# Targeting the WNT Pathway in Colorectal Cancer

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $38,135

## Abstract

PROJECT SUMMARY!
More than 1.4 million people are diagnosed with colorectal cancer (CRC) each year, and while increased rates
of endoscopic screening have led to a slight reduction in mortality, the disease still accounts for more than
600,000 deaths worldwide annually. Compounding this problem, in recent years there has been a
disproportionate increase in early onset CRC, highlighting it as a major, ongoing public health problem.
Treatments for CRC have changed little over the past 10-15 years, and we still have no effective targeted
therapies for the majority of CRC patients; new strategies are urgently needed. Hyperactivation of the WNT
signaling pathway is a hallmark and major oncogenic driver of CRC, occurring in ~95% of tumors. Indeed,
there is strong evidence from pre-clinical model systems that targeting hyperactive WNT signaling can provide
significant therapeutic benefit in CRC. However, unlike many other oncogenic signaling networks, controlling
WNT pathway activity with drugs has proven quite challenging. Relatively recent work has drawn attention to
Tankyrase (TNKS) enzymes as an exciting therapeutic target in CRC. These enzymes positively regulate WNT
signaling levels, but their activity can be inhibited by certain small molecule inhibitors. Early work has
demonstrated that TNKS inhibitors can suppress hyperactive WNT signaling and impede cancer cell
proliferation; however, those same inhibitors are extremely toxic in vivo, due to their suppression of WNT
signaling in normal intestinal stem cells.
Tumors often contain significant disruptions to their genomes, including gains and losses of large chromosome
segments. These losses are presumed to support cancer cell growth, but also lead to loss of `passenger'
genes that do not drive cancer progression, but may unintentionally `rewire' the signaling networks. I will test
the hypothesis that large chromosomal deletions, common in CRC, create a tumor-specific vulnerability for
selective inhibition of one specific Tankyrase family member – TNKS2. Because normal cells do not carry
these tumor-associated deletions, they should remain unaffected when inhibiting this single TNKS enzyme. In
Aim 1, using a combination of new CRISPR-based genome editing technology, with inducible and reversible
shRNA tools, I will determine how heterozygous and homozygous chromosome deletions impact the response
to TNKS2 inhibition. Further, I aim to test small molecule inhibitors that selectively target TNKS2. In Aim 2 I will
utilize a unique transgenic shRNA technology, developed by my mentor, to examine the toxicity and efficacy of
selective TNKS2 inhibition in vivo. This genetic approach is powerful, as it allows an assessment of potent and
systemic gene silencing without the limitation of poor drug delivery or specificity.
Identifying a safe and effective approach to disrupt hyperactivated WNT signaling will have a profound impact
on the clinical management of CRC. Thus, we believe our work will contribute ...

## Key facts

- **NIH application ID:** 10002203
- **Project number:** 5F31CA224800-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Emma M Schatoff
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,135
- **Award type:** 5
- **Project period:** 2017-09-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002203

## Citation

> US National Institutes of Health, RePORTER application 10002203, Targeting the WNT Pathway in Colorectal Cancer (5F31CA224800-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10002203. Licensed CC0.

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