# Sensitizing Colorectal Cancer to Checkpoint Inhibitors by WNT Pathway Suppression

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $46,036

## Abstract

PROJECT SUMMARY
More than 1.8 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
800,000 deaths worldwide annually. Treatments for CRC have changed little over the past 10-15 years, though
immune checkpoint inhibitors (ICIs) have recently become an exciting therapeutic option for the treatment of
hypermutated metastatic CRC (15% of all CRCs) and various other tumor types. However, for the remaining
majority of CRC patients, there exist no effective targeted therapies. Clinical studies have revealed a correlation
between WNT pathway activation and T-cell exclusion, that may explain why ICIs do not generate anti-tumor
immune responses in CRC. Hyperactivation of the WNT signaling pathway is a hallmark and major oncogenic
driver of CRC, occurring in ~95% of tumors. Early work from our lab in mice supports the notion that WNT
signaling promotes immune suppression and regulates immune cell recruitment and that WNT pathway inhibition
can block immune suppression in established tumors. Using precision models in the lab, I will test the
hypothesis that WNT signaling drives immune suppression in CRC and inhibiting WNT signaling in CRC
will activate tumor immune responses to ICIs. To address this question, I will utilize a model system of
metastatic CRC using tumor organoid transplants—the disease setting in which ICIs are used in the clinic. Three
organoid lines will be generated to have three distinct levels of WNT activation, all of which can regulated to
undergo complete WNT pathway suppression. In Aim 1, I will determine the effect of distinct levels of WNT
signaling on effector immune populations within colon tumors. Further, I aim to test whether WNT signaling
suppression within established, WNT-active colon tumors facilitates recruitment of anti-tumor immune
populations and reverses immune suppression. The genetic approach I am employing allows for inducible and
reversible control of WNT-signaling modulation. This system is uniquely powerful to address my hypothesis as
it allows an assessment of potent WNT activation and suppression within tumor cells. In Aim 2, I aim to determine
if WNT signaling suppression stimulates immune response to ICIs resulting in tumor regression. I will first
evaluate immune responses in tumors with tumor intrinsic WNT suppression. I will then assess pharmacological
WNT pathway inhibition, that targets non-specifically but is clinically relevant, in its ability to recapitulate the
genetic findings. Identifying a safe and effective approach to stimulate anti-tumor immunity will have a profound
impact on the clinical management of CRC. Thus, we believe our work will contribute significant pre-clinical data
to develop combination therapies for the activation of immunotherapies in CRC and potentially other tumor types
with activated WNT signaling.

## Key facts

- **NIH application ID:** 10082292
- **Project number:** 5F31CA247351-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alyna Katti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10082292

## Citation

> US National Institutes of Health, RePORTER application 10082292, Sensitizing Colorectal Cancer to Checkpoint Inhibitors by WNT Pathway Suppression (5F31CA247351-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10082292. Licensed CC0.

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