It is time to move beyond cancer chemotherapy
In this editorial, I propose a move away from cytotoxics, towards precision medicine, and discuss the future of genomics in drug discovery.
In 1946, the first chemotherapeutic drug, a compound called nitrogen mustard, was discovered. It was found to work against a cancer of the lymph nodes called non-Hodgkin's lymphoma (1). This agent provided a model for alkylating agents, which kill rapidly growing cancer cells by damaging their DNA. Soon after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a vitamin folic acid-related compound, produced remissions in children with acute lymphoblastic leukemia(2). This drug was the predecessor of methotrexate, a cytotoxic drug used commonly today. With this, the era of widespread chemotherapy began. Eli Lilly and Company in 1960 introduced the vinca alkaloids as anticancer agents. Vinblastine was used to treat Hodgkin's disease and vincristine to treat pediatric leukemia. Soon thereafter, the era of combination chemotherapy came into use to overcome drug resistance as well as to minimize the toxicity. Over 50 cytotoxics are in use today for cancer therapy. Chemotherapy has made a huge difference for cancer patients around the globe and research is still being conducted which tinkers with the cytotoxics to improve efficacy, reduce the dosage and toxicity and use in combination with other drugs, biologics, radiation etc. A search of the Clinical Trials database in the US (https://clinicaltrials.gov/) revealed the following number of clinical trials with results available: chemotherapy (8,247); combination chemotherapy (599); biologics and cancer (649) and precision medicine and cancer (110). Thus, the bulk of clinical trials still revolves around chemotherapeutics.
With the advances in the human genome sciences, we are beginning to learn how to personalize treatment (3). The 20,000 proteins in the genome as well as the noncoding RNAs are beginning to provide a strong rationale for discovering druggable targets. The 1000 genome project (http://www.1000genomes.org/) from the International Genome Sample Resource (IGSR) and the 10K project in the UK (http://www.uk10k.org/) provide valuable clues to response to therapy (pharmacogenomics). Bioinformatics and chemoinformatics approaches are shaping all aspects of drug discovery starting from target prediction, assay development, lead verification and toxicology prediction. In silico modeling is beginning to replace the random screening approaches, which drove drug discovery in the past.
With the power of the genome in our hand, drug discovery is made more efficient and cost effective. It is time to move away from the cytotoxics and move towards precision medicine and less toxic therapy. This is beginning to happen (4, 5). It requires, however, a major shift in the thinking about drug discovery at the level of industry, academia and government funding agencies. Cancer patients deserve more specific and less toxic drugs. It is not unreasonable to predict and hope that in a decade from now cytotoxic chemotherapy will be a bygone era of medical history.
- Fenn JE, Udelsman R. First use of intravenous chemotherapy cancer treatment: rectifying the record. Journal of the American College of Surgeons. 2011;212(3):413-7.
- Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. The New England journal of medicine. 1948;238(23):787-93
- Schork NJ. Personalized medicine: Time for one-person trials. Nature. 2015;520(7549):609-11.
- Bachy E, Salles G.Are we nearing an era of chemotherapy-free management of indolent lymphoma? Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(20):5226-39.
- Abramson, R. 2016. Overview of Targeted Therapies for Cancer. My Cancer Genome https://www.mycancergenome.org/content/molecular-m... (Updated April 26).