Imaging therapy resistance in 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 King’s College London and St Thomas’ PET Centre will investigate the role of altered tumour metabolism as an indicator of drug resistance. Specifically, we are developing novel positron emission tomography (PET) imaging techniques to investigate altered tumour metabolism. PET captures images of high-energy gamma-rays that are emitted from inside a subject following intravenous administration of a radioisotope-tagged molecule, termed ‘radiotracer’. 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.

[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.

Tumour redox imaging

“Investigating the fine balance between the synthesis of intracellular antioxidants and drug-induced oxidative stress.”

Mammalian cells have developed an exquisite system of biochemical processes with which to maintain redox homeostasis. The overall purpose of this system is to prevent damage from unregulated redox reactions. For example, harmful reactive oxygen species (ROS) generated during oxidative phosphorylation are buffered by the activity of multiple enzymes including superoxide dismutase, catalase, and glutathione peroxidase, which convert ROS to increasingly benign products. Other toxic redox-active compounds include exogenous electrophiles, which can be neutralized by an array of intracellular antioxidants, such as glutathione (GSH) and thioredoxin (Trx), along with associated oxidoreductase enzymes. While these mechanisms are usually sufficient to maintain redox homeostasis, prolonged or elevated exposure to ROS or exogenous electrophiles can result in damage to DNA, proteins and cell membranes. The consequences of redox dysregulation – cumulatively referred to as oxidative stress – play an important role in a myriad of diseases, including cancer, arthritis, cardiovascular disease, Alzheimer’s disease and Parkinson’s disease.

Working with our Industrial collaborators, Life Molecular Imaging, we have shown that the PET radiotracer [18F]FSPG, already used in pilot clinical trials, can be used to monitor spatiotemporal changes in redox status. [18F]FSPG tumor retention provides an index of redox status through its sensitivity to levels of intracellular cystine, which are controlled by the plasma membrane transporter, system xc-. Physiologically, system xc- functions as a cystine/glutamate antiporter, allowing extracellular cystine, the dimeric form of cysteine, to be taken up in exchange for intracellular glutamate. Within the cell, cystine is reduced to cysteine, the rate-limiting substrate in the biosynthesis of glutathione, the cell’s most abundant small molecule antioxidant. Cystine levels represent a point of convergence between multiple arms of the cell’s antioxidant system, making the responsiveness of [18F]FSPG uptake to this amino acid a valuable surrogate marker of oxidative stress.

We are currently investigating how tumour redox status dictates tumour responses to traditional anti-cancer therapies (e.g. chemotherapy and radiotherapy). Previously, we have shown that [18F]FSPG provides an early marker of treatment response, occurring days before changes in tumour size are evident [1]. Furthermore, levels of [18F]FSPG retention in individual lesions may predict their response to therapy, opening up the possibility that alternative treatments may be sought for those patients that are refractive to therapy.

[1] McCormick et al. 2019. Cancer Res. DOI: 10.1158/0008-5472.CAN-18-2634