# Effective combination therapy for MTAP-deficient bladder carcinoma by targeting metabolic vulnerability and modulating tumor immune microenvironment

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $535,778

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term goals of this project are to define the mechanisms of resistance to immunotherapy and to develop
effective therapies for patients with metastatic bladder cancer (BC). The overall objective of this proposal is to
establish successful combination therapies for patients with a specific genomic subset of metastatic BC
harboring homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene from the chromosome
9p21 region. Although novel immune checkpoint therapy (ICT), including anti-PD1/PD-L1, provides substantial
benefits to patients with metastatic BC, response rates are usually modest at 15% to 25%. This is partly because
this biologically heterogeneous cancer is still treated clinically as a uniform disease. Therefore, identification of
specific genomic subtypes of BC that confer insensitivity to ICT may provide novel opportunities to improve
clinical responses. We have confirmed that ~1/4 of BC contain homozygous deletion of MTAP (MTAPdef) from
the 9p21region. The MTAP gene encodes for an essential enzyme to catalyze methylthioadenosine (MTA) in
the salvage pathway for adenine synthesis. Tumor MTAPdef leads to both immunologic and metabolic
consequences. Immunologically, tumor MTAPdef results in accumulation of its substrate MTA, which acts through
the adenosine 2B receptor (A2BR) to inhibit IFN signaling and T cell function. Therefore, MTAPdef BC may foster
a “cold” tumor immune microenvironment (TIME) unfavorable to ICT. Metabolically, tumor MTAPdef results in a
lack of salvage pathway adenine synthesis; thus, MTAPdef BC should be very sensitive to the cytotoxic effects of
anti-folate agents (e.g., pemetrexed), which effectively inhibit de novo adenine synthesis. This concept is
confirmed by pre-clinical and clinical data to be presented. Importantly, our data also indicate that pemetrexed
increases tumor immune cell infiltration and PD-L1 expression and thus may sensitize BC to ICT. Based on
these data, we hypothesize that, by targeting the metabolic vulnerability of MTAPdef BC and directly modulating
its tumor immune microenvironment, effective combination therapies can be established for MTAPdef BC. To test
this hypothesis, we proposed two Specific Aims: (1) Define the immunological consequences of MTAPdef in BC;
(2) Identify successful combination therapies specifically targeting MTAPdef BC. Patient-derived BC tissues, gene
knockout and “rescue” mouse BC models, and samples from an IRB-approved clinical trial will be used to
address these goals. At completion, we expect to establish the contribution of MTAPdef and/or loss of adjacent
genes such as CDKN2A in the 9p21 region to the BC TIME. In addition, we will determine the extent of TIME
modulation by pemetrexed +/- avelumab (anti-PD-L1) in relation to their therapeutic efficacy in patients with
metastatic BC. Furthermore, we will define the preclinical therapeutic benefits of triple combination treatment
with pemetrexed, anti-PD-L1, and A2...

## Key facts

- **NIH application ID:** 10449255
- **Project number:** 5R01CA254988-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jianjun Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,778
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449255

## Citation

> US National Institutes of Health, RePORTER application 10449255, Effective combination therapy for MTAP-deficient bladder carcinoma by targeting metabolic vulnerability and modulating tumor immune microenvironment (5R01CA254988-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10449255. Licensed CC0.

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