# P2: CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $302,814

## Abstract

Abstract
Endometrioid-type endometrial carcinoma (EEC) accounts for approximately 75% of all endometrial
carcinomas, the fourth most common cancer in women in the US. Many patients with early stage and low
grade EEC will be cured by surgery alone but for women who present with higher grade, advanced stage EEC,
more aggressive therapeutics are needed to control the disease. From TCGA data (and validated from our
own patients) we have identified four transcriptome subtypes of EEC with distinct clinicopathologic
characteristics and mutation spectra. Cluster II consists of younger, obese patients with low grade EEC yet
diminished survival. Although the Cluster II tumors had the lowest overall mutation rate, CTNNB1 exon 3
mutations were very common. These mutations were associated with activation of the Wnt/β-catenin signaling
pathway. We hypothesize that mutations in exon 3 of CTNNB1 reprogram the molecular landscape leading to
clinically aggressive EEC. Understanding of these mutations will better inform specific strategies targeting the
Wnt pathway including cyclin D and CDK4. The following specific aims are proposed to test this hypothesis.
Specific Aim 1. Test the hypothesis that exon 3 mutations of CTNNB1 alter cellular epigenetic programs, thus
suppressing the hormonal gene expression program and activating a mesenchymal/neuronal and
immunosuppressive gene expression programs. 1.1. Functionally characterize the 7 hot spot mutants by
establishing isogenic stable lines expressing each of the mutants. 1.2. Characterize the regulatory network of
mutant CTNNB1 by transcriptome and miRNA profiling of the stable lines and identify the target genes, initially
focusing on ESR1, PGR, N-cadherin, PDGFA, WNT5A, WNT5B, IL-10, and TGFB2. 1.3. Determine the
possible driver effect of N-cadherin, WNT5A, and WNT5B by gain of function or loss of function via siRNA
(individually or in combinations) and examining relevant in vitro cellular endpoints. Specific Aim 2. Establish
preclinical and clinical models to test the hypothesis that activating mutations of CTNNB1 are important drivers
of tumorigenesis. 2.1. Evaluate the effects of CTNNB1 mutation in vivo. 2.2. Utilize a 3D in vitro system to
test alternative therapeutics targeting Wnt/β-catenin signaling. 2.3. Determine if CTNNB1 mutation promotes
the formation of an immunosuppressive microenvironment in hysterectomy specimens. Specific Aim 3.
Conduct a phase II, single arm therapeutic trial of ribociclib (Novartis CDK4/6 inhibitor), letrozole, and
everolimus for advanced/recurrent EEC. We have previously shown that letrozole+everolimus is effective in a
subset of these patients. Cyclin D1 is one of the highest induced proteins in CTNNB1-mutated endometrial
carcinomas, and it interacts with CDK4/6 to promote cell cycle progression. We hypothesize that patients with
carcinomas with CTNNB1 mutation will have higher expression of Cyclin D1 and therefore be more responsive
to treatment with this combination. The tria...

## Key facts

- **NIH application ID:** 10006204
- **Project number:** 5P50CA098258-15
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RUSSELL R BROADDUS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,814
- **Award type:** 5
- **Project period:** 2003-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006204

## Citation

> US National Institutes of Health, RePORTER application 10006204, P2: CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma (5P50CA098258-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10006204. Licensed CC0.

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