# Targeting regenerative reprogramming in colorectal cancer

> **NIH NIH K08** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $292,594

## Abstract

ABSTRACT
Poorly defined fitness features enable a subset of cancer cells to survive therapy, ultimately giving rise to
treatment-refractory tumors. The expanded use of sequencing tools have led to the recognition that refractory
tumors often lack a genetic mechanism of resistance, and instead co-opt a regenerative program characterized
by activation of developmental, inflammatory, mesenchymal and stem cell features. Importantly, these
regenerative states are conserved across diverse cancers of epithelial origin, and are potentially reversible. Our
preliminary data indicate that therapy resistance in colorectal cancer (CRC) is fueled by preexisting cells via a
YAP-driven regenerative program that is strikingly similar to the consensus molecular subtype 4 of CRC, a poor
risk phenotype often observed in treatment-refractory tumors.
Our central hypothesis is that a preexisting population drives regenerative reprogramming and tumor escape
through epigenetic adaptations that can be targeted therapeutically. First we propose characterizing the
preexisting (pre-resistant) state using barcode lineage tracing and single-cell technologies. Using patient-derived
organoids (PDOs) to isolate the founding clones of resistance, we will study the contribution of preexisting versus
actively gained fitness features through whole-exome (WES) and RNA sequencing (RNA-seq). Using pre-clinical
models of resistance to KRAS-inhibition (KRASi), we will define the role of genetic and non-genetic drivers of
tumor escape. To develop approaches that abrogate regenerative reprogramming, we will perform a focused
shRNA screen targeting 50 chromatin regulators. To expedite clinical translation, we will test readily available
compounds targeting the top hits of the screen, in combination with standard therapies. We believe that our
innovative tools will maximize our opportunity to develop treatment approaches with immediate clinical impact.
During the award period, the candidate will conduct research at Weill Cornell Medicine (WCM) and Memorial
Sloan Kettering (MSK) under the mentorship of Dr. Lukas Dow and an advisory committee. The candidate will
commit at least 9 person-months of his professional effort to the research and career development activities
outlined here. With his mentor and advisory committee, the candidate has designed a 5-year plan aimed at
expanding his knowledge and expertise in cancer research, including single cell technologies, computational
biology, genetic engineering, and functional screens. The goal of the career plan is to launch an independent
career as a laboratory investigator focused on therapy resistance and biomarkers of response in CRC.

## Key facts

- **NIH application ID:** 11162104
- **Project number:** 7K08CA279499-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Salvador Alonso Martinez
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $292,594
- **Award type:** 7
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11162104

## Citation

> US National Institutes of Health, RePORTER application 11162104, Targeting regenerative reprogramming in colorectal cancer (7K08CA279499-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11162104. Licensed CC0.

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