1st Supervisor: Rick Southworth, King’s College London
2nd Supervisor: Samantha Terry, King’s College London
Clinical Champions: George Mikhaeel and Amedeo Chiribiri, King’s College London
Additional Supervisor: Thomas Eykyn, King’s College London
Aim of the PhD Project:
- Cancer radiotherapy/chemotherapy can inadvertently damage the heart.
- Cancer therapy-induced cardiac injury is currently detected by contractile dysfunction using ultrasound/MRI, which is too late in the pathology to be useful.
- We will develop molecular imaging approaches to detect the biochemical injury preceding contractile dysfunction, providing new opportunities for cardiac protection.
Project Description / Background:
This project would best suit a biologist/biochemist.
- Off-target radiotherapy and tyrosine kinase receptor inhibitor chemotherapy both cause heart failure by invoking microvascular injury and mitochondrial dysfunction.
- Nuclear molecular imaging agents targeted at tissue hypoxia and mitochondrial depolarisation could detect early cardiac injury during cancer therapy to optimise and personalise cancer therapy whilst minimising cardiac risk.
Chest radiotherapy is standard treatment for patients with lymphoma, breast or lung cancer. Treatment planning is often image-guided to ensure accurate targeting, but regardless of the techniques used, the heart is frequently inadvertently irradiated. This can induce arrhythmias, cardiac fibrosis, myocardial infarction and heart failure [1,2]. There is increasing evidence that mitochondrial DNA is a key determinant of sensitivity to radiation injury as it is more vulnerable to oxidative damage than nuclear DNA, with lesser capacity for repair. Furthermore, mitochondrial DNA damage leads to mitochondrial dysfunction and increased production of reactive oxygen species, invoking a vicious cycle which leads to loss of ATP production, apoptosis, and cell death. Mitochondrial dysfunction therefore represents a relevant imaging target for evolving radiation injury . The vascular endothelium is also particularly vulnerable to radiation injury. Radiation-induced microvascular dysfunction and decreased capillary density lead to progressive diffuse myocardial ischaemia, which is likely central to the progression from acute injury to progressive heart failure .
Similarly, tyrosine kinase receptor (TKR) and vascular endothelial growth factor receptor (VEGFr) inhibitors, widely used chemotherapy drugs in the treatment of renal cell carcinomas, gastrointestinal tumours and neuroendocrine tumours, are also associated with a variety of cardiovascular complications and morbidities . While the exact mechanism underlying their cardiovascular toxicity remains unclear, as antiangiogenic agents there is evidence that they may also invoke cardiac microvascular injury, leading to diffuse ischaemia, metabolic remodelling , and a descent into contractile dysfunction and heart failure . Co-treatment with chemotherapies and radiotherapies have unpredictable and often synergistic risks, which make combination cancer therapy planning extremely difficult [8-11].
The heart is a functionally robust organ which can sustain significant injury before contractile function manifests. Unfortunately, this means that by the time cardiac dysfunction is measurable clinically using MRI or echocardiography (as is currently done), the cardiotoxicity is frequently beyond meaningful intervention. We are therefore currently developing a library of PET and SPECT molecular imaging agents aimed respectively at hypoxia, oxidative stress and mitochondrial dysfunction to detect the biochemical changes which precede and predict contractile dysfunction [12-15]. We have recently acquired a state-of-the-art small animal irradiator (X-RAD SmART) which is able to perform radiotherapy (and invoke “off target” cardiac irradiation) exactly as would happen clinically. In this project, we will develop and characterise small animal models of cardiac injury in response to both radiotherapy and TKR/VEGFr chemotherapy. We will then determine whether our novel molecular imaging tools are able to detect and quantify the earliest stages of biochemical injury before contractile dysfunction manifests. This work will underpin future studies that will allow clinicians to better plan and deliver cancer therapies which maximise tumour dose while minimising cardiovascular risk.
- Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of randomised trials. Lancet 366: 2087-2106, 2005.
- Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol 11: 1208–1215,1993.
- Kawamura K, Qi F, Kobayashi J. Potential relationship between the biological effects of low-dose irradiation and mitochondrial ROS production. J Radiat Res 59(suppl_2):ii91-ii97, 2018.
- Tapio S. Pathology and biology of radiation-induced cardiac disease. Journal of Radiation Research 57(5): 439–448, 2016.
- Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Invest. 1999;17(6):408–22.
- Sourdon J, Lager F, Viel T, et al. Cardiac metabolic deregulation induced by the tyrosine kinase receptor inhibitor sunitinib is rescued by endothelin receptor antagonism. Theranostics . 2017;7:2757–2774.
- Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A. et al. Vascular Toxicities of Cancer Therapies: The Old and the New-An Evolving Avenue. Circulation. 2016 Mar 29;133(13):1272–89.
- Lipshultz SE, Cochran TR, Franco VI, Miller TL. Treatment-related cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol 10(12):697–710, 2013.
- Ky B, Vejpongsa P, Yeh ET, Force T, Moslehi JJ. Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res 113(6):754-64, 2013.
- Sivagnanam K, Rahman ZU, Paul T. Cardiomyopathy Associated With Targeted Therapy for Breast Cancer. Am J Med Sci 351(2):194-9, 2016.
- Murtagh G, Yu Z, Harrold E, Cooke J, Keegan N, Fukuda S, Addetia K, Kim JH, Spencer KT, Takeuchi M, Kennedy J, Ward RP, Patel AR, Lang RM, DeCara JM. Monitoring Ionizing Radiation Exposure for Cardiotoxic Effects of Breast Cancer Treatment. Am J Cardiol 117(10):1678-1682, 2016.
- McCluskey, S., Haslop, A., Coello, C., Gunn, R., Tate, E., Southworth, R., Plisson, C., Long, N. J. & Wells, L. Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations. 2019 Journal of Nuclear Medicine.
- Safee, Z. M., Baark, F., Waters, E. C. T., Veronese, M., Pell, V. R., Clark, J. E., Mota, F., Livieratos, L., Eykyn, T. R., Blower, P. J. & Southworth, R., Detection of anthracycline-induced cardiotoxicity using perfusion-corrected Tc-99m sestamibi SPECT 2018 Scientific Reports. 9, 1, p. 216-227 , 216.
- Medina, R., Mariotti, E., Pavlovic, D., Shaw, K., Eykyn, T., Blower, P. & Southworth, R., 64CuCTS: a promising radiopharmaceutical for the identification of low grade cardiac hypoxia by PET.2015 Journal of Nuclear Medicine. 56, 6, p. 921 , 56.
- Handley, M. G., Medina, R. A., Mariotti, E., Kenny, G. D., Shaw, K. P., Yan, R., Eykyn, T. R., Blower, P. J. & Southworth, R., Cardiac Hypoxia Imaging: Second Generation Analogues of 64Cu-ATSM 2014 Journal of Nuclear Medicine. 55, 3, p. 488-494.