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According to the researchers, new inhibitors of these proteins have generated a lot of excitement in cancer research because they may work well to block growth in diverse cancer types and seem to be less toxic than traditional chemotherapies. However, they also have known for a long time that the three proteins don\u2019t always work together.<\/p>\n
\u201cThe field of the bromodomain proteins is fascinating\u201d said the study\u2019s first author Guillaume Andrieu, PhD, post-doctoral research associate at BUSM. \u201cA decade ago, the first drugs targeting the BET proteins were discovered. Since then, researchers have identified them as promising targets for cancer therapy, notably in lymphomas, but also in breast and prostate cancer. Yet, the contribution of each BET protein to cancer progression remains an obscure area as strategies aiming to block all of them at once have only been developed so far.\u201d<\/p>\n
\u201cIn this study, we show that sometimes individual BET bromodomain proteins even oppose each other. Therefore, any of the pan-BET inhibitors that are currently available, which block all three, could have unexpected side effects or leave us working in the dark about their exact mechanisms of action,\u201d explained Denis, associate professor of medicine and pharmacology at BUSM and corresponding author of the study. \u201cIt has been established for several years now that BET proteins also exert protective roles in the body, notably by restricting viral infections including HIV,\u201d added Andrieu. \u201cTherefore, it is urgent to develop new strategies to specifically target them to avoid deleterious effects.\u201d<\/p>\n
Using human breast cancer cell lines that model estrogen receptor positive and triple negative tumor types, the researchers exposed them to a pan-BET inhibitor and compared what happened when they blocked expression of the three genes individually. They saw four patterns of expression important for \u2018epithelial-to-mesenchymal transition\u2019 (a program that tumor cells often activate to metastasize and resist treatment): one for the inhibitor and one for each of the individual genes, with surprisingly little overlap among them. \u201cThe results clearly show that the three proteins work independently and confirm our long stated concern that current pan-inhibitors are not sufficiently selective among the three. Based on this research, there are promising avenues to explore for more fine-tuned experiments and treatments,\u201d said Denis.<\/p>\n
Denis believes this discovery should be seen in light of personalized medicine because some patients have high level expression of one or more BET proteins, some are intermediate and some are low. \u201cTargeted drugs and patient profiling help oncologists understand which patients are most likely to benefit from tailored approaches, and which patients should be directed to alternate therapies. Personalized medicine is the most important innovation in cancer therapy since methotrexate was discovered in the 1950s as a chemotherapeutic drug for cancer, so it\u2019s important that the field move forward both quickly and carefully.\u201d<\/p>\n
Cancer clinical trials using BET inhibitors are currently recruiting for leukemias, lymphoma, multiple myeloma, metastatic prostate cancer, lung cancer, glioblastoma and subtypes of breast cancer, including triple negative breast cancer. \u201cOur findings are urgently relevant to all of these trials, because the fundamental mechanisms we explored are shared across many cancer types,\u201d said Denis.<\/p>\n