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Can bone anabolic agents be used to limit breast cancer-induced bone disease?


Department of Oncology and Metabolism

About the Project

This project aims to find new ways to reduce the damage that breast cancer cells cause when they spread to the skeleton

Due to improvements in early cancer diagnosis and the introduction of new therapies, around 80% of UK breast patients now survive for more than 5 years. However, the remaining 20% of patients develop advanced metastatic disease with cancer spread to other organs, at which point the disease can no longer be cured. Of these patients, 70-80% will have cancer spread to the skeleton (bone metastasis), resulting in pain and weakening of bones that can lead to fractures. This is caused by tumour cells stimulating bone destruction (resorption), as well as inhibiting bone formation, resulting in development lytic bone lesions.

There are currently effective bone-targeted agents for patients with bone metastases that inhibit bone destruction and slow down cancer-induced bone loss. However, there is no current treatment aimed at stimulating bone formation that could potentially repair breast cancer-induced bone lesions and prevent weakening of the bones. This project will use models of breast cancer bone metastasis to investigate whether it is possible to stimulate bone formation (alone and in combination with anti-resorptive agents and chemotherapy) and whether this can limit the extent of cancer-induced lytic lesions without damaging side-effects.

Project plan: Using models of the B cell malignancy multiple myeloma, we have found that a TGFβ inhibitor combined with the bone-targeted drug zoledronic acid (ZOL), repaired cancer-induced bone lesions more effectively than either therapy alone. However, multiple myeloma is a ‘liquid tumour’, where cancer cells are found throughout the bone marrow causing widespread bone lesions. In contrast, breast cancer is a solid tumour that when it spreads form fewer, larger colonies in bone, resulting in more localised but extensive tumour-associated lytic bone lesions. These lesions may be more difficult to repair compared to those found in multiple myeloma, hence a triple combination of a bone anabolic agent (targeting TGFβ), an anti-resorptive agent (ZOL) and a chemotherapy agent (to limit tumour growth) may be required to successfully limit cancer-induced bone destruction.

This project aims to determine whether addition of bone anabolic agents targeting TGFβ reduces the extent of breast cancer-induced bone destruction in models of bone metastasis. This will provide essential information required to further explore the use of bone anabolic therapies in breast cancer patients with bone metastasis.

About the team: This project is suitable for applicants with an interest in breast cancer and/or bone biology. You will be part of the highly successful bone oncology group in the Mellanby Centre for Bone Research, joining a team of post docs, technicians and students all investigating how cancer spreads to bone and how this can be modified by new therapeutic agents and combinations. The project is a collaboration between Dr Michelle Lawson (expert in multiple myeloma) and Prof Ingunn Holen (expert in breast cancer), both highly experienced at supervising PhD students.

Training: You will gain experience in use of a number of different cutting-edge methods (molecular and cell biology, use of complex model systems) to study how cancer cells spread to bone. All PhD students at the University of Sheffield complete a compulsory wide-ranging doctoral training programme. This includes literature searches, scientific writing, how to structure a thesis, research ethics, statistical analyses, science communication and presentation skills, as well as a number of modules tailored to the skills and interests of the individual student. Full training will be provided; to carry out this project, you must also obtain a personal UK Home Office license for animal work, involving a training course followed by a test of understanding and competencies.


Funding Notes

This project is open for self-funded students only.

References

Entry Requirements:
Candidates must have a first or upper second class honors degree or significant relevant research experience.

Enquiries:
Interested candidates should in the first instance contact Prof Ingunn Holen ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Department of Oncology and Metabolism as the department.

Proposed start date - March 2021

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