Therapeutics
rapidly advance the project toward the clinic, using key objectives and milestones. The goal is to iden- tify therapeutics that meet our criteria for effective use in humans. Simultaneously, the teams also work to define a focused clinical plan that includes patient-stratification biomarkers to identify those individuals most likely to benefit, as well as early ‘proof-of-biology’ biomarkers to show the drugs are working in humans. Progress on the portfolio is monitored through regular review meetings with internal and external advisory boards and resources are redirected according to needs and progress. Culling investigational agents early in the devel-
opment process can be a difficult step, particularly when substantial resources have already been expended. However, we know that more than half of drugs fail in Phase III clinical trials due to a lack of efficacy, thus we are ruthless in our assessments of target candidates and project advancement. We can be ruthless because we own the compounds under investigation and our decision-making is not bound by contractual agreements with other insti- tutions. Through this approach, we maintain con- trol of the programme and can commit a greater amount of time and resources to rapidly move the compound through clinical development. Because we are treating patients with drugs
developed within MD Anderson, we are now about as close as we can get to developing a drug at the bedside, conducting real-time assessments of
Drug Discovery World Fall 2018
the drug’s effects on a tumour in patient-derived material, such as patient-derived xenografts and ex vivo organo-typic cultures. Leveraging patient-cen- tric translational research catalyses knowledge transfer to the clinic to further refine our patient- stratification strategies for our new therapeutics.
A major milestone One of our first successes using this approach is the compound IACS-10759, a small-molecule inhibitor
of oxidative
phosphorylation
(OXPHOS). With the wealth of clinical data avail- able to us at MD Anderson, we were able to iden- tify OXPHOS as a critical, but often overlooked, tumour vulnerability in many cancer patients. Although the study of metabolic reprogramming in cancer is not new, much of the recent focus has been on upregulation of glycolysis. It is now becoming clear that OXPHOS is also upregulated in certain tumour types, such as lymphoma and leukaemia, which rely on use of the electron trans- port chain to sustain bioenergetic and biosynthetic processes5. Additionally, multiple solid tumours either are hardwired to depend on OXPHOS for their energetic needs, or they upregulate OXPHOS as a resistance mechanism to other therapeutic treatments. When we saw a need in our patients for therapies that combat tumours driven by OXPHOS, we were able to move quickly and deci- sively. IACS-10759 is the first small-molecule drug to
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