PhD Student position: "Mechanisms and Therapeutic Targeting of NSD2 in Advanced Prostate Cancer" ...

Employer
Bellvitge Biomedical Research Institute (IDIBELL) - Catalan Institute of Oncology (ICO)
Location
Spain
Posted
November 17 2017
Discipline
Life Sciences, Biology
Position Type
Full Time
Organization Type
Academia

”la Caixa” Foundation, which firmly believes in the importance of scientific progress, research, mobility, and professional qualification for the development of society, is offering a fellowship programme for young researchers of any nationality to pursue a doctoral degree, co-funded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action.


The Bellvitge Biomedical Research Institute / Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) offers several PhD positions at the Catalan Institute of Oncology (ICO), in Barcelona (Spain).


One of them is titled "Mechanisms and Therapeutic Targeting of NSD2 in Advanced Prostate Cancer" with Dr. Alvaro Aytes as PhD Supervisor.


Research Project / Research Group Description:


Recurrence invariably occurs in prostate cancers treated with androgen deprivation therapy and for a subset of patients, this results in the emergence of a castration resistant (CRPC) phenotype that is highly aggressive and lethal. Lineage plasticity and transdifferentiation is an increasingly recognized mechanism of resistance to targeted cancer therapies. Evidence of this plasticity has been shown in metastatic prostate cancer treated with anti-androgen suggesting that regulatory programs controlling cell fate and differentiation are aberrantly activated.


Our preliminary data has identified a signature of epigenetic remodelers clearly associated to disease outcome. These include the histone methyltransferase NSD2 for which we now have evidence of interaction with the AR and modulation of its transcriptional activity. Functional studies indicate that upon NSD2 silencing, tumor growth and metastasis are delayed, while expression of pluripotency markers is prevented in the context of castration plus Enzalutamide treatment. Taken together, we hypothesize that co-targeting epigenetic programs that control AR-driven transcription in CRPC and in androgen independent tumors will have significant impact in preventing or delaying lethality in prostate cancer patients. Our objective is to identify key epigenetic remodelers causally linked to anti-AR therapy failure to design combination treatments with epigenetic drug


Our group utilizes Genetically Engineered Mouse (GEM) models and computational biology to uncover mechanisms of castration resistance and metastatic progression on prostate cancer. In particular the main areas of interest include; (i) the role of the disregulated epigenome in the acquisition of the CRPC phenotype., (ii) to identify and validate molecular classifiers to predict drug activity and resistance, and (iii) to conduct preclinical investigations in GEM models and associated in vitro cultures that are representative of clinically relevant phenotypes to test actionable targets for new drugs and/or combinations. Our lab is affiliated with the Program Against Cancer Therapeutic resistance at the Catalan Institute of Oncology and the Molecular Mechanisms and Experimental Therapeutics Department at IDIBELL.


Job position description:


We are seeking highly motivated early career scientists interested in pursuing their doctoral degree in any of the fields of of cancer biology, molecular biology, regulatory genomics and/or epigenetics.


The position is to conduct research at the Catalan Institute of Oncology (ICO, Barcelona, Spain), a public comprehensive cancer center, affiliated to the Bellvitge Biomedical Research Institute (IDIBELL). Successful candidates will have the opportunity to initiate and lead, with the supervision and guidance of the principal investigator of the project, high-quality research within the newly launched research program ProCURE (Program Against Cancer Therapeutic Resistance) at the ICO. ProCURE encourages strong clinical interactions and multidisciplinary approaches. The program offers a stimulating research atmosphere, fosters independence and provides an environment in which collaboration and exchange of ideas and know-how is actively encouraged with a strong commitment to translational research, which overall provides a lively and stimulating training environment for young talents.


In particular, the PhD candidate´s project aims at:


Aim 1. Investigating the causal role of NSD2 in aggressive prostate cancer lineage plasticity. We have crossed the Nkx3.1CreERT2; Ptenflox/flox; p53flox/flox double knockout (DKO) mice, which undergo neuroendocrine transdiferentiation upon Enzalutamide treatment with an Nsd2flox/flox allele to generate a triple knockout (TKO) mice. We will now perform (i) preclinical assays with Enzalutamide in TKO and DKO to assess whether Nsd2 is necessary for the lineage switch; and (ii) Functional validation of the dependency for NSD2


Aim 2. Investigating the changes in chromatin accessibility and AR interactome. We will define the accessible chromatin in Enzalutamide treated DKO and TKO and investigate how Nsd2 shapes the AR interactome.


Aim 3. Preclinically validate Nsd2 as a therapeutic target. Here we will test whether pharmacological inhibition of Nsd2 with small molecule inhibitors has potential clinical implications for the treatment of anti-AR resistant CRPC and/or NEPC patients.


RELATED LINK TO THE POSITION


www.alvaroayteslab.eu 


www.procure-ico.eu


To apply, you will have to follow the steps explained at la Caixa INPhiNIT website and provide the documents required under the Call for application document before the official deadline: 1st February 2018. But, if interested on this specific position, please, contact Dr. Alvaro Aytes at aaytes@idibell.cat before 10th January 2018.



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