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Dissecting the role of the epigenetic reader function of TRIM24 in driving endocrine therapy-resistant prostate cancer

Applicant Groner Anna
Number 167938
Funding scheme Ambizione
Research institution Computational Systems Biology Department of Biosystems, D-BSSE ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Cancer Research
Start/End 01.10.2016 - 31.12.2017
Approved amount 194'300.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Biochemistry
Molecular Biology

Keywords (7)

bromodomain inhibitor; prostate cancer progression; castration-resistance; endocrine therapy-resistance; androgen receptor-mediated transcription; TRIM24/TIF1a protein; hormone-dependent cancer

Lay Summary (German)

Lead
Der Prostatakrebs ist eine weitverbreitete, bösartige Krebserkrankung, die im Gewebe der Vorsteherdrüse, auch Prostata genannt, entsteht. Weil das Tumorwachstum von Testosteron abhängt, werden fortgeschrittene Stadien dieses Krebses durch Hormonentzug behandelt. Im Laufe der Therapie kann jedoch eine Kastrationsresistenz eintreten und es kommt zu einem Fortschreiten der Erkrankung, die, in diesem Stadium, nicht mehr heilbar ist.
Lay summary

Über die molekularen Grundlagen dieser Progression ist noch wenig bekannt. Um neue und effizientere Methoden der Prostatakrebsbehandlung zu entwickeln ist jedoch ein detailliertes Verständnis dieses Prozesses nötig.  Unsere Studie versucht deshalb, die Rolle der epigenetischen Funktion des TRIM24 Proteins, dessen Expression in kastrationsresistenten Prostatakarzinomen erhöht auftreten kann, in der Entwicklung dieser Resistenz zu erörtern. Um dieses Ziel zu erreichen, werden wir neu entwickelte, molekularbiologische Techniken verwenden in der Hoffnung langfristig neue Therapieansaetze zu entwickeln.

Direct link to Lay Summary Last update: 25.08.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Role of steroid receptor and coregulator mutations in hormone-dependent cancers
Groner Anna C, Brown Myles (2017), Role of steroid receptor and coregulator mutations in hormone-dependent cancers, in The Journal of Clinical Investigation, 127(4), 1126-1135.

Collaboration

Group / person Country
Types of collaboration
Peter Wild/Institute of Surgical Pathology (University of Zurich) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Jean-Philippe Theurillat/ Institute of Oncology Research (Bellinzona) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Philip Jones/ MD Anderson Cancer Center (Houston, Texas) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Awards

Title Year
Young Investigator Award, C.R. Brupbacher Foundation, Zurich (Switzerland) to Anna C Groner 2017

Abstract

Title: Dissecting the role of the epigenetic reader function of TRIM24 in driving endocrine therapy-resistant prostate cancer Summary: Prostate cancer (PC) is one of the leading causes of male cancer deaths worldwide, with many men dying of metastatic outcomes. Most tumors depend on the steroid hormone androgen for growth. Therefore, endocrine therapies either based on androgen antagonists or through androgen deprivation, have been developed as targeted strategies in advanced disease. These approaches have been highly successful and prolong PC patient survival, but they are not curative. While treatment usually induces initial PC remission, most tumors relapse and progress to endocrine therapy-resistant or “castration-resistant PC” (CRPC) upon prolonged exposure. I am proposing to investigate molecular epigenetic mechanisms regulating the interplay between transcription factor recruitment and chromatin structure, that can be targeted to inhibit essential transcriptional programs in CRPC, potentially resulting in the development of novel treatments for this stage of disease.On a molecular level, androgen activates the androgen receptor (AR) transcription factor, which in turn drives oncogenic gene expression programs in PC cells. Androgen blockade by endocrine therapy strongly decreases these pro-proliferative programs, and halts tumor growth. Seemingly paradoxical, CRPC, which is resistant to endocrine therapy, still depends on sustained transcriptional activation by AR, even in the absence of hormone stimulation. How the genomic function of AR is “reprogrammed” in CRPC cells and how this can be targeted for epigenetic therapies will be addressed through experiments described in this proposal. I will assess if the histone acetyl-lysine (H3K23ac) reader TRIM24 regulates oncogenic transcriptional programs in CRPC by anchoring AR to the genome, and will establish if this interaction can be targeted to block AR function with TRIM24 selective inhibitors. The proposal has two major aims:Aim 1. Identify AR-dependent transcriptional programs regulated by the interaction between H3K23ac and TRIM24 in PC cells. Generating a TRIM24-dependent and CRPC-specific AR transcriptional signature in cells and using it to query PC patient gene expression will establish if disrupting the interaction between TRIM24 and chromatin is a therapeutic option to block AR function in CRPC.Aim 2. Assess if the interaction between TRIM24 and H3K23ac during mitosis contributes to the stable inheritance of AR-dependent gene expression programs in CRPC cells. Exploring the TRIM24-H3K23ac interaction on mitotic chromosomes may explain how reprogrammed AR is stably targeted to novel sites in proliferating CRPC cells. Results from these mechanistic studies will establish (i) how the epigenetic reader function of TRIM24 contributes to AR-driven oncogenic transcriptional programs in CRPC cells and (ii) how blocking this function can be translated into developing new therapeutic strategies for CRPC patients.
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