Brain Tumour Magazine: World Edition 2020/2021

Page 8

Re-Thinking Brain Tumor Drug Development Nader Sanai, MD Francis & Dionne Najafi Chair in Neurosurgical Oncology; Director, Division of Neurosurgical Oncology; Director, Ivy Brain Tumor Center, Barrow Neurological Institute, Arizona, USA


ecently, new cancer drugs have generated notable successes in tumor control. For patients with advanced lung or skin cancer, for example, a growing arsenal of approved therapeutics are yielding historical improvements in survival. Why has this surge in successful drug development not yet touched the brain tumor community? At least part of the reason has to do with our ability to translate a successful result from the brain tumor laboratory to the brain tumor patient. Drug development typically begins with ‘preclinical’ studies that experimentally treat animals harboring brain tumors. These tumors are generated from genetic manipulation of the animal or direct injection of a human tumor into an animal’s brain. A more simplified approach to drug testing entails treating brain tumor cells or lumps of human brain tumor tissue in a Petri dish. At best, these models are loose approximations of a patient’s reality. Thus, it is no surprise that laboratory studies have never accurately predicted the results of human brain tumor clinical trials.

Breaching the blood-brain barrier and other pillars of resistance But replicating the complexities of a human brain tumor in the laboratory is not the only front in this war. For its own protection, the brain is designed to keep things out. This self-defense mechanism, enabled by the ‘blood-brain barrier,’ is why drugs effective for other human ailments are, thankfully, not detrimental for the brain. In fact, 99% of all new drugs are incapable of crossing the blood-brain barrier. Identifying which new drugs have the potential to Right: Members of the multidisciplinary Ivy Brain Tumor Center at Barrow Neurological Institute


Brain Tumour

Dr Nader Sanai, Ivy Brain Tumor Center, USA

gain access to brain tumors is a matter of chemistry. The challenge, however, lies in recognizing which drugs actually succeed at this in patients. The most common method of estimating a new drug’s capacity for human brain penetration is to administer the drug to an

animal and then measure its concentration in the animal’s brain and brain tumor tissue. Unfortunately, the assumption that these results will represent the human experience is fraught with risk. Specifically, the bloodbrain barrier is assembled differently for every species. So, what penetrates the mouse brain does not necessarily penetrate the human brain. Beyond this structural issue, there is the issue of drug metabolism. Each species processes drugs differently, which means an identical dose (adjusted by body weight) for a mouse and a human can yield two divergent results. A final pillar of resistance for brain tumors is their diversity. For many other cancers, the biology of each tumor type is very similar from patient to patient. Skin cancer, for example, can be subcategorized into different genetic subtypes, but within each subtype, there is little variation between patients. Brain cancers are far more fluid. Within each patient, tumors are continuously reorganizing with hyper-evolutionary speed. This not only