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Development of antisense morpholino oligonucleotides for the treatment of cancer

  • Full or part time
  • Application Deadline
    Tuesday, October 22, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

The development of traditional drugs such as small molecule inhibitors or monoclonal antibodies is an expensive process often hampered by the development of resistance to therapy. An alternative approach is to target genes directly with antisense oligonucleotides (ASOs). These are based on specific genetic sequences and offer the advantage of being highly selective. There are several different types of ASOs. Morpholino ASOs, invented by our industrial collaborators at GeneTools LLC, Oregon USA, require perfect base pairing over 15 bases, are chemically non-reactive, and very stable in a cellular environment. The drug Eteplirsen, now FDA approved, is a morpholino that corrects the aberrant splicing of the DMD gene and, for the first time, children with this terrible disease are able to walk.
There is now interest in developing morpholinos for the treatment of cancer. We have recently successfully designed ASO morpholinos that target the ERG oncogene, inhibiting cancer cell growth (see Jumbe et al. 2019; PMID:30296658). Some genes are specifically expressed during fetal development and re-activated in cancer cells because they provide growth advantages. These are known as oncofetal genes and are optimal targets for therapy as they are specifically active in cancer cells. These include i) the beta subunit of hCG (human chorionic gonadotropin). The main function of hCG is to protect the fetus from the mother’s immune system. hCG is re-activated in cancer cells to help evade the immune system; ii) MBNL3, an oncofetal splice factor that promotes tumorigenesis by modifying splicing of key cancer genes; and iii) IGF2BP1, an RNA-binding protein that promotes mRNA stability of important oncogenes. With GeneTools we plan to design and test morpholinos that target these and other oncofetal transcripts. It is envisaged that the morpholinos could be developed into effective cancer therapies.
The aim of this PhD is to design and test morpholino ASOs that target oncofetal transcripts in a range of cancer cell line models, evaluating their ability to knockdown their expression, and then testing their effect on key cancer cell biology parameters including proliferative capacity, apoptosis, cell migration and invasion, cell morphology and the expression of EMT markers.


Funding Notes

The studentship is available from 1 January 2020 for a period of three (3) years, subject to satisfactory progress and includes a tax exempt stipend, which is currently £15,009 per annum. In addition, full-time tuition fees will be covered for up to three years (Home/EU rates only). International applicants will be required to cover the difference between Home/EU and the overseas tuition fee rates in each year of study. Please see our fees and funding webpage for information.

References

Applicants must have a BSc(Hons) in a suitable subject area: genetics, molecular biology, biomedical science and ideally will have obtained a first class or at least a 2:1 degree. Applicants will ideally also have additional research experience, for example, through an MSc / MRes in a related area, and/or have worked as a technical/research assistant. Previous laboratory experience in a project in a related area, with experience in standard molecular biology techniques and cell culture is preferred. A recognised English language qualification is required.

How good is research at University of the West of England, Bristol in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 45.40

Research output data provided by the Research Excellence Framework (REF)

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