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Chemical probing of transcriptional RAS effectors

Objective

Targeted therapies have been widely used in tumors driven by RAS oncogenes. Unfortunately, no effective RAS inhibitors have been translated to the clinic, and attempts to block other signaling nodes usually fail due to the emergence of drug resistance. Chromatin dependent signal transduction and transcription are a point of confluence of multiple signaling networks elicited by hyperactive RAS. Hence, pharmacologic disruption of gene-regulatory dependencies imposed by mutant RAS represents an attractive therapeutic interface less prone to the emergence of resistances. The urgent clinical need of RAS-related therapies is well exemplified by pancreatic cancer, one of the most aggressive and deadly cancers, which will be the disease background of my studies.
Using the innovative approach of targeted protein degradation, I want to characterize and understand the consequences of acute mutant KRAS degradation on chromatin remodeling and transcription. Further engineering the models of acute KRAS degradation will enable to devise cellular reporters of KRAS-dependent chromatin regulation amenable to high-throughput phenotypic drug and genetic screens. Coupled to a facile readout via high-throughput microscopy, these screens will allow me to identify molecules and genetic perturbations that interfere with KRAS-dependent, transcriptionally active chromatin. Lead molecules will be characterized for the underpinning mechanism of action and assessed for therapeutic potential. Building on already existing experimental and computational pipelines in the Winter laboratory at CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, this project will increase the understanding of transcriptional control elicited by oncogenic KRAS and could open new avenues for the treatment of RAS-driven tumors based on chemical modulation of critical chromatin and transcription regulators.

Fields of science (EuroSciVoc)

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

(opens in new window) H2020-MSCA-IF-2017

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Coordinator

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 178 156,80
Address
LAZARETTGASSE 14 AKH BT 25.3
1090 Wien
Austria

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Region
Ostösterreich Wien Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 178 156,80
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