Role of the SWI/SNF complex in the Androgen Receptor cistrome regulation

Project Information

RegARcis

Grant agreement ID: 896909

DOI

10.3030/896909

Project closed

EC signature date 11 March 2020

Start date 31 March 2020

End date 30 March 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 160 932,48

EU contribution

€ 160 932,48

Coordinated by

FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE
Spain

Periodic Reporting for period 1 - RegARcis (Role of the SWI/SNF complex in the Androgen Receptor cistrome regulation)

Reporting period: 2020-03-31 to 2022-03-30

Summary of the context and overall objectives of the project

Lineage plasticity and trans-differentiation towards cancer cellular state that no longer depends on the drug target and becomes insensitive to the targeted therapy is increasingly renowned as a mechanism of therapeutic resistance. While this has been observed in prostate cancer patients with castration resistant prostate cancer (CRPC) tumors that progress upon anti-androgen receptor (anti-AR) therapies, the molecular boosters remain elusive, thus hampering the development of novel therapeutic strategies. The significance of epigenetic deregulation is a very hot topic in current prostate cancer (PCa) research. New mutations have been identified in several epigenetic regulators known for their interaction with the androgen receptor (AR). Therefore, this MSCA project aimed at elucidating the role of epigenetic regulators such as Nsd2 and the SWI/SNF chromatin-remodeling complex in the emergence of resistance to anti-AR signaling inhibitors in the malignant phenotype of PCa. To achieve this goal during this MSCA, Dr. Rana EL BIZRI (MSCA-IF recipient) and her mentor Dr. Alvaro Aytes (i) explored the potential benefits of targeting Nsd2 and/or the core components of the SWI/SNF complex (Baf155 and Baf170) in CRPC specifically in NPp53 cells; (ii) investigated the changes in the chromatin accessibility mediated by Nsd2 loss and upon anti-AR treatment (e.g. Abiraterone); and (iii) defined the Nsd2-dependent AR interactome.

Dr. Rana EL BIZRI (MSCA-IF recipient) and her mentor Dr. Alvaro Aytes concluded during this action that (i) Nsd2 overexpression co-operates with AR to drive metastatic CRPC and resistance to anti-AR therapies; (ii) Nsd2 antagonizes with the SWI/SNF complex and confers resistance to AR signaling inhibitors; (iii) Nsd2 is a potential therapeutic target to re-sensitize metastatic CRPC to anti-AR therapies; (iv) and that targeting the core component of SWI/SNF subunits in the presence of Nsd2 is not efficient to re-sensitize metastatic CRPC to anti-AR therapies. Together, our data suggests that Nsd2 overexpression drives aggressive castration resistant and androgen independent PCa in part through destabilizing SWI/SNF interaction and altering the specificity of the AR cistrome.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Dissemination and Exploitation activities: All the results raised during the course of this action will be published soon in a peer-review journal like “Nature Cell Biology”. The research paper is generally entitled by “The role of the epigenetic regulators Nsd2 and SWI/SNF complex in castration resistant prostate cancer”, and will be available to the research community through open access journal, in order to make the scientific observations generated during this MSCA freely available to the scientific community and to the general public as well. Additionally, IDIBELL institute, where this action took place, has a close proximity to both hospital centers (Bellvitge University Hospital and ICO) and academic center (University of Barcelona), promoting Dr. EL BIZRI to communicate with investigators of both clinical and basic research through (in person meetings and online seminars/conferences due to COVID pandemic). Moreover, “No website has been developed for the project”.
o Conference, workshop attendance, and /or seminar presentations:
8 virtual national and international conferences and seminars were attended by Dr. Rana EL BIZRI during this action. Due to COVID, a lot of internships and in person meetings were cancelled and thus the mobility funding amount was not used.

Communication and outreach activities: Communication and public engagement strategy is central in the MSCA fellowship and I am enthusiastic about communicating my research and my inspirational story about getting to this position to scientific and lay audiences. Therefore, my communicational activities during this MSCA year are as following: i. Scientific Twitter account: Dr. Rana EL BIZRI (MSCA-IF recipient) has created Twitter account @Eb90Rana with the idea of offering access to the research progress and reinforces outreach and knowledge transfer. This twitter account serves the broad purpose of being a window to the life of a MSCA fellow and a scientist in the biomedical field in Europe and Worldwide. Specifically, Dr. EL BIZRI posts scientific news for (conferences, workshops, seminars, publications, etc.), videos for the support of cancer patients worldwide, and innovative personal videos like disseminating her idea about creating of scientific passport. Notably, Dr. EL BIZRI always uses a format and vocabulary suitable for all audiences with the hash tag of #MSCA; #womeninscience; #academictwitter and #prostatecancer.
ii. Participating in activities to young students in Lebanon and Spain. I am volunteering to make inspirational and scientific presentations to young students in Lebanon where I talked about my path towards the MSCA fellow.
iii. Communication in the mass media: I did with my team members at Aytes Lab an international scientific video for “Movember” event to raise awareness of men´s health issues, such as prostate cancer in both November 2020 and 2021. This video was shared at the outstanding IDIBELL and ICO communication units. Plus, I am volunteering to communicate via facebook and emails with the “Lebanese scientific community”

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Impact: This MSCA addresses 2 Overarching Challenges in Europe, (I) “to develop effective treatments and understanding mechanisms of resistance for men with high-risk metastatic prostate cancer”, and (II) “to develop strategies to prevent progression to lethal prostate cancer”.

(I) The project mainly focused at identifying potential new targets for therapeutic intervention and possibly new drugs to be evaluated in appropriate clinical settings. This will accelerate the design of interventional studies to assess the feasibility and efficacy of these targets and drugs singly or in combination with standard of care, with direct implications for PCa patients, initially in clinical trials. Considering the limited available therapeutic options, none of them curative, for patients who have progress into androgen insensitive phenotypes, including NEPC, this is potentially a real breakthrough. Therefore, this actin directly addresses the Overarching Challenges of developing effective treatments and understanding mechanisms of resistance for men with high-risk metastatic prostate cancer.
(II) Since Dr. EL BIZRI also intent at validating the epigenetic remodeler such as Nsd2 and the SWI/SNF subunits as modulators of AR signaling and causally linked to therapy failure, these partners will become ideal candidates for biomarkers of disease outcome, including those that can predict what patients may benefit from new targeted therapies. Additionally, these will become the object of follow up studies to assess whether these proteins can be readily detected in liquid biopsies like plasma or urine. Thus, this proposal also addresses the Challenge of developing strategies to prevent progression to lethal prostate cancer.
This MSCA project sheds light into the fundamental mechanisms governing AR signaling and functional output in androgen dependent and independent states and provides rationale and testable hypothesis for personalized medicine approaches, in which targeting the AR signaling axis may be counterproductive for a subset of patients with molecular make up, who may better benefit from other treatments including targeted therapies and/or chemotherapy.

Schematic representation of the role of epigenetic regulators (Nsd2 and SWI/SNF complex) in androgen