Detecting off-target chemo/radiotherapeutic cardiac injury using nuclear molecular imaging

1st Supervisor: Rick Southworth, King’s College London
2nd Supervisor: Samantha Terry, King’s College London
Clinical Champions: George Mikhaeel, King’s College London; Maria Hawkins, University College London; Amedeo Chiribiri, King’s College London
Additional Supervisor: Thomas Eykyn, King’s College London

Aim of the PhD Project:

• Cardiac injury caused by cancer therapy is currently only detectable by measuring contractile dysfunction using ultrasound/MRI, often too late for meaningful intervention.
• We are developing molecular imaging tools to detect the biochemical injury preceding contractile dysfunction, allowing earlier intervention and specific biomarker readouts for developing new cardioprotective approaches and drugs.

Project Description / Background:

This project would best suit a biologist/biochemist or a biologically-minded chemist.

Background:

The heart is a functionally robust organ which can sustain significant injury before contractile function manifests. Unfortunately, this means that by the time cardiac injury is measurable clinically using MRI or echocardiography (which are the current clinical standard), it can be too advanced for meaningful intervention. This is particularly true for cancer patients who are increasingly surviving their cancer only to succumb to heart failure caused by their treatment. We are therefore developing a library of PET and SPECT molecular imaging agents to detect the biochemical changes which precede (and may predict) contractile dysfunction with a view to maximising cancer therapy effectiveness while minimising cardiovascular risk [1-4].

Chest radiotherapy is standard treatment for patients with lymphoma, breast or lung cancer. Despite improvements in image-guided treatment planning and targeting, the heart can still be inadvertently irradiated, which can ultimately lead to heart failure [5,6]. There is evidence that mitochondrial DNA may be a determinant of cardiac susceptibility to radiation injury as it is particularly vulnerable to oxidative stress. Such DNA damage leads to mitochondrial dysfunction and increased production of reactive oxygen species, invoking a vicious cycle of energetic derangement, apoptosis, and cell death [7]. The vascular endothelium is also particularly vulnerable to radiation injury, leading to a progressive diffuse myocardial ischaemia/hypoxia, which is likely central to the progression from acute injury to chronic failure [8].  

Tyrosine kinase receptor (TKR) and vascular endothelial growth factor receptor (VEGFR) inhibitors, widely used in the treatment of renal cell carcinomas, gastrointestinal tumours and neuroendocrine tumours, are also cardiotoxic [9]. As antiangiogenic agents it is likely that they also invoke cardiac microvascular injury, leading to diffuse ischaemia/hypoxia, metabolic remodelling [10], and a descent into heart failure [11].

The project:

Chemotherapies and radiotherapies have unpredictable and often synergistic risks, which make cancer therapy planning extremely difficult [13-15]. However, both approaches elicit common injury mechanisms: ischaemia, hypoxia, oxidative stress, and mitochondrial dysfunction. Over the past 15 years, we have been developing nuclear molecular imaging probes targeted at each of these phenomena [1-4]. This project aims to harness them to detect these earliest stages of biochemical injury before contractile dysfunction manifests.

The student will develop clinically relevant small animal models of cardiac injury using (i) 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, and (ii) rodent dose-response studies with TKR/VEGFR chemotherapy. They will characterise the evolution of cardiac biochemical injury in each case over time using a panel of biochemical and histologic tests available within our labs, tracking contractile dysfunction using echocardiography/MRI as appropriate.

This longitudinal characterisation of cardiotoxicity will inform which of our library of imaging agents would be most suitable for detecting this injury non-invasively by PET/SPECT, and importantly, when each could be used (as Dr Southworth discusses here (https://www.youtube.com/watch?v=W4suoXUs4ZE), which the student will determine in the final in vivo imaging phase of their project.

Figure 1: Radiotracer development for imaging evolving cardiac injury. A: PET/CT imaging of doxorubicin cardiotoxicity by increased washout of the mitochondrial-targeting lipophilic cation ¹⁸F-mitophos-07 (left, McCluskey et al JNM 2019) and the accumulation of our novel ROS sensing probe ¹⁸F-FM074 (right Mota et al ChemComm, 2020 currently under review). Development and characterization of our hypoxia-targeting PET probes showing validation/quantification of cardiac hypoxia by pimonidazole staining (B), cardiac hypoxia inducible factor HIF1a stabilization by Western blotting (C), perturbation of cardiac energetics by ³¹P NMR spectroscopy (D), and the corresponding hypoxia-dependent cardiac uptake of our lead hypoxia-targeting PET probes (Medina et al JNM 2015).

References:

1. 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.
2. 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.
3. 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.
4. 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
5. 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.
6. 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.
7. 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.
8. Tapio S. Pathology and biology of radiation-induced cardiac disease. Journal of Radiation Research 57(5): 439–448, 2016.
9. Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Invest. 1999;17(6):408–22.
10. 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.
11. 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.
12. 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.
13. 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.
14. Sivagnanam K, Rahman ZU, Paul T. Cardiomyopathy Associated With Targeted Therapy for Breast Cancer. Am J Med Sci 351(2):194-9, 2016.
15. 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.