# Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $402,618

## Abstract

Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial
carcinoma
Bladder cancer is the ninth most common cancer worldwide and the fourth most common cancer in men. Despite
intensive multi-modality therapy, approximately 50% of patients with muscle-invasive disease develop distant
metastases and historically such patients had little hope of long-term survival. The development of immune
checkpoint inhibitors is the most significant therapeutic advance in bladder cancer in three decades and the
development of these agents have provided renewed hope to many patients with previously incurable metastatic
disease. Anti-PD1/PD-L1 antibodies can induce durable complete responses in patients with metastatic bladder
cancer with several immune checkpoint inhibitors are now FDA-approved for this indication. However, the
majority of patients with metastatic urothelial cancers do not benefit from immune checkpoint blockade and some
patients who initially respond later develop acquired resistance. The biologic basis for innate and acquired
resistance to immune checkpoint blockade in urothelial cancer remains poorly defined. Urothelial cancers display
a wide spectrum of variant morphologies that often co-exist within individual tumors. We have shown that this
morphologic heterogeneity is often associated with intra-tumoral mutational heterogeneity. The current proposal
is based upon preliminary data indicating that morphologic heterogeneity in bladder cancer is associated with
genomic and immune heterogeneity and is predictive of a worse response to atezolizumab (an anti-PD-L1
inhibitor). Three aims are proposed. In Aim 1, we will perform integrated histologic, genomic and immune
analyses of paired, macro-dissected, morphologically distinct areas from morphologically heterogeneous tumors
from patients treated with immune checkpoint blockade to define the prevalence and extent of intratumoral
genetic and immune heterogeneity. In Aim 2, these tissue profiling studies will be integrated with detailed clinical
and patients response data to define the role of pre-existent histologic, genomic and immune heterogeneity in
determining response to systemic immunotherapy. Finally, in Aim 3, we will study tumors collected at the time of
disease progression in patients treated with immune checkpoint inhibitors to determine whether pre-existent drug
resistant clones were present in morphologically heterogeneous primary tumors and that these less
immunogenic cancer cells are a basis for drug resistance and disease progression in patients with
morphologically heterogeneous tumors. The long-term translational objective will be to use the biologic insights
gained to develop improved biomarkers of immunotherapy sensitivity and resistance, and to develop rational
immune-based combination strategies that prevent or delay the emergence of drug resistant clones.

## Key facts

- **NIH application ID:** 10337035
- **Project number:** 5R01CA233899-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Hikmat Al-Ahmadie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,618
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337035

## Citation

> US National Institutes of Health, RePORTER application 10337035, Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma (5R01CA233899-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10337035. Licensed CC0.

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