# Harnessing the CRL4 ubiquitin ligase for antagonizing colorectal carcinogenesis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $517,885

## Abstract

Colorectal cancer (CRC) is the 4th most common cancer and the 2nd leading cause of cancer–related deaths
in the United States. The American Cancer Society estimates that 134,490 people will be diagnosed and
49,190 will die from CRC in 2016. Although biologic agents have received much attention, the first-line
chemotherapy for treatment of metastatic CRC remains based on a cytotoxic combination chemotherapy
backbone of either FOLFIRI (folinic acid+5-FU+irinotecan) or FOLFOX (folinic acid+5-FU+oxilaplatin). It is
noteworthy that only 18-25% of CRC patients respond favorably to irinotecan. Although the FDA-approved
irinotecan has been used in clinic for 20 years, there is still no diagnostic biomarker to help oncologists decide
which of the two regimens is more likely to be effective for a given CRC patient. Our studies suggest that the
CULLIN 4B (CUL4B) ubiquitin ligase is a promising predictive biomarker, as well as a therapeutic target for
tumor response to irinotecan. The CUL4B gene has been found amplified or overexpressed in a wide range of
solid tumors, including colorectal, breast, lung, ovarian, and prostate cancers. Upon treatment with the
camptothecin family of chemotherapy drugs, CUL4B, but not its paralog CUL4A, targets topoisomerase I
(Top1) for degradation in cancer cells. As a result, CRCs with high levels of CUL4B expression induce
excessive destruction of Top1, effectively attenuating the cytotoxicity of this chemotherapy drug. We
hypothesize that excessive Top1 degradation by CUL4B is a major mechanism by which CRCs become
refractory to irinotecan. Importantly, we showed that inactivation of CUL4B, but not CUL4A, effectively
sensitized irinotecan-resistant CUL4Bhigh tumors to cytotoxic killing by Top1-directed chemotherapy drugs.
This data suggest that CUL4B is an attractive target for intervention, potentially leading to sensitization of the
75-82% CRC patients who were previously resistant to treatment with a Top1-directed chemotherapeutic agent
(e.g. FOLFIRI regimen). In three specific aims, we will (1) assess the value of CUL4B as a biomarker for
treatment decisions of CRC using our unique collection of 572 well annotated CRC patient samples treated
with irinotecan or FOLFIRI; (2) further develop and validate potent small molecule CUL4B inhibitors we
identified via high throughput screening to increase their potency and pharmacological properties; (3) examine
our lead CUL4B inhibitors that synergize with irinotecan to enhance its tumoricidal activity in vivo using CRC
cell line xenografts, genetic WNT/APC-induced intestinal and colon adenomas, and patient-derived tumor
xenograft (PDTX) models of CRC. We are uniquely prepared for both Laboratory-to-Clinic studies to develop
a predictive biomarker for irinotecan-based chemotherapy that is immediately applicable for informing decision-
making of CRC management in the clinic, and Clinic-to-Laboratory studies aimed at validating CUL4B as a
feasible drug target in pre-clinical CRC m...

## Key facts

- **NIH application ID:** 10074541
- **Project number:** 5R01CA213992-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Pengbo Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,885
- **Award type:** 5
- **Project period:** 2017-01-17 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074541

## Citation

> US National Institutes of Health, RePORTER application 10074541, Harnessing the CRL4 ubiquitin ligase for antagonizing colorectal carcinogenesis (5R01CA213992-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10074541. Licensed CC0.

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