established tumors. Cellular senescence, a tumor suppressive process involving durable
cell cycle arrest and activation of a senescence-associated secretory phenotype (SASP), can recruit immune
cells to target and clear tumors. During my postdoctoral work, I identified molecularly targeted agents that can
reestablish senescence, SASP, and a unique form of Natural Killer (NK) immune surveillance that drives
tumor regressions and long-term survival in KRAS mutant lung cancer. This research proposal aims to
characterize and exploit the SASP to sustain immune and stromal control of RAS-driven solid tumors, with the
goal of identifying new or potentiating existing therapies for these deadly diseases. My expertise in mouse
modeling, target discovery, and the biology of senescence and immune surveillance that I have acquired
during my postdoctoral studies puts me in a unique position to significantly contribute to elucidating the role of
senescence in cancer therapy and identifying new therapeutic strategies for KRAS mutant tumors.
To accomplish the research outlined in this application, I will leverage modular and immune competent mouse
models of KRAS mutant lung and pancreas cancer, as well as methods to reestablish senescence, SASP, and
NK cell immune surveillance that I have already developed in the Lowe lab. In Aim 1, with the hypothesis that
methods to overcome NK cell dysfunction are needed to establish disease control, I will explore mechanisms
and strategies to further potentiate NK cell responses in KRAS mutant lung cancer through transcriptional and
immune profiling and functional screening. In Aim 2, the organ-specific and pleiotropic effects of the SASP on
tumor-stromal interactions in pancreas tumors will be interrogated to determine SASP factors necessary for
productive tumor control and how they impact the efficacy of standard-of-care therapies. Together, these
approaches will unveil new ways by which the SASP can be used to control KRAS-driven tumors.
To achieve the goals of this award, I will be mentored by Dr. Scott Lowe and guided by an exceptional advisory
committee I have established at MSKCC. Dr. Lowe is an internationally recognized expert in cancer biology,
and is focused on understanding tumor suppressor networks through the use of sophisticated mouse models.
The advisory committee, constituted by Dr. Lowe, Dr. Sun, Dr. Rosen, Dr. Iacobuzio-Donahue, and Dr. Rudin
will monitor and support my transition to independence. Moreover, they will provide invaluable guidance during
the process of applying and interviewing for faculty positions. MSKCC will provide me institutional support,
including resources for experimental work and career development, as well as an engaging scientific
env...

## Key facts

- **NIH application ID:** 10474386
- **Project number:** 5R00CA241110-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Marcus A. Ruscetti
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474386

## Citation

> US National Institutes of Health, RePORTER application 10474386, Senescence-Associated Secretory Phenotype (SASP) modulation of the tumor microenvironment as a therapeutic strategy for KRAS-driven tumors (5R00CA241110-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10474386. Licensed CC0.

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