Project 1 Genetic and Immunologic Mechanisms Underlying Combination Sacituzumab plus Radiation Therapy for Bladder Cancer

PROJECT SUMMARY
Research Project 1
An organ sparing standard-of-care for patients with muscle invasive bladder cancer (MIBC) involves
concurrent chemotherapy plus radiation (RT). However, even after receiving current therapies (surgery or
chemoradiation), bladder preservation and overall survival remains low, at approximately 50-60%. The
molecular pathogenesis of bladder cancer and the mechanisms of resistance to chemoradiation remain poorly
understood. Our long-term goal is to understand the mechanisms of efficacy and resistance of bladder cancer
to radiation plus sacituzumab or cisplatin and to use this information to develop better therapeutic modalities
for bladder cancer patients. Perhaps one of most promising immunomodulatory biologicals used with radiation
is the antibody-drug conjugates (ADC). Sacituzumab govitecan (SG) is an antibody drug conjugate that
combines the anti-TROP2 antibody with an active metabolite of irinotecan. ADCs act by inducing tumor cell
damage as well as immune activation. The central hypothesis of this application is that specific genetic and
immune determinants underlie sensitivity and resistance to radiation-based combination therapies with SG
ADC versus cisplatin in MIBC patients. Our hypothesis has been formulated based on strong preliminary data
from our group. We plan to accomplish our objectives with 3 specific aims. In Aim 1, we will elucidate the
genetic and microenvironmental mechanisms that drive efficacy and resistance to combined sacituzumab plus
radiation therapy in bladder cancer. The working hypothesis here is that combinations of distinct tumor
determinants, such as somatic mutations in DDR genes, and microenvironmental features, may be important
for the anti-tumor effects of RT+SG. We will systematically elucidate the molecular, genetic, and immunologic
effects of treatment with standard-of-care radiation + cisplatin versus radiation + ADC. We will also utilize
single cell sequencing to reveal treatment-related changes in the tumor ecosystem in MIBC undergoing each
approach. In Aim 2, we will characterize tumor clonal dynamics, immune repertoire editing, and imaging
changes following treatment with sacituzumab plus radiation. We postulate that ADC therapy may induce
sculpting of both the tumor clonal variants and the immune microenvironment and associate with an improved
response to radiation treatment. We will reveal adaptive changes to radiation + cisplatin versus radiation +
ADC using comprehensive genomic, transcriptional, and immunologic profiling. We will integrate the temporal
kinetics of tumor clonality and immune repertoire editing with tumor genomics and imaging. In Aim 3, we will
examine the mechanisms of acquired resistance to radiation plus cisplatin versus radiation plus sacituzumab.
We will uncover the differential effects of these two treatment approaches, systematically characterize
emergence of driver mutations, changes in the tumor clonal composition, immune reprogramming, and identify
molecular and cellular mechanisms of acquired resistance.

Grant Number: 5U54CA274513-04
NIH Institute/Center: NIH
Principal Investigator: Timothy Chan