# Targeting Wnt-dependent colorectal cancer

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2021 · $239,304

## Abstract

Constitutive activation of WNT signaling drives the growth of a broad array of human tumors, including nearly
all colorectal cancers (CRCs). Despite this prominence, no Wnt inhibitors are currently approved for clinical
use. The major reasons for this lack of inhibitors are the paucity of druggable WNT pathway components and
the on-target gastrointestinal (GI) toxicity observed in animal models with many candidate inhibitors. Our
unpublished results show that reduced expression of Casein Kinase 1α (CK1α), a negative regulator of Wnt
signaling, is associated with decreased survival of CRC patients. These findings validate CK1α as a druggable
target in CRC. We therefore characterized a novel, small molecule activator of CK1α, SSTC3, with
pharmacokinetic properties that would allow us to target CK1α in vivo. SSTC3 attenuated CRC growth in vitro
and in vivo, prolonging the survival of a mouse colorectal tumor model and inhibiting the growth of CRC
xenografts. Importantly, SSTC3 did not exhibit significant GI toxicity. Thus, CK1α is a bona fide druggable
target in CRC, activation of which inhibits tumorigenesis without inducing the GI toxicity that has
hampered the clinical development of Wnt inhibitors. Despite this promise, many mechanistic questions
remain regarding this novel class of Wnt inhibitors, which we will begin to address here. Specifically, we
propose to i) determine how this class of small-molecules functions to activate CK1α activity, ii) identify the
CK1α substrates that drive its efficacy but limit its effect on normal GI homeostasis, and iii) develop biomarkers
that could be used to identify those CRC patients most likely to respond favorably to such inhibitors.

## Key facts

- **NIH application ID:** 10468445
- **Project number:** 7R01CA219189-05
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** DAVID J ROBBINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $239,304
- **Award type:** 7
- **Project period:** 2021-08-12 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468445

## Citation

> US National Institutes of Health, RePORTER application 10468445, Targeting Wnt-dependent colorectal cancer (7R01CA219189-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468445. Licensed CC0.

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