Defining Mechanisms of Progression and Treatment Resistance in Localized Bladder Cancer
PI: Eugene Pietzak, MD
SUMMARY
Our overall goal is to develop therapies that selectively target molecular alterations responsible for progression
of bladder cancers from non-invasive to the often-lethal muscle-invasive disease state. For patients with non-
muscle invasive bladder cancer (NMIBC), the current standard is bacillus Calmette-Guérin (BCG), a
nonspecific immunotherapy instilled directly into the bladder lumen. While BCG can reduce the risk of disease
recurrence, a proportion of patients subsequently progress to muscle-invasive bladder cancer (MIBC). Our
preliminary results indicate that this disease state, termed “secondary MIBC”, is resistant to cisplatin-based
chemotherapy. The goals in the current proposal are to understand the genomic basis for treatment resistance
to BCG and to identify alternative molecularly directed treatments that can achieve disease cure without the
need for radical surgery. The studies proposed are based on preliminary data indicating that cytotoxic
chemotherapy sensitivity in bladder cancer is influenced by somatic and germline genomic profiles, in
particular mutations in DNA damage response (DDR) pathway genes, most commonly within the nucleotide
excision repair gene ERCC2. As our preliminary data suggest that mutations in DDR pathway genes may also
confer sensitivity to BCG, we hypothesize that prior treatment with BCG results in cross-resistance to
subsequent systemic chemotherapy. To test this hypothesis, we will leverage several prospectively assembled
bladder cancer cohorts, including tumor pairs collected pre-BCG and following progression to MIBC. These
cohorts will be used to validate DDR mutations as predictors of BCG and cisplatin-based chemotherapy
sensitivity and to identify mechanisms of progression from NMIBC to secondary MIBC. As genomic
heterogeneity is common in bladder cancer, we will supplement bulk sequencing studies with multi-regional
sequencing and analysis of cell-free DNA from urine to define the influence of tumor heterogeneity on cancer
outcomes in early-stage bladder cancer. Our preliminary analyses of high-risk NMIBC and secondary MIBC
have also identified ERBB2 mutations/amplifications as potential mediators of progression to muscle-invasive
disease. Several unique patient cohorts will be used to define the frequency of ERBB2 mutation/ amplification
and HER2 overexpression in high-risk NMIBC and secondary MIBC. Prior functional studies of the role of
HER2 in bladder cancer pathogenesis have been impeded by a lack of patient-derived models with ERBB2
mutations and gene amplification. We will thus leverage a recently developed biobank of patient-derived
organoid models containing ERBB2 mutation/amplification to study the associations between ERBB2
mutational status/HER2 expression, oncogenic dependence on HER2, and sensitivity to HER2-directed
antibody drug conjugate therapy, a promising breakthrough therapy for metastatic bladder cancer. In sum, our
long-term translational goals are to use integrated clinical and laboratory studies to develop more effective
and less toxic treatments for patients with localized bladder cancer, a frequently fatal yet understudied disease.