1. Balakrishnan, Vijay Shankar

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When tumor roguery renders treatments futile in a cancer clinic, it is equally depressive for both patients and treating oncologists. However, a new study from Oxford University, U.K., published in Clinical Cancer Research in February this year might raise their hopes.

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Tumor roguery can occur due to a variety of reasons, but primarily the tumor microenvironment. A variety of studies have previously shown the influence of tumor microenvironment on its resistance to chemotherapy and radiotherapy. Of all the aspects, tumor hypoxia is notorious.


Since tumors tend to be metabolically very active, their oxygen requirement is high. While there is a high demand for oxygen, the blood vessels that deliver oxygen to tumors do not work well since they can be leaky. "So, you have this mismatch between increased oxygen demand and reduced oxygen supply," said Geoff Higgins, BSc (Hons), MBChB, MRCP, FRCR, DPhil, consultant oncologist at the Oxford University Hospitals Trust and lead author of the study.


Oncologists have known hypoxia to cause radiotherapy to be less effective for decades. "[We] have tried different things in the past to try to get rid of tumor hypoxia, usually trying to increase the amount of oxygen that gets to the tumor, [but] they've had at best or very limited efficacy and you could argue, in most cases, they've had no effect at all," said Higgins.


Then Higgins and colleagues set to look for a new trick to tackle tumor hypoxia.


"So we wanted to come up with a different strategy where, rather than trying to push more oxygen into the tumor, we reduce how much oxygen the tumor was using and it would have the effect that whatever oxygen was left would be able to diffuse to the hypoxic parts and get rid of tumor hypoxia," he explained.


About 5 years ago, Higgins and team searched for a cheap and safe drug that might have such an effect on the tumor oxygen play. Screening over 1,500 various low-cost medical drugs, their team demonstrated in cell cultures, 3D models of lung cancers, and mouse xenografts that the antimalarial drug atovaquone could make the tumors use up less oxygen (Nat Commun 2016:


It is not the first time researchers have tried using antimalarials in cancer clinics. For instance, artemisinins were shown to discourage vascular development in tumors and chloroquines to target PPT1, an enzyme that controls the major growth regulator mTOR in cancer cells (IntechOpen 2013;DOI: 10.5772/54109). However, side effects of other drugs over atovaquone in addition to its biochemistry helped Higgins and team pin down on the drug to study it in humans.


"Atovaquone actually works as an antimalarial by inhibiting the electron transport chain of the malaria parasite, and it works exactly the same way in cancer," he explained. "It's inhibiting complex III of the electron transport chain in the mitochondria in human cancer cells."


Called the ATOM trial, Higgins and colleagues recruited eligible patients who showed up for screening of non-small cell lung cancers, namely, patients with large enough tumors, meaning more likelihood of tumor hypoxia. At the time of screening, 30 of the eligible patients would receive a tracer that can reveal hypoxic regions of the tumor in a PET CT scan. Then the patients were separated into two cohorts: one receiving atovaquone for 12 days and the other who would not.


Higgins and team were looking for shrinkage in tumor volume as a result of atovaquone treatment. Eleven out of 15 atovaquone recipients showed a significant shrinkage in tumor volume and an average 55 percent reduction in tumor hypoxia, meaning more oxygen near the tumor. Upon gene profiling, they also observed downregulation in hypoxia-related genes in atovaquone recipients. This means that the tumor microenvironment would now be more yielding to chemotherapy and radiotherapy.


"I'm delighted that the results from the study are so positive so that we can take the next step towards repurposing a well-established drug as a new, effective anti-cancer treatment," said Higgins. It is the first time a mitochondrial inhibitor has been shown to reduce tumour hypoxia content in patients, with the potential therapeutic implications of this approach.


"This study is important to the field and leads to potential hypoxia-targeting strategies in cancer, as it is known that high hypoxic content in tumours is associated with poor prognosis and therapy resistance," said Isabel Monteiro dos Santos Pires, PhD, a cancer biologist from the University of Hull, U.K., who did not take part in Higgin's study.


"Another aspect of this study which is really exciting is the utilization of several hypoxia-content biomarkers, both through imaging using PET-CT and transcriptomic analysis of tumor samples for enrichment of hypoxic gene expression signatures," said Santos Pires. Robust hypoxia biomarkers for clinical use are still an area of unmet need in the field, and the authors show that combining currently available biomarkers is a feasible strategy for a clinical setting, she added.


Higgins and team are now busy expanding this study into the larger ARCADIAN trial, in which they hope to demonstrate the safety of using atovaquone in combination with both chemotherapy and radiotherapy to assess whether combining this drug with such treatments improves survival of patients with lung cancer. Higgins hopes that the ARCADIAN trial will be finished within 18 months. Should the results be promising, then they would move on to an efficacy trial.


"[By then], we should have a pretty good idea whether it works and whether it should be being used in patients or not," concluded Higgins. "Within 5-6 years, I would hope we have a pretty good idea of how effective atovaquone is or isn't."


Vijay Shankar Balakrishnan is a contributing writer.