# Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $221,286

## Abstract

Abstract
 In the United States, colon cancer and rectal cancer are the third most common cancer diagnosed in
both men and women. The standard of care for stage II-III rectal cancer is neoadjuvant chemoradiation or
short-course radiation followed by total mesorectal excision. However, the response to neoadjuvant radiation
varies across patients, with some having minimal response to 10-30% having a pathologic complete response.
Pathologic complete response is associated with improved clinical outcomes including resectability, sphincter
preservation, local control, and overall survival. Therefore, novel strategies that sensitize rectal cancers to
radiation therapy will have great potential to increase pathologic response rates, improve clinical outcomes,
and support the emerging total neoadjuvant therapy paradigm and the experimental watch-and-wait approach.
The long-term goal of this project is to increase the efficacy of radiation therapy for rectal cancer by targeting
calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2). Camkk2 belongs to a family of
multifunctional Ser/Thr kinases that participate in the calcium/ calmodulin (CaM) signaling pathway and play a
crucial role in controlling energy balance, inflammation and tissue regeneration. Several studies have reported
that blocking Camkk2 using genetic approaches or the small molecule inhibitor STO-609 suppresses the
growth of breast, prostate and liver cancers in vitro and in vivo. Furthermore, in preliminary studies we found
that STO-609 sensitizes mouse colorectal cancer organoids to radiation in vitro. To investigate this question in
vivo, we pioneered novel methods to generate solitary, autochthonous tumors in the distal colon that can be
monitored with colonoscopy and reproduce the histology of human disease. In preliminary studies, we found
that focal pelvic radiation effectively inhibits growth of these tumors. These models represent a major advance
over other commonly used colorectal cancer mouse models, which develop many tumors predominantly in the
small intestine and are therefore poorly suited to studying radiation therapy of rectal cancer. Based on these
findings, we hypothesize that blocking Camkk2 signaling will improve the response to radiation in our novel
mouse models of rectal cancer.

## Key facts

- **NIH application ID:** 10312803
- **Project number:** 5R21CA256414-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Chang-Lung Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,286
- **Award type:** 5
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312803

## Citation

> US National Institutes of Health, RePORTER application 10312803, Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy (5R21CA256414-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10312803. Licensed CC0.

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