Mapping cancer-specific enhancer activity that drives BCL-2 dependence in multiple myeloma

PhD position

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

A 4-year 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 stipend of €22,000. We are seeking a highly enthusiastic applicant with a passion for the scientific method and discovery. The applicant should have a 2.1 or higher Bachelor’s degree from a relevant biological discipline such as Genetics or Biochemistry. Applicants should send a C.V, cover letter and reference details to aisling.coughlan@ucd.ie.

Project:

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 is one of the classic hallmarks of cancer which makes the anti-apoptotic BCL-2 family proteins attractive therapeutic targets.

This project will define the mechanism-of-action of differential dependency of MM on BCL-2. Specifically, examining epigenetic regulation of BCL-2 expression and resistance to BCL-2 inhibition, using a combination of in vitro and primary patient samples. This will primarily involve wet-lab experimentation using genomics assays (4C-seq, CUT&RUN/CUT&Tag). 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 next-generation sequencing technologies and genomics assays. They will attend international conferences with leading experts in the field, and high profile training courses in cutting-edge genomics, such as Chromatin, Epigenetics and Gene Expression CSHL 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. The group is affiliated with the UCD School of Medicine and 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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