PhD Scholarship project 1

SBBS Research Scholarships 2023: Project 1

Inhibition of oncogenic RAF and RAS signalling through disruption of protein-protein complexes

PI: (opens in a new window)Dr Jens Rauch


Project description:

Applications for a 4-year structured PhD are invited from ambitious and enthusiastic individuals to join the group of Dr. Jens Rauch at Systems Biology Ireland, University College Dublin. Our group has identified crucial targetable protein-protein interactions that mediate oncogenic RAS and BRAF signalling in human cancer. This PhD project focuses on the in vitro and in vivo characterization of existing lead compounds in human cancer and Zebrafish models.

RAS and RAF genes are the most frequently mutated oncogenes in human cancer. Despite targeted therapies against RAF and RAS are or becoming available, respectively, unmet clinical needs remain due to the development of resistance and lack of efficacy in important cancer types, such as malignant melanoma, pancreatic and colorectal cancer. Our recently published data suggest that RAS mutated cancers can be successfully targeted by using synergistic combinations of specific, structurally diverse RAF inhibitors (Rukhlenko, Rauch et al., Cell Systems, 2019 and Imoto, Rauch et al. Biomolecules, 2023). With RAF kinases being inhibited by this approach, RAS mutated cancers seem to compensate this by driving oncogenic signaling through alterative signaling pathways (Liu, Rauch et al. IJMS, 2023). We have identified a number of novel signalling complexes as targetable protein-protein interactions (PPI) that mediate oncogenic RAS and BRAF signalling in human cancer. This PhD project focuses on the in vitro and in vivo characterization of existing lead compounds in human cancer and Zebrafish models.

The successful PhD candidate will benefit from this highly interdisciplinary research approach and environment and will have the possibility to study signalling complexes and drug development from different angles incl. in vitro characterization, molecular and cell biology, drug development, cancer therapeutics and Zebrafish models. This projects aims to test a new pharmacological principle to inhibit RAS and RAF mutated cancers and establish potentially a new class of drugs that protein complexes. The long-term plan is to establish a patent protecting this class of compound and license the compounds to pharma.

Techniques to be employed:

• In vitro characterization of chemical derivatives (e.g. protein expression and purification, ELISA, Co-IP, SPR and Fluorescence Polarization (FP) assays).
• Cell-based characterization of lead compounds (e.g. eukaryotic tissue culture techniques, 2D and 3D cancer cell models, assays for cell proliferation, invasion and transformation)
• In vivo testing of lead compounds using advanced Zebrafish models

Applications for a 4-year structured PhD are invited from ambitious and enthusiastic individuals to join the group of Dr. Jens Rauch at Systems Biology Ireland, University College Dublin. Our group has identified crucial targetable protein-protein interactions that mediate oncogenic RAS and BRAF signalling in human cancer. This PhD project focuses on the in vitro and in vivo characterization of existing lead compounds in human cancer and Zebrafish models.

RAS and RAF genes are the most frequently mutated oncogenes in human cancer. Despite targeted therapies against RAF and RAS are or becoming available, respectively, unmet clinical needs remain due to the development of resistance and lack of efficacy in important cancer types, such as malignant melanoma, pancreatic and colorectal cancer. Our recently published data suggest that RAS mutated cancers can be successfully targeted by using synergistic combinations of specific, structurally diverse RAF inhibitors (Rukhlenko, Rauch et al., Cell Systems, 2019 and Imoto, Rauch et al. Biomolecules, 2023). With RAF kinases being inhibited by this approach, RAS mutated cancers seem to compensate this by driving oncogenic signaling through alterative signaling pathways (Liu, Rauch et al. IJMS, 2023). We have identified a number of novel signalling complexes as targetable protein-protein interactions (PPI) that mediate oncogenic RAS and BRAF signalling in human cancer. This PhD project focuses on the in vitro and in vivo characterization of existing lead compounds in human cancer and Zebrafish models.

The successful PhD candidate will benefit from this highly interdisciplinary research approach and environment and will have the possibility to study signalling complexes and drug development from different angles incl. in vitro characterization, molecular and cell biology, drug development, cancer therapeutics and Zebrafish models. This projects aims to test a new pharmacological principle to inhibit RAS and RAF mutated cancers and establish potentially a new class of drugs that protein complexes. The long-term plan is to establish a patent protecting this class of compound and license the compounds to pharma.

Techniques to be employed:

• In vitro characterization of chemical derivatives (e.g. protein expression and purification, ELISA, Co-IP, SPR and Fluorescence Polarization (FP) assays).
• Cell-based characterization of lead compounds (e.g. eukaryotic tissue culture techniques, 2D and 3D cancer cell models, assays for cell proliferation, invasion and transformation)
• In vivo testing of lead compounds using advanced Zebrafish models

Your profile:

• BSc or MSc in biomolecular, biomedical sciences or pharmacology. First Honours.
• Experimental experience in molecular cell biology, biochemistry or pharmacology using cancer cell line models (e.g. protein purification, Co-IP, ELISA, eukaryotic cell culture, proliferation/migration assays); basic knowledge of drug development or Zebrafish models is of great advantage.
• Highly motivated academic and creative achiever, a quick learner and extremely enthusiastic about science and discovery beyond own project scope.
• Having excellent communication and organisation skills with ability to manage multiple tasks independently as well as working in a highly interdisciplinary research environment.
• EU/UK applicants only.

For more information on the project, please contact Dr. Jens Rauch ((opens in a new window)jens.rauch@ucd.ie).

• EU tuition fee + €22,000 tax-free stipend per annum over four years. 
• Each student will be enrolled in a structured PhD programme, associated with SBBS.
• Each student is required to demonstrate in appropriate laboratory practicals as part of their funded scholarship.  Demonstrating hours and lab practicals are detailed and assigned by the SBBS Demonstrating Committee (maximum hours: 288 per annum).  Students will be remunerated at standard UCD demonstrating rates.
• (For more information: https://www.ucd.ie/sbbs/study/researchprogrammes/)

Please email your motivation letter, CV (including final grades/transcripts) and contact details of two referees to: Jens.rauch@ucd.ie

Closing date: Friday 16th August 2024