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Project

Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

Funder: American Association For Cancer Research

Funding period
USD 25 K
Funding amount
Abstract
Bladder cancer (BC) is the fifth most common cancer in the US and survival for Stage II (muscle-invasive BC, MIBC) cancer approaches 50% at 5 years. The most effective treatment for MIBC include systemic therapy prior to radical cystectomy, yet half of patients are unable to receive cisplatin-based chemotherapy due to advanced age, decreased performance status or poor renal function with the overall use of only 20%. Neoadjuvant immune checkpoint blockade (ICB) for MIBC is not FDA, but was recently reported by my collaborator, Andrea Necchi in which patients received 3 cycles of pembrolizumab prior to radical cystectomy(PURE-01). PURE-01 was successful as all patients tolerated therapy, and 42% achieved a pathologic complete response with 55% downstaged to Stage I or less. Yet, half of tumors did not respond and could have potentially benefited from the addition of a second agent targeting a complimentary pathway. In BC, the FGFR pathways, predominately driven by FGFR3, are altered in up to half of BCs and are often associated with resistance to both chemotherapy and immunotherapy. One agent, rogaratinib, is an oral pan FGFR-inhibitor that demonstrated a 73% disease control rate (complete, partial and stable disease) in patients with advanced BC with FGFR1-4 overexpression. We hypothesize over-expression of FGFR genes, pathways and subtypes are enriched in ICB non-responders. Therefore, if FGFR-responsive tumors could be identified prior to treatment, combination of ICB with FGFR targeting therapy may improve the overall response resulting in a significantly improved survival.From our collaborator Dr. Necchi, 100 pre-treatment TURBT samples have been identified of patients accrued to PURE-01 study. From FFPE slides, tumors will be macrodissected and extraction of RNA will be performed using the Qiagen AllPrep FFPE RNA/DNA extraction methods. RNA will be quantified and analyzed for purity. Libraries will be constructed using Illumina platform TruSeq TotalRNA library construction followed by next generation sequencing. After alignment, trimming and differential expression analysis, we will compare differential expression of FGFR1-4, evaluate for FGFR-fusions and develop tumor subtyping to determine the frequency of “luminal” and luminal-papillary tumors between responders and non-responders to ICB. We will also compare FGFR expression with PDL1 immunohistochemistry, total mutation burden (TMB) and targeted gene sequencing analysis to identify FGFR3 mutations already performed on these tumors. Given published data on response and tolerability to rogaratinib in advanced BC, an increased frequency of FGFR alterations (expression, mutations, and/or subtype) in pembrolizumab non-responders would provide preliminary data to support a clinical trial of neoadjuvant therapy with ICB and rogaratinib for patients with MIBC overexpressing FGFs, FGF alterations or luminal subtype and FGFR alterations may be a biomarker of combination therapy.

 
31
Projects
USD 14.1 M
Aggregated funding amount
USD 615 K
Average funding amount
Project list item
Engineering Smart Solutions for Disorders of the Bladder Urothelium

Engineering and Physical Sciences Research Council

 
2019 - 2023
Project list item
Refined phenotyping and personalized targeting of muscle-invasive bladder cancer

Swiss National Science Foundation to Roland Seiler, Vera Genitsch, Franziska Singer, Federico La Manna, Marianna Kruithof-de Julio, Martina Minoli, Kiu Yan Charlotte Ng, Eugenio Zoni

USD 709,398
2019 - 2023
Project list item
Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

National Cancer Institute to RANDY F. SWEIS

USD 425,338
2018 - 2022
Project list item
Role of B-arrestins in bladder cancer progression and response to chemotherapy

United States Department of Veterans Affairs to BAL L LOKESHWAR

 
2018 - 2022
Project list item
Development of Classifiers for Novel Bladder Cancer Subtypes

Congressionally Directed Medical Research Programs to Woonyoung Choi

USD 856,134
2017 - 2018
Project list item
Development of Classifiers for Novel Bladder Cancer Subtypes

Congressionally Directed Medical Research Programs to Seungchan Kim

USD 706,947
2017 - 2018
Project list item
INTRAVESICAL ONCOLYTIC THERAPY FOR BLADDER CANCER

National Cancer Institute to ROSA MARIA DIAZ, LUKKANA SUKSANPAISAN, BRADLEY C. LEIBOVICH

USD 1,990,950
2017 - 2020
Project list item
Defining the Immune Response to Chemotherapy and Chemo-Immunotherapy in Muscle-Invasive Bladder Cancer

Bladder Cancer Advocacy Network to Tracy L Rose, William Youngkwan Kim, Matthew Milowsky, Benjamin Vincent

USD 50,000
2017 - 2018
Project list item
Development of personalized surgical algorithms for muscle-invasive bladder cancer patients

National Cancer Institute to PHILIP ABBOSH

USD 437,828
2017 - 2019
Project list item
Combining cystectomy and external beam radiotherapy for patients with muscle invasive bladder cancer: a phase II trial

Belgian Federal Science Policy Office to Valerie Fonteyne

 
2016 - 2020
Project list item
Targeting FGFR3 in muscle-invasive bladder cancer.

Bladder Cancer Advocacy Network to David J. McConkey, Colin P Dinney, Charles G Drake, Bogdan Czerniak, woonyoung choi, Trinity Bivalacqua, Noah M. Hahn, Arlene O Siefker-Radtke

USD 299,720
2016 - 2019
Project list item
Identifying Genomic Determinants of Chemoradiotherapy Response in Muscle-Invasive Bladder Cancer

Bladder Cancer Advocacy Network to Kent William Mouw, Alan D'Andrea, Jason Efstathiou, Anthony John Iafrate

USD 50,000
2016 - 2018
Project list item
Bladder Fiducial Markers and Diffusion-MRI to Optimize Bladder Chemo-Radiotherapy

National Cancer Institute to MAURICE MARCEL GARCIA

USD 1,574,130
2016 - 2023
Project list item
BladderPath: Image Directed Redesign of Bladder Cancer Treatment Pathways

NIHR Evaluation Trials and Studies Coordinating Centre to Nicholas James

USD 1,974,056
2016 - 2021
Project list item
Epigenetic regulation of bladder cancer progression

Bladder Cancer Advocacy Network to Cory Abate-Shen, Michael M Shen, David Brian Solit, Cathy Mendelsohn, Hikmat Al-Ahmadie, James M. McKiernan

USD 300,000
2015 - 2017
Project list item
Novel Approach to Facilitate Decisions in Patients w/ Muscle Invasive Bladder CA

National Cancer Institute to MICHAEL A DIEFENBACH, MATTHEW GALSKY

USD 449,777
2015 - 2018
Project list item
Investigating the cell of origin for bladder cancer

National Cancer Institute to CORY ABATE-SHEN

USD 2,359,626
2015 - 2020
Project list item
Development of novel molecular targeted therapy for bladder cancer using Hsp90 and FGFR3 inhibitors

Japan Society for the Promotion of Science to Hajime TANAKA

USD 34,532
2015 - 2018
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