Mobiele menu

Towards individualized therapy in bladder cancer: new molecular targets and biomarkers

Projectomschrijving

In dit VENI-project zijn verschillende aspecten van gerichte behandelingen bij blaaskanker onderzocht. Respons op
chemotherapie voorafgaand aan een operatie lijkt beter te zijn indien bepaalde genetische veranderingen (mutaties in ERBB2)
aanwezig zijn. Daarnaast kan respons op chemotherapie met het meten van veranderd DNA in urine of bloed gevolgd worden.
Momenteel worden FGFR remmers onderzocht voor de behandeling van blaaskanker met veranderingen in de FGFR genen.
Ons onderzoek laat zien dat deze remmers wel eens beter zouden kunnen werken in combinatie met andere remmers.
Indien deze bevindingen bevestigd worden in grotere studies, zou dit de behandeling meer gericht kunnen maken op specifieke
aspecten van een individuele tumor, “personalized medicine”.

Producten

Titel: Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer
Auteur: Patel, K. M., van der Vos, K. E., Smith, C. G., Mouliere, F., Tsui, D., Morris, J., Chandrananda, D., Marass, F., van den Broek, D., Neal, D. E., Gnanapragasam, V. J., Forshew, T., van Rhijn, B. W., Massie, C. E., Rosenfeld, N., van der Heijden, M. S.
Magazine: Scientific Reports
Titel: A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma
Auteur: Wang, Liqin, Šuštic, Tonci, Leite de Oliveira, Rodrigo, Lieftink, Cor, Halonen, Pasi, van de Ven, Marieke, Beijersbergen, Roderick L., van den Heuvel, Michel M., Bernards, René, van der Heijden, Michiel S.
Magazine: European Urology
Link: https://www.sciencedirect.com/science/article/pii/S0302283817300374?via%3Dihub
Titel: ERBB2 Mutations Characterize a Subgroup of Muscle-invasive Bladder Cancers with Excellent Response to Neoadjuvant Chemotherapy
Auteur: Floris H. Groenendijk Jeroen de Jong Elisabeth E. Fransen van de Putte Magali Michaut Andreas Schlicker Dennis Peters Arno Velds Marja Nieuwland Michel M. van den Heuvel Ron M. Kerkhoven Lodewijk F. Wessels Annegien Broeks Bas W.G. van Rhijn Rene´ Bernards Michiel S. van der Heijden
Magazine: European Urology

Verslagen


Samenvatting van de aanvraag

RATIONALE Bladder cancer is the fifth most common cancer worldwide and is diagnosed in approximately 5000 patients in the Netherlands each year. For patients with metastatic bladder cancer, platinum-based chemotherapy is the mainstay of treatment. Although initial response rates are high, almost all patients with metastatic cancer will eventually present with platinum-refractory disease. For this group of patients, treatment options are limited and new therapeutic approaches are urgently needed. Genetic activation of kinases causing oncogenic pathway activation could provide new targets for treatments. Comprehensive molecular studies investigating critical pathways are needed to improve the treatment of metastatic bladder cancer. AIM To find new molecular targets for the treatment of metastatic bladder cancer and improve the use of known targets by exploring biomarkers and mechanisms of resistance. KEY OBJECTIVES 1. To analyze high-risk bladder cancers for oncogenic activation of kinases by mutation, amplification or translocation. 2. To find molecular mechanisms of resistance to FGFR inhibition in bladder cancer 3. To design novel therapeutic strategies for the treatment of metastatic bladder cancer using a) novel molecular targets, b) targeted therapy in combination with FGFR inhibitors and c) biomarkers to select patients for treatment with FGFR inhibitors METHODS 1. Kinome sequencing We have created a clinically annotated database of over 300 bladder cancers. The DNA and RNA of a set of 120 high-risk bladder cancers will be sequenced for genetic events activating kinases, using a next-generation sequencing assay that can discover mutations as well as genetic translocations and amplifications. The complete set of bladder cancers will be used to validate promising findings. 2. Modulators of sensitivity to FGFR inhibitors The fibroblastic growth factor (FGF) receptor is activated in a subset of bladder cancers. FGFR inhibitors are currently tested clinically. Molecular resistance of cancer cells, which is seen with virtually all targeted therapies, is likely to be a major concern. We will use large collections of siRNA’s to selectively silence specific genes in bladder cancer cells, to study the effect on the sensitivity to FGFR inhibition. As this approach is unbiased, functional genetic screens can uncover resistance mechanisms that have remained overlooked by hypothesis-driven research. Additionally, we will explore the perturbations in phosphorylation events caused by FGFR stimulation and inhibition. Tools for these analyses include phosphorylation assays for receptor tyrosine kinases and a high-throughput method in which we look at multiple phosphorylation events in several oncogenic pathways. CLINICAL UTILIZATION This project aims to find new therapeutic strategies for advanced bladder cancer. As a result of the high number of bladder cancer patients at the NKI/AvL, and the close collaboration between laboratory research and the clinical departments, findings can rapidly be translated into clinical studies.

Onderwerpen

Kenmerken

Projectnummer:
91614036
Looptijd: 100%
Looptijd: 100 %
2013
2017
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. M.S. van der Heijden MD PhD
Verantwoordelijke organisatie:
Nederlands Kanker Instituut