Researchers at Baylor College of Medicine have developed a drug candidate that overstimulates proteins critical to tumor growth. In the August 10 issue of Cancer Cell, as reported in Science Daily, the researchers demonstrate that the drug candidate inhibits tumor growth in a mouse model of breast cancer and efficiently kills a broad range of human cancer cells. They claim that rapid cell division strains cancer cells, and "the approach works by tipping cell stress over the edge" (http://www.sciencedaily.com/releases/2015/08/150810132114.htm).
According to co-senior study author David Lonard of Baylor College of Medicine, "No prior drug has been previously developed or proposed that actually stimulates an oncogene to promote therapy. Our prototype drug works in multiple types of cancers and encourages us that this could be a more general addition to the cancer drug arsenal."
Cancer cells acquire mutations in oncogenes, which can transform cells into cancer cells. Research on identifying oncogenes that could be targeted by cancer drugs has uncovered the role of members of the steroid receptor coactivator (SRC) family of oncogenes. They appear to have great potential as therapeutic targets, because they are "at the nexus of key signaling pathways that cancer cells use to quickly grow, spread to other tissues, and acquire drug resistance," the researchers explain. In a prior investigation, Lonard and co-senior study author Bert O'Malley of Baylor College of Medicine screened compounds to discover "SRC-inhibiting molecules that kill a wide variety of cancer cells and inhibit tumor growth in animal models."
According to an article in the International Journal of Biological Sciences (Walsh CA, Qin L, Tien JCY, Young LS, Xu J. The Function of Steroid Receptor Coactivator-1 in Normal Tissues and Cancer. Int J Biol Sci 2012; 8(4):470-485. doi:10.7150/ijbs.4125), "Coregulator proteins were initially thought to be mere ‘acceptor proteins' that facilitated the interaction of specific ligand-bound nuclear receptors with general transcriptional machinery. Over the last seventeen years, however, complex and essential roles for a cohort of over 350 coactivator proteins have steadily emerged. Coregulator proteins have the uncanny ability to bind across unrelated families of transcription factors and coordinately facilitate the efficient and successful transcriptional activity of multiple target genes"
(http://www.ijbs.com/v08p0470.htm).
Lonard and O'Malley decided to disrupt key signaling pathways and kill cancer cells by overstimulating SRCs. They screened hundreds of thousands of compounds to identify a potent SRC activator, MCB-613, that killed human breast, prostate, lung, and liver cancer cells, while sparing normal cells. When they administered MCB-613 to 13 mice with breast cancer, the drug candidate almost completely eliminated tumor growth without causing toxicity, whereas tumors continued to grow in the control group of 14 mice.
O'Malley concludes, "We are optimistic that these drugs will eventually find their way into the clinic for use in patients."
