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Precision Medicine DTP - Cooperative Omics analysis and cell-based studies to position the first-in-class total SRC inhibitor eCF506 towards the right cancer indication


College of Medicine and Veterinary Medicine

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Dr A Unciti-Broceta , Dr A Sims , Prof N Carragher , Prof V Brunton No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Background
The discovery of SRC kinase and its role in cancer more than 40 years ago, led to a revolution in our understanding of this heterogeneous group of disorders and to the advent of targeted strategies in cancer drug discovery. The quest to inhibit SRC oncogenic activity was arguably one the first target-centric drug discovery races to be initiated in oncology. Decades of research have served to confirm that, while SRC is rarely mutated, it plays a central role in transducing numerous oncogenic signals and in the progression and resistance mechanisms of many advanced malignancies. However, despite several inhibitors being approved, clinical inhibition of SRC kinase activity has not yet translated into patient benefit.

The Edinburgh Cancer Research Centre has developed a SRC/nonABL inhibitor, eCF506 (1), that blocks SRC in an inactive conformation, providing enhanced inhibition of the SRC-FAK pathway (2). This results in highly potent and selective inhibition of cancer cells that are dependent on SRC activity and in a high therapeutic index in vivo. SRC inhibition by eCF506 mediates potent anticancer activity in murine models of breast cancer and, contrary to dasatinib (gold-standard SRC/ABL inhibitor), does not induce cardiotoxicity at active doses. The superior potency and selectivity of eCF506 provide us with a unique tool to elucidate the on-target anticancer effects and potential limitations of selective SRC inhibition.

In partnership with the Sanger Institute’s Genomics of Drug Sensitivity in Cancer (GDSC) project (4), the antiproliferative properties of eCF506 has been tested across a panel of 750 genetically-characterised cancer cell lines. As the starting point of this proposal, it is anticipated that analysis of this available dataset will serve to identify and rank the cancer types/subtypes that can benefit best from treatment with a highly selective SRC inhibitor such as eCF506 and, thereby, accelerate its clinical translation and therapeutic impact. Outputs will be supplemented with the analysis of clinical cancer datasets and then validated preclinically using a wealth of cell based assays and animal models.

Aims
We propose a multidisciplinary project that is summarised in the following aims:
Aim 1. Analyse the GDSC dataset to identify sensitive/resistant cell lines and/or potential molecular markers. The information will be supplemented by the analysis of publically-available clinical cancer datasets (e.g. TCGA) to further examine the cancer types or subtypes that might best respond to treatment.
Aim 2. Validate the sensitivity of identified cancer types/subtypes through biological assays in vitro and in vivo. This will include: cell based assays (cell proliferation, cell cycle, combination studies with approved drugs, in vitro DMPK), molecular biology (Western blot, co-IP, subcellular fractionation), animal studies (PD / efficacy studies in immunocompromised/immunocompetent models).
Aim 3. Use high-throughput mRNA / protein microarray / MS analysis in validated cancer types/subtypes and negative controls to identify markers of sensitivity at transcriptomic and post-translational pathway level (Nanostring, RPPA, mass-spec pre-and post-treatment), anticipate potential resistance mechanisms and propose evidence-driven drug combinations.

Training outcomes
The selected candidate will benefit from learning a wide range of techniques that are essential in current drug discovery, including analysis of genomics/transcriptomic/proteomics/phenomics datasets, cell assays, molecular biology techniques, DMPK/PD and in vivo cancer models.
In addition, she/he will received training/expertise from four different research groups with broad interests in cancer drug discovery: bioinformatics (Sims); kinase inhibitors / preclinical drug discovery (Unciti-Broceta); HT proteomics-transcriptomics / image-based phenotypic analysis (Carragher); in vivo cancer models (Brunton).
The student will attend postgraduate courses tailored to their specific needs to account for any gaps in their knowledge of genomic technologies and analytical techniques.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

Enquiries regarding programme: [Email Address Removed]

References

(1) Fraser, C. et al. Rapid Discovery and structure-activity relationships of pyrazolopyrimidines that potently suppress breast cancer cell growth via SRC kinase inhibition with exceptional selectivity over ABL kinase. J. Med. Chem. 59, 4697–4710 (2016).
(2) Temp, C. Preclinical investigation of the novel SRC inhibitor eCF506 in cancer. PhD thesis, Universiy of Edinburgh (2020).
(3) Unciti-Broceta, A.; Fraser, C.; Carragher, N. O. Pyrazolopyrimidines. WO/2016/185160. Priotity date: 21/05/2015.
(4) The Genomics of Drug Sensitivity in Cancer Project, www.cancerrxgene.org


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