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IMAGING THERAPY RESISTANCE IN OVARIAN CANCER

" Monitoring the acquisition of therapy resistance in cancer is a pressing and unmet clinical challenge

Resistance to chemotherapy and molecularly-targeted therapies provides a major hurdle for cancer treatment due to the underlying genetic and biochemical heterogeneity of tumours. Despite intensive research, the field has struggled to provide a solution for sensitive and specific molecular imaging of tumour response and resistance to therapy.

Ovarian cancer remains a leading cause of death worldwide, with a 10-year survival rate of just 35% [1].  First-line platinum-taxane chemotherapy yields high initial response rates, however patients often relapse with drug-resistant disease [2]. At the moment there is no satisfactory way to predict which patients will to respond to therapy upon relapse. A new diagnostic imaging test that can predict platinum resistance at the point of relapse will enable patient stratification, enabling the clinician to select the most appropriate second-line therapy for the individual patient using a precision medicine approach. Where no suitable treatment options are available, patients with resistant disease will no longer receive inappropriate second-line treatment, thus avoiding associated side effects; resulting in substantially improved quality of life and the opportunity to initiate palliative care at an earlier stage.

Employing a combination of innovative preclinical imaging and metabolomic strategies, we are developing new tools to noninvasively assess the mechanisms that tumour cells employ to resist treatment. Working across the disciplines of oncology, biochemistry and molecular imaging, this collaborative approach between University College London and the Francis Crick Institute is investigating the role of altered tumour metabolism as an indicator of drug resistance. Specifically, we are devloping novel positron emission tomography (PET) imaging techniques to investigate altered tumour metabolism. Using a similar approach, we have previously used PET to image the rate-limiting enzyme in tumour glycolysis [3], deregulated glycogen synthesis [4], fatty acid β-oxidation [5], and choline metabolism [6] that are associated with malignant transformation. Importantly, the the molecular imaging tools developed as part of this project are not confined to ovarian cancer, but have the potential for widespread impact in cancer management for many other cancer types.

Strategy for the noninvasive detection of tumour resistance to therapy using radionuclide imaging. Figure adapted from Nguyen, Q.D. & Aboagye, E.O. Integr Biol 2:483-95

[1] Cancer Research UK, 2012.
[2] Coleman, M.P., et al., 2011. Lancet 377(9760): p. 127-38.
[3] Witney et al., 2015. Sci Transl Med. 7(310): 310ra169.
[4] Witney et al., 2014. Cancer Res 74(5): p. 1319-28.
[5] Witney et al. 2014. J Nucl Med 55(9): p. 1506-12.
[6] Witney et al. 2012. Clin Cancer Res 18(4): p. 1063-72.