MICA: The role of Src in cancer-induced bone pain

Of the 300,000 new cases of cancer diagnosed in the UK every year, nearly 100,000 are from breast or prostate cancer. Both of these types of cancer preferentially spread to bones, where they can cause pain and fractures as well as other disabling effects. Controlling bone pain in cancer patients can be difficult, as not all cancers respond well to radiotherapy, and sometimes the side-effects of strong painkillers like morphine can limit the dose of drug that can be given. Although we know a lot about how pain develops after inflammation or nerve damage, our understanding of pain due to bone cancer is not so good, and this lack of knowledge hampers the development of new painkillers that might be particularly good at controlling bone pain. The aim of this project is to study the pathways in the nervous system that are activated in bone cancer. Initially we will focus on identifying changes in the nervous system that occur in bone cancer, with a view to increasing our knowledge. We will also test a new drug, Saracatinib, on patients with pain from cancer that has spread to bones to investigate whether it is useful as a painkiller. If successful, the project might improve the quality of life of patients with bone pain from cancer.

Bone pain is a significant clinical feature of several common cancers, including breast, prostate and lung cancers, which all have a tendency to spread to bone. Adequately control of bone pain is a significant unmet clinical need in almost half of cancer patients with bone metastases, and therefore understanding the mechanisms of cancer-induced bone pain would be helpful in developing rationale-based therapy. The current proposal is a collaborative project between basic and clinical scientists at the University of Sheffield and a commercial partner, AstraZeneca, to test the hypothesis that the non-receptor tyrosine kinase Src is a critical component of cancer-induced bone pain, and that its inhibition represents a novel analgesic strategy for controlling bone pain in cancer patients. A series of preclinical studies using an animal model of bone cancer pain will investigate the effects of inhibiting Src on pain-related behaviour, spinal cord neuron phosphorylation and signalling as well as bone resorption to identify potential analgesic mechanisms of Src inhibition. We will also translate these studies into patients by performing a randomized controlled trial of the Src inhibitor Saracatinib, to investigate whether it has a role as an analgesic in cancer patients with bone metastases. The results of this study will elucidate the role of Src in bone cancer pain, and they will confirm whether Src inhibition shows clinical promise as a mechanism of analgesia.

Who might benefit from this research ?
The principal beneficiaries from this research are academic Neuroscientists and Oncologists/Palliative Care Physicians, who will benefit from the enhanced knowledge economy that results from this proposal. Patients may also benefit from the study in the longer term, if positive results emerge from the clinical trial that are replicated in a larger, definitive study. If patients do benefit then there will be knock-on financial benefits for our commercial partner, Astra-Zeneca, as the project would provide a new clinical avenue for one of their drugs.
Additionally, the project will contribute to the health of the discipline of whole animal physiology, which is an area of research that the BBSRC has designated as a vulnerable niche area of UK research expertise that needs to be protected. The training of a post-doctoral research scientist will also deliver a highly skilled researcher who is equipped with additional skills that will be useful in their future scientific career, as well as adding to the pool of UK scientific expertise.

How might they benefit from this research ?
Beyond the increase in knowledge that this project will produce, there is potential for improved quality of life for cancer patients if their pain is better controlled; this benefit may not be realized for 5 years as even if the small trial proposed here was successful, a larger, definitive study would take longer. A positive outcome from the study would also result in increased global economic performance for Astra-Zeneca that could benefit the wider UK economy.