Harnessing functional epigenomics to define BCL-2 dependence in multiple myeloma

PhD position

Institute: University College Dublin
Country: Ireland
More information: https://www.coughlan-lab.com/

A 4-year computational biology PhD is available in the functional epigenomics laboratory led by Dr. Aisling Coughlan. This PhD is fully funded by Science Foundation Ireland, including fees and an annual tax-free stipend of €22,000. We are seeking a highly enthusiastic applicant with a passion for the scientific method. Applicants should have a 2.1 or higher Bachelor’s degree from a relevant biological discipline such as Genetics or Computer Science.

Project description

Multiple Myeloma (MM) is an incurable disease with an extremely poor 10-year survival rate (~29%). It is caused by uncontrolled proliferation of the plasma cells. Over the last decade there have been several advances in its treatment, such as immunomodulators and proteasome inhibitors, however it remains incurable.

Unfortunately, therapy resistance remains a major challenge, as resistant cells eventually regrow, causing relapse. Cancer cells evade programmed cell death through the activity of anti-apoptotic BCL-2 family proteins. An imbalance in this complex interplay of the BCL-2 family can result in unrestricted cell proliferation. Due to its anti-apoptotic function, many cancers become dependent on BCL-2 to evade cell death. In particular, MM patients harbouring the t(11;14) translocation have a strong dependence on BCL-2. This process of is one of the classic hallmarks of cancer which makes the anti-apoptotic BCL-2 family proteins attractive therapeutic targets.

This project will identify the key epigenetic regulators of MM sensitivity to BCL-2 targeting drugs. It will focus on analysing functional genomics data (4C-seq, CRISPR screen, CUT&RUN/CUT&Tag) on in vitro and primary patient samples, to identify sensitizing targets to BCL-2 inhibitor therapy. This inter-disciplinary project will involve close collaboration with clinical haematologists at St. Vincent’s hospital, wet-lab & computational biologists and international research groups. The successful applicant will gain experience in analysis of next-generation sequencing technologies and work alongside some of the leading computational biologists in Ireland. They will attend international conferences with experts in the field, and high-profile training courses in genomic analyses, such as CSHL Advanced sequencing technologies course.

Lab description

Our work is focused on leveraging epigenomic and functional genomics methods to find new therapeutic avenues in difficult-to-treat cancers. With a particular focus on haematological malignancies, we are using CRISPR-Cas9 screening to uncover therapy resistance mechanisms, and to identify novel sensitizing drug targets. In close collaboration with clinical oncologists, we are also striving to understand the epigenomic differences that underlie drug sensitivity, both inter- and intra-patient. The advent of low-input and single-cell epigenomics techniques provides a hugely promising therapeutic opportunity in this area. The group is affiliated with the UCD School of Medicine. Our group is located in the UCD Conway Institute of Biomolecular and Biomedical Research, an interdisciplinary research centre exploring the mechanisms of health and disease towards the development of preventative strategies and novel diagnostic and therapeutic solutions.

Relevant Publications
- Flanagan L, Coughlan AY et al. (2024) Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma. Haematologica. PMID: 38511268
- Coughlan AY, Testa G (2021) Exploiting epigenetic dependencies in ovarian cancer therapy. International journal of cancer. PMID: 34213777

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