Grant Number:	1R01CA307511-01 Interpret this number
Primary Investigator:	Abbosh, Philip
Organization:	Research Inst Of Fox Chase Can Ctr
Project Title:	Intratumor Heterogeneity as a Correlate of Clinical Outcome in Patients Avoiding Radical Cystectomy
Fiscal Year:	2026

PROJECT SUMMARY/ABSTRACT In 2025, patients and physicians are seeking to avoid radical cystectomy - a life altering, complicated, and expensive surgery that is often employed in the effort to cure bladder cancer - in situations where complete response to neoadjuvant therapy has been achieved. To address this desire, two clinical trials testing approaches to select patients for cystectomy avoidance have now been completed at Fox Chase. Unfortunately, many subjects who were deemed to have had complete clinical response experienced significant local or distant recurrences though. Better tools for selection of patients and for surveillance of patients who avoid radical cystectomy are needed. To this end, the genetic evolution of cancers prior to and during chemotherapy likely impacts patient clinical outcome/recurrence risk. We and others have molecular signatures of endogenous and exogenous mutagenic processes shape the bladder cancer genome. APOBEC3 is a human protein whose function is to enhance immunity through its mutagenic funcion. The unintended consequence of this protective function is the most prevalent endogenous mutagenic process that causes bladder cancer. Similarly, cisplatin is known to cause DNA damage and result in mutagenesis, and this exogenous process also results in widespread DNA alteration. The molecular signatures that result from these two processes will be studied in detail during this proposal and used to infer the origin of local recurrence in patients with clinical complete response to chemotherapy (in Aim 1) and to develop biomarkers that are positioned to translate these experiments into clinical reality (in Aim 2). The scientific hypothesis that undergirds this project is that these mutagenic processes result in increased genetic heterogeneity promoting recurrence, chemoresistance, and metastasis. The goal of this project is therefore to quantify these two mutagenic signatures over the lifetime of subjects enrolled in cystectomy avoidance clinical trials to determine the genetic origin of recurrences and to develop urinary biomarkers of recurrence. Recurrences may originate from subclinical residual disease or from new primaries that arise at remote locations within the bladder, and we will use deep whole genome sequencing to distinguish these origin stories. We will use the same approach to develop urine biomarkers that quantitate relevant mutagenic processes and genetic heterogeneity and then measure associations between heterogeneity and clinical outcome with the intent to translate this knowledge to the next iteration of clinical trials evaluating new cystectomy avoidance approaches.