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New approaches to treating metastatic bone disease in breast and prostate cancer


Project Description

Bone is a common metastatic site for breast and prostate cancers. Once metastasised to bones, one-year survival for prostate cancer is 29% (4) compared with 59% for breast cancer. (5) However, 5 year survival for breast cancer with bone metastases drops to 13%. (6) At 5 years only 3% of patients with prostate cancer that has spread to the bone survive and if these require surgical intervention, survival at 5 years drops to less than 1% (7).

In bone, cancer cells can weaken the bone structure, resulting in breaks, which can lead to fractures without preceding injury, known as pathological fractures. Treatment usually involves surgical stabilisation with intramedullary (IM) nails (metal rods placed inside the bone) followed by radiotherapy to the affected bone after the wounds have healed. The delay in commencing radiotherapy is to avoid wound complications should radiotherapy precede surgery. However, the concern with the current treatment approach is the risk of widespread dissemination of malignant cells e.g. in the form of circulating tumour ells (CTCs) that could give rise to new secondary deposits in other organs especially since visceral metastases carry a worse prognosis than bone metastases alone (1).

Through NHSG endowment grant awarded to the applicants, we have piloted an alternative approach, testing the hypothesis that by reversing the current treatment order, to radiotherapy followed by surgery, it may be possible to reduce the micro-metastatic potential following surgery by killing more tumour cells. Having provided proof of principle, we now wish to expand this work by exploring the biology of CTCs liberated from bone using the 2 types of operative procedures.

We are seeking a highly motivated student, to join our team. The student will work on developing methods to isolate and characterise CTCs from blood samples using flow cytometry. CTCs will be characterized extensively using further flow cytometry methods, immunocytochemistry / immunofluorescence and cell viability will be determined. As CTC phenotype may potentially predict response to alternative treatments driven by hormone/growth factor receptors, these will be profiled in CTCs making these cells targets, potentially, for different therapeutic interventions. Allied to this RNA-seq will be conducted on CTCs to analyse the transcriptome to identify potential therapeutic targets acquired in metastatic disease. This will be compared to historic samples obtained prior to the development of metastases and a cohort of patients will be recruited prospectively to study CTC receptor switch in relation to tumour stage and progression.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php

Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

References

1. Donnelly TD, Woolf DK, Farrar NG. Management of metastatic bone disease in the appendicular skeleton. Bone & Joint360. 2018;7(1).

2. Hall JA, McKee MD, Vicente MR, et al. Prospective Randomized Clinical Trial Investigating the Effect of the Reamer-Irrigator-Aspirator on the Volume of Embolic Load and Respiratory Function During Intramedullary Nailing of Femoral Shaft Fractures. J Orthop Trauma. 2017;31(4):200-4.

3. Hoare JR. Pathological fractures. The Journal of Bone and Joint Surgery. 1968;50B(1):232.

4. Weiss RJ, Forsberg JA, Wedin R. Surgery of skeletal metastases in 306 patients with prostate cancer. Acta Orthop. 2012;83(1):74-9.

5. Cetin K, Christiansen CF, Svaerke C, et al. Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval. BMJ Open. 2015;5(4):e007702.

6. Durr HR, Muller PE, Lenz T, Baur A, Jansson V, Refior HJ. Surgical treatment of bone metastases in patients with breast cancer. Clin Orthop Relat Res. 2002(396):191-6.

7. Norgaard M, Jensen AO, Jacobsen JB, et al. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-7.

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