Drug discovery in neuro-oncology: challenges in the path forward

It is an honor to have been asked to write an editorial for Neuro-Oncology, the highly ranked journal of the Society for Neuro-Oncology (SNO). My goal is to enunciate my vision for what I believe we, as a group dedicated to curing central nervous system (CNS) malignancies, need to achieve.

During the lifetime of SNO, we have witnessed an enormous unfolding of molecular and genetic research that has informed more precise classification of most primary CNS tumors and descriptions of tumor subgroups that are more and less sensitive to radiation therapy and alkylating agent chemotherapy.^1–7 Paralleling this expansion of sophisticated molecular-genetic research have been efforts to address patient quality of life and palliative interventions when required by tumor progression or treatment side effects. The content of the two SNO journals, Neuro-Oncology and Neuro-Oncology Practice, reflects those trends, as have the enormously successful SNO annual meetings.

While we better understand many oncogenic drivers of CNS tumors, we have had trouble defining the impact of signaling pathways on these drivers. Many of these signaling pathways represent nonlinear molecular interactions, protein-protein interactions, differing phosphorylation states and sites, and other poorly understood interactions and dependencies that enable tumor cells to survive, replicate, and invade. These are the areas of research I worry most about as they, as drivers of tumor growth, are also the likely targets for drug discovery/development. Furthermore, while target(s) inhibition represents the primary pharmacological goal of chemotherapy, the unfortunate reality may be that inhibiting one target may be insufficient to control CNS tumor growth.

Given the enormous explosion in research and our understanding of how many primary CNS tumors grow, why have we not seen a commensurate increase in drug therapies?

In retrospect, my research, the goals of which have been to quantify how drugs move into the CNS and cerebrospinal fluid and to develop new drugs and drug therapies, drug-radiation combinations, and combination chemotherapy strategies, placed me in the minority of researchers over the years. My laboratory research began in 1967 when I started work at the National Cancer Institute in the Laboratory of Chemical Pharmacology and Office of the Associate Scientific Director (David Rall, MD, PhD). It was initially focused on quantifying transport of standard chemicals and anticancer drugs into brain, cerebrospinal fluid, and experimental tumors and to understand how drugs affected intracerebral rodent brain tumor models. My research expanded, first at the Massachusetts General Hospital and then as faculty of the University of California San Francisco (UCSF) Schools of Medicine and Pharmacy, and culminated at the University of Texas M.D. Anderson Cancer Center, where I developed and chaired the Department of Neuro-Oncology for nearly a decade. My laboratory and clinical research formed the path of my life and, even though I no longer do laboratory research, I remain on this path hoping that what I do will enable others to make the scientific advances that will help reduce the suffering and death from CNS neoplasms.

In the period 1967–1975, the number of neuro-oncology laboratory researchers in the USA, Europe, and Japan numbered less than 100. Today, that number is unknown to me, but my guess is that it is several thousand worldwide (SNO alone has over 2000 members). Most of this research over the past two decades has been fueled by the explosion in genetics, molecular biology, neuroimaging, statistics, bioinformatics, immunology, and, of course, ready access to computers and software. These newer avenues of research, as mentioned previously, have enabled colleagues to define the molecular-genetic fingerprint of many primary tumors and parse responses to current therapies (irradiation, alkylating agents) based on molecular-genetic profiles; essentially, they have helped us to understand what drives tumor cells to divide, invade, change phenotype to greater malignancy, interact with undifferentiated stem cells, and evade current therapies.

Why have scientists in academia and industry failed to provide us with the new drugs we need to treat our patients? I naïvely thought that the creation of SNO and better dissemination of research would form a driving force to achieve this end; however, I realize now it is not that simple.

Research, after all, is dependent on training, experience, vision, and funding opportunities. It is hard to sustain new and risk-taking research without the stimulus of funding, and funding historically has followed research rather than stimulated its creation. I know from experience that this is a difficult road to follow. To create disease-changing therapies for cancer, I was elected to lead a group of internationally known scientists from the UCSF School of Medicine, UCSF School of Pharmacy, and UC Berkeley to create protein tyrosine kinase (PTK) inhibitors of the proto-oncogene Src. Our group received the first National Cooperative Drug Discovery Group grant in the early 1980s and was funded for 15 years until 1997. We were optimistic that our approach would change the way cancer (and CNS tumors) were treated. Like many new research endeavors initiated with confidence, our goal to create a specific and irreversible drug inhibitor of the Src catalytic region proved to be impossible for us and for the pharmaceutical industry over the past 30 or more years. This failure came 10 years after our initial grant and following our determination that the catalytic site of Src required a cyclic peptide to fill the 3-dimensional space.⁸ This 3-dimensional binding, unfortunately, could not be mimicked by any known chemistry at the time or since, as far as I know. This outcome led us and others to develop PTK inhibitors based on the ATPase site using combinatorial chemistry approaches to maximize specificity for the PTK being developed.⁹ This was very disappointing to me and the others who worked on this research from UCSF, UC Berkeley, and later the University of Texas M.D. Anderson Cancer Center and Signase (a company I founded with Ray Budde). Failure can be a tremendous catalyst for new research and positive actions, so I moved into different research areas and stayed on the path. Eventually, my frustration led to finding colleagues of like interest and frustration to organize the first CNS Anticancer Drug Discovery and Development Conference (CADDDC) in 2014 and the second CADDDC in 2016 to bring academic and pharmaceutical/biotech scientists together to educate and encourage research. For those interested, the third CADDDC is scheduled for November 14–15 prior to the 2018 SNO Annual Meeting.

The path I started on in 1967 has not changed, and I still believe that to help future patients with primary infiltrative gliomas and primitive neuroectodermal (eg, medulloblastoma) tumors as well as other primary CNS tumors, we need to continue to encourage the discovery and development of new drugs and new therapies. Today, our society focuses too much on financial gain, political power, and regulatory overreach in the name of safety and progress. The financial disincentives to new drug development for rare cancers (ie, all primary CNS neoplasms) are virtually impenetrable¹⁰; their cause is the financial risk related to the uncertainty of target identification, the potential need for more than one specifically targeted drug to control tumor growth, and the long duration of clinical trials to provide proof of overall survival gain. Solutions may require changes in patent law so that the patent clock does not start until later, say in the clinical trial, or other legislation to provide financial carrots to industry based on the magnitude of the benefit (survival). In addition, we must develop efficient clinical outcome surrogates to reduce the risk of failure and accelerate the time to clinical application for active treatments. The research needs today are those possible in academic, pharmaceutical, and biotech laboratories; the financial needs are societal and legislative and will require leadership and commitment from organizations such as SNO, philanthropies, and the members of the US Congress. This future will not be deliberate unless women and men of generous thought and action work to improve the environment needed for development of new drugs to treat CNS tumors; to create the legislative and philanthropic carrots that will provide the funding stimulus and opportunities to enable and encourage scientists in academia and industry to create the drugs of tomorrow and persuade the regulators in government to approve surrogate endpoints so that clinical trials can be conducted more quickly at less cost. To me, this is the greatest challenge facing SNO members and leaders in the next decade.