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The role of gankyrin as a fertility sparing therapy in children with cancer and men with testicular germ cell tumours.

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  • Full or part time
    Dr R Mitchell
    Prof N Carragher
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

The newly established four-year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme will combine medical science and translational research projects with integrated and credited teaching in science communication, public engagement, patient involvement, data design and informatics, via established MSc courses and/or new Engagement for Impact courses. Our vision is to teach a generation of researchers equipped to address and solve real-world problems through excellent science and who have the engagement and impact skills we believe will give them an edge in their future careers.
https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme

This potential PhD project, selectable by successful applicants to this Programme, is supervised by Dr Rod Mitchell (www.ed.ac.uk/centre-reproductive-health/dr-rod-mitchell) at the MRC Centre for Reproductive Health, with co-supervisors Dr Aaron Muth and Prof Neil Carragher

Project Summary:
Current treatments for childhood cancers and testicular tumours in adults can compromise fertility. Gankyrin is an oncogene involved in the pathogenesis of several cancers. We have recently shown that inhibition of gankyrin signalling enhances tumour cell death and reduces requirement for gonadotoxic chemotherapy in a testicular cancer cell line [1].
We hypothesise that downregulation of gankyrin signalling is an effective adjuvant treatment for testicular cancer in adult men. Conversely, we hypothesise that upregulation of gankyrin in healthy germ cells of prepubertal testis can reduce their sensitivity chemotherapy-induced damage.
The project involves validated models (in-vitro, xenograft) of testicular development and function utilising human fetal, prepubertal, adult and testicular cancer tissues [2], [3]. We will determine the in-vitro effects of several recently identified small molecules (SM) that target gankyrin [4] on normal testis and testicular cancer tissues. SM treatments will also be combined with chemotherapy to determine their potential as an adjuvant to chemotherapy in testicular cancer, and the potential for these SMs to reduce chemotherapy-induced germ cell damage in the prepubertal testis. SMs that alter cell response to chemotherapy will be taken forward into mechanism-of-action to demonstrate the anti-cancer signalling pathways perturbed and in-vivo efficacy studies involving xenografting of human tissues.

References:
[1] Camacho-Moll ME, Macdonald J, Looijenga LHJ, Rimmer MP, Donat R, Marwick JA, Shukla CJ, Carragher N, Jørgensen A, Mitchell RT. The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells. BMC Cancer. 2019 Nov 19;19(1):1124.
[2] van den Driesche S, Macdonald J, Anderson RA, Johnston ZC, Chetty T, Smith LB, Mckinnell C, Dean A, Homer NZ, Jorgensen A, Camacho-Moll ME, Sharpe RM, Mitchell RT. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Science Translational Medicine. 2015 May 20;7(288):288ra80.
[3] Jørgensen A, Macdonald J, Nielsen JE, Kilcoyne KR, Perlman S, Lundvall L, Langhoff Thuesen L, Juul Hare K, Frederiksen H, Andersson AM, Skakkebæk NE, Juul A, Sharpe RM, Rajpert-De Meyts E, Mitchell RT. Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis. Cell Reports. 2018 Nov 13;25(7):1924-1937.e4.
[4] Kanabar D, Farrales P, Gnanamony M, Almasri J, Abo-Ali E, Otmankel Y, Shah H, Nguyen D, El Menyewi M, Dukhande V, D’Souza A, Muth A. Structural Modification of the Aryl Sulfonate Ester of cjoc42 for Enhanced Gankyrin Binding and Anti-cancer Activity. Bioorg. Med. Chem. Lett. 2019 Dec 16; 126889.
Engagement for Impact:
Preventing long-term morbidity after cancer treatment and developing strategies to preserve fertility is of scientific, clinical and public interest. This provides far-reaching opportunities for engagement with a wide variety of stakeholders including cancer patients, cancer/fertility charities, policy makers, and pharmaceutical/fertility industries. The research group attracts frequent national/international attention for work in this area (e.g. BBC TV - https://bit.ly/2xyWC3K). The CRH recently ran an MRC-funded open day for schoolchildren in which PhD students led organisation and delivery of a fertility preservation programme. The group also has frequent interaction with public engagement teams locally (CRH, University Press Office), nationally (Science Media Centre) and internationally (Fertility Europe), providing opportunities for the student to develop their ideas and broaden experience of engagement. We will continue to work closely with national charities e.g. Children with Cancer UK (CWCUK) and CLIC Sargent, to raise awareness and develop a two-way interaction with stakeholders (e.g. workshops, patient forums). Previous activities included producing a public information ‘Doodle’ video (www.childrenwithcancer.org.uk/Blog/fertility-preservation), for the CWCUK website. The Carragher group has multiple interactions with pharmaceutical and biotech industry representatives and life science investors and is active in promoting academic-industry networking and industry secondments, providing the student with further opportunities for engagement.

Funding Notes

This is one of the potential projects in the University of Edinburgh College of Medicine and Veterinary Medicine’s new 4 year Medical Sciences & Translational Research PhD with integrated studies in Engagement for Impact Programme. Successful applicants will select their preferred PhD projects from the available options in discussion with proposed supervisors. Three studentships are available in the programme, providing full tuition fees (EU/UK rate only), stipend of at least £15,000 per year, £450 annual travel and conference allowance, dedicated engagement support grant of £1,500, and £5,000 annually towards research consumable costs.
Apply before 26th January 2020 at https://www.ed.ac.uk/inflammation-research/postgraduate-training/phd-programme



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