# NIH grant: Deciphering tumor heterogeneity, metastatic spread, and treatment resistance in advanced bladder cancer (1R01CA317052-01) — retained record

> Retained us-gov-api record from us-gov-api:nih-reporter.

Canonical: https://highsignal.app/data/records/fb48b299007a241d

[← sources](https://highsignal.app/data)


source: [us-gov-api](https://highsignal.app/data/us-gov-api) (us-gov-api:nih-reporter)  published 2026-07-02 00:00 ingested 2026-07-06 10:11

[original source ↗](https://reporter.nih.gov/project-details/1R01CA317052-01)

## retained text



```
NIH grant 1R01CA317052-01: Deciphering tumor heterogeneity, metastatic spread, and treatment resistance in advanced bladder cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Gavin  Ha. Award: $752751.
Start: 2026-07-02T00:00:00.
PROJECT SUMMARY/ABSTRACT
Metastatic bladder cancer (mBLCA) is a highly lethal disease characterized by extensive histological and
molecular heterogeneity. Histological variants such as plasmacytoid, squamous, neuroendocrine, and
sarcomatoid subtypes are associated with aggressive clinical behavior and poor outcomes. Despite recent
therapeutic advances—including cisplatin-based chemotherapy, immune checkpoint inhibitors, and antibody-
drug conjugates—the mechanisms driving treatment resistance and metastatic progression remain poorly
understood. A major barrier to progress is the lack of comprehensive resources to study tumor evolution across
multiple metastatic sites and histological subtypes.
 To address this gap, we established the Fred Hutch/UW Bladder Cancer Rapid Autopsy Program, a one-
of-a-kind resource designed to study tumor evolution and heterogeneity in mBLCA. Since 2015, we have
collected tumors and matched benign tissues from 34 patients within hours of death, with cohort enrichment for
histological variants. Multi-omic profiling of 20 patients—including whole genome sequencing, RNA-seq, and
post-mortem circulating tumor DNA (ctDNA)—has revealed that metastasis-to-metastasis seeding and
polyclonal dissemination are dominant modes of spread, particularly from early oligometastatic disease. These
findings suggest that clonal diversity and early dissemination are key drivers of poor prognosis and may be
targetable through localized therapies such as radiation.
 We hypothesize that genomic heterogeneity underlies the aggressive nature of mBLCA and significantly
influences treatment response. To test this, we propose three integrated aims: (1) delineate the role of polyclonal
seeding from oligometastatic disease in driving aggressive, treatment-resistant mBLCA; (2) elucidate the role of
the Fanconi anemia (FANC) pathway in modulating cisplatin sensitivity and genomic scarring, using mechanistic
and therapeutic perturbation studies; and (3) characterize tumor evolution and resistance mechanisms in
patients treated with enfortumab vedotin and pembrolizumab, leveraging rapid autopsy specimens and serial
ctDNA profiling.
 This proposal is conceptually and technically innovative. It leverages rare multi-organ sampling,
histological variant patient-derived xenograft models, and a novel multi-clone dosing strategy to study clonal
dynamics. It includes the first in-depth multi-omic characterization of cfDNA heterogeneity and proposes a
therapeutic rationale for targeting clonality through radiation in oligometastatic disease. Completion of this work
will provide a deep biological understanding of mBLCA progression, uncover new paradigms of treatment
resistance, and inform precision medicine strategies to improve patient survival.
```



document fetched 2026-07-12 08:14