Aberrant metabolism is known to be central to oncogenic transformation. Indeed, some of the first treatments empirically identified to treat cancer target metabolic pathways. Although cancers undergo metabolic transformation to promote their growth, these changes can render tumours more sensitive than non-cancerous tissues to the targeting of their metabolic network. We have identified several nodes in Acetyl-CoA metabolism that impact the growth of cancer cells under the nutrient stress conditions found in the tumour microenvironment (Schug* & Peck* et al 2015 Cancer Cell)(Peck* & Schug* et al 2016 Cancer & Metabolism). More recently, we have uncovered novel tumour suppressors, such as CREBBP, whose loss promotes growth under nutrient stress conditions (Peck et al 2021 Cancer Research). To date, there are limited therapies that target Acetyl-CoA metabolism and those that do have substantial off-target effects. Thus, there is a need to identify novel tractable nodes in Acetyl-CoA metabolism in cancer. Our preliminary evidence suggests that CREBBP is a biomarker for fundamental metabolic rewiring resulting in increased Acetyl-CoA metabolism.

During this PhD we aim to:

1) Comprehensively elucidate the metabolic architecture of CREBBP-deplete cancer models.

2) Establish key regulators of Acetyl-CoA metabolism in CREBBP-deplete cancer cells.

3) Identify and validate novel metabolic inhibitors that have anti-cancer efficacy alone and in combination with first line therapy.

This work will significantly forward our knowledge of Acetyl-CoA metabolism in aggressive cancers. All the work in the Translational Cancer Metabolism lab has a direct line of sight to the clinic, working towards the ultimate goal of responsibly and reproducibly improving lives. Ultimately, this work will provide the rationale for testing these novel dependencies in patients with aggressive cancers.

The project would be suitable for a highly motivated candidate with a background in cell and molecular biology and an interest in using interdisciplinary approaches in cancer research. Previous experience of cancer metabolism and/or mammalian 3D models is not essential but would be advantageous.

References

Peck B et al. 3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer. Cancer Research. 2021 Feb 15;81(4):847-859. doi: 10.1158/0008-5472.CAN-20-1822. Epub 2021 Jan 28. PMID: 33509944; PMCID: PMC7611219.

Peck B* & Schug ZT* et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metabolism. 2016 Apr 1;4:6. doi: 10.1186/s40170-016-0146-8. PMID: 27042297; PMCID: PMC4818530.

Schug ZT* & Peck B* et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015 Jan 12;27(1):57-71. doi: 10.1016/j.ccell.2014.12.002. PMID: 25584894; PMCID: PMC4297291.

Academic Entry Requirements

These studentships are open to graduates with

• a 2:1 or 1st degree in a related subject, with a background in cell and molecular biology

English Language Requirements

Applicants for whom English is not a first language will also require a minimum IELTS score of 6.5 (with 6.0 in the written component) or equivalent, unless your undergraduate degree was studied in, and awarded by, an English speaking country. For more information on acceptable English language qualifications please see here.

Fee Status

The funding for this studentship only covers tuition fees at the Home rate. Overseas applicants are welcome to apply, but will be required to fund the difference in tuition fees.

The studentship includes the following funding for 4 years:

• A tax-free annual stipend of £23,000
• Tuition fees at the Home fee rate*
• Project consumables

*If you are considered an Overseas student for fee purposes, you are welcome to apply for this studentship, however, you will be required to cover the difference in tuition fees.

To apply you will need to complete an online application form. Please select the Non-Clinical PhD option.

The following supporting documents will be required as part of your application:

• Your CV
• Statement of purpose
• Details of 2 referees
• Copy of your transcript(s), including a breakdown of marks
• Copy of your passport
• If applicable, proof of English proficiency

If you have a question about the project, or would like to arrange an informal discussion, please contact the supervisor directly (subject ‘PhD applicant’). For general enquiries about the PhD studentship or application process please contact the Teaching Office.

Successfully shortlisted candidates will be invited to an interview at Barts Cancer Institute.