# Patient-derived organoids reveal rectal cancers develop radiosensitivity

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $243,278

## Abstract

The Fearon and Vogelstein multistep cancer progression model of colon cancer defines key genetic
changes associated with progression from normal colorectal tissue to early/late adenoma, primary
carcinoma and metastatic dissemination. Extensive research has defined genetic/epigenetic
alterations that drive colorectal cancer progression. However, systematic stage-by-stage assessment
of genetic changes associated with colorectal tumor response is limited. Recent emergence of
organoid technology has bridged the gap between cancer cell lines and xenografts, and advanced the
ability to explore therapeutic responses of tumors cultured ex vivo as organoids derived from freshly-
isolated tumor tissue. Furthermore, such patient-derived organoids (PDOs) recapitulate the
mutational spectra in colorectal cancer. Here we will employ this technology to characterize the
radiation responses of multi-stage colorectal cancer. Our biospecimen protocol (IRB-15-191) to
harvest tissue from primary human colorectal cancer and normal colorectal mucosal epithelium pre-
and post-neoadjuvant chemoradiotherapy and to grow/study PDOs therefrom has revealed 2 findings:
1) While normal colon and adenoma PDOs are radioresistant, surprisingly adenocarcinoma PDOs are
as much as 1-log radiosensitive; and 2) Selection post neo-adjuvant therapy reveals loss of
radiosensitivity. To our knowledge, these are the first data demonstrating that colorectal cancers
develop inherent radiosensitivity when progressing from normal tissue and adenoma into
adenocarcinoma. The goals of this study are: 1) To determine using foci technology the dysfunctional
DNA repair mechanism (HR, NHEJ or both) that leads to human colorectal cancer radiosensitivity and
to identify its molecular basis and 2) To determine whether the most radiosensitive cancers yield
complete response after neo-adjuvant therapy.

## Key facts

- **NIH application ID:** 10343663
- **Project number:** 5R21CA245636-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Richard N Kolesnick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,278
- **Award type:** 5
- **Project period:** 2021-02-05 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343663

## Citation

> US National Institutes of Health, RePORTER application 10343663, Patient-derived organoids reveal rectal cancers develop radiosensitivity (5R21CA245636-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10343663. Licensed CC0.

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