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Molecular mechanisms of acquired chemotherapy resistance in colorectal cancer and their implications for novel therapeutics development

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  • Full or part time
    Dr M Gerlinger
    Dr J Choudhary
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.

Molecular mechanisms of acquired chemotherapy resistance in colorectal cancer and their implications for novel therapeutics development

Project Description:
Metastatic colorectal cancer (CRC) is the third commonest cause of cancer death worldwide. Chemotherapy remains the most effective therapeutic modality for these tumours but resistance eventually develops in all patients. Detailed insights into drug resistance mechanisms in other tumour types enabled the development of innovative drugs that overcome resistance and increase patient survival. However, the molecular details of chemotherapy resistance remain poorly understood in CRC which precludes similar advances in this tumour type.
Recent patient derived organoid (PDO) culture technologies allow establishing long-term cancer cell cultures directly from CRC patients. We have generated PDOs from chemotherapy resistant CRCs and also acquired PDOs from untreated CRCs. Exome- and RNA-sequencing of both PDO groups found no genetic alterations associated with resistance but identified genes and signalling pathways that were significantly over- or underexpressed in resistant PDOs. This supports the notion that deregulated gene expression is important for resistance.
This PhD project will use our unique PDO collection for a detailed characterization of the molecular features (including transcriptomic analysis by high throughput sequencing and proteomic characterization by tandem mass spectrometry) and of functional phenotypes (e.g. DNA damage induction, apoptotic threshold quantification, cell cycle response) of chemotherapy resistant vs sensitive CRC PDOs. These results will inform genetic (CRISPR and transgene expression) and drug screens in PDOs which will determine the key mechanism of CRC chemotherapy resistance. This will finally inform novel strategies to reverse drug resistance or to kill drug resistant CRC cells through synthetic lethality. Our overall aim is to develop new therapies and hence improve the survival of patients with drug resistant CRC.
The project is ideal for candidates seeking to learn high throughput RNA and proteomics analyses, CRISPR and molecular cell biology technologies and to obtain profound knowledge in cancer biology, genetics and drug resistance.

Keywords /Subject Areas
Cancer drug resistance
Colorectal cancer
Proteomics
Transcriptomics
Genetic screens

Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.
See icr.ac.uk/phds to apply
Applications close 11:55pm UK time on Sunday 17th November 2019

Candidates must have a first class or upper second class honours BSc Honours/MSc in Biology or a similar area



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