Cancer Research UK Edinburgh Centre

Identification of new therapeutic approaches for undifferentiated pleomorphic sarcoma

Supervisors: Professor Valerie Brunton, Professor Neil Carragher, Professor Donald Salter

Sarcoma UK

Undifferentiated pleomorphic soft tissue sarcoma (UPS) is a rare cancer with a dismal prognosis for which there are very few effective treatment options. We have established a high content phenotypic screening assay applicable across a panel of molecularly defined UPS lines, which has identified potent inhibitors of UPS survival. The successful applicant will carry out detailed analysis to triage “hits”, carry out validation in further primary UPS models and understand their mechanism-of-action at the transcriptomic and post-translational pathway level. In addition, it will build on preliminary analysis of the UPS proteome to annotate the tumour microenvironment which is well recognized to be a key determinant of treatment response. This information will be used to develop 3D models of UPS. These models will provide a versatile platform that encapsulates the in vivo features of the tumour and its microenvironment, and will be used in secondary assays for exploration of hits identified in the phenotypic screen.

The overarching goal of this project is to take a more empirical, phenotypic-led, approach to the identification and mechanistic characterization of small-molecules with potent cell activity across a panel of UPS models. We anticipate that clinical translation will be supported by mapping pathway biomarkers of compound sensitivity and mechanism-of-action (MoA) to ongoing genomic profiling in UPS. This will support future patient stratification hypotheses and facilitate more successful and rapid translation of potential therapies to the clinic.

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The project builds on ongoing sarcoma research in Edinburgh and will benefit from current projects focused on understanding the genetic and immune landscape of human UPS, and development of mouse models of UPS, while providing invaluable models for evaluating further treatments and detecting vulnerabilities through drug screening platforms available at the Edinburgh Drug Discovery Unit. It will provide the student with training in a number of disciplines including drug screening, image informatics, use of primary patient-derived material and proteomics.

Application procedure

Applicants are invited to apply for this 3.5 year PhD studentship funded by Sarcoma UK and must hold a first or upper-second class UK honours degree or equivalent.  Applicants should apply via the University of Edinburgh postgraduate degree finder by 12 February 2021 at:

https://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&edition=2021&id=237

References

  1. Network, T.C.G.A.R. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell 171, 950 (2017)
  2. Cornillie, J., et al. Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing. Mol Cancer Ther 18, 1168  (2019)
  3. Moffat, J.G., Rudolph, J. & Bailey, D. Phenotypic screening in cancer drug discovery - past, present and future. Nature Rev Drug Discov 13, 588 (2014)
  4. Warchal, S.J., et al. Next-generation phenotypic screening. Future Med Chem 8, 1331 (2016)

Funding information

This is a 3.5 year PhD studentship, funded by Sarcoma UK which is open to UK and International students.  Starting stipend £15,667.