Not satisfied with an "undruggable" target in myeloma. Myeloma expert Dr. Jay Bradner goes after the most common myeloma target - MYC
BY KAREN CROWLEY Scientists are learning more about the gene responsible for myeloma and for all cancers and this knowledge will lead to better treatments for the disease. Myeloma Crowd founder Jenny Ahlstrom interviewed Dr. James Bradner for the mPatient Myeloma Radio podcast Sept. 11. Dr. Bradner is a staff physician at Dana-Farber Cancer Institute and associate professor in medicine at Harvard Medical School. On the podcast, Dr. Bradner explained discoveries hes made in his lab that could lead to better myeloma drugs. When Dr. Bradner trained as a hematologist in the late 1990s, he became frustrated with the few myeloma treatments available, such as melphalan, prednisone, and autologous transplantation. They were medicines that, its fair to say, werent developed or discovered with the disease myeloma in mind, he said. They were hand-me-downs. While these drugs did extend the lives of myeloma patients, Dr. Bradner said, they were crude, early substances. The drugs that were developed for myeloma in the 1950s, 60s, 70s, all the way through to around the year 2000, they werent directed at the disease itself, he said. They were medicines that could kill myeloma cells at doses that would not kill patients. Dr. Brander decided to retrain in chemistry at Harvard, hoping that a better understanding of the disease would lead to better drugs. When you take all of the things that a myeloma cell does that are toxic and all of the mutations that a myeloma cell possesses and all of the rearrangements of the chromosomes that can happen to lead to myeloma, one target rises to the top, he said. That target? A gene called Myc, which regulates cell growth. Its a gene that normally lives and exists in your body, Dr. Bradner explained. Everybodys born with two copies of Myc. And this gene exists so that during development, one cell can become two and then a fetus and then a child and then an adult. Normally, Myc is naturally regulated to turn off and on. If, God forbid, you cut your arm and you lost a lot of blood, your bone marrow will turn Myc on so that you could make more blood, but then would turn it off when there was enough blood made, Dr. Bradner said. In myeloma as in nearly all cancers this natural regulation of Myc is lost. The cell finds a way to keep Myc on and then fails to turn it off. In myeloma, Dr. Bradner explains, the Myc gene is taken out of its context where normally the body would say, Well, we have enough plasma cells, please stop making them, but now that gene is hooked up to a faucet that never shuts off in that cell. While current myeloma drugs are able to turn this faucet down for a time, eventually the myeloma cells figure out how to turn Myc back on. Its clear then what we need, Dr. Bradner said. We need Myc inhibitors. And while researchers have been trying to drug Myc since its discovery in 1984, there is still no drug that can directly bind to and impair the functioning of the Myc gene. Myc is, in the parlance of the field of drug discovery, a term I hate, called undruggable, Dr. Bradner said. Undruggable just means that theres no drug yet for a given protein target, and Myc is the prototypical example. Dr. Bradner set up a lab at Dana-Farber, not to create drugs, but to completely study Myc. The researchers in his lab have three goals: Discover what causes Myc to turn on, target the proteins that help Myc work, and develop technologies to drug Myc. We dont accept that Myc is undruggable, he said. We think that with new types of chemistry, new types of therapeutic approaches, new drug discovery technologies that maybe we can in 2014 do something that was impossible in 1984. Dr. Bradner said the most progress has been made in finding Mycs collaborators: the proteins that help it to work. If Myc doesnt work alone, he said, if its the godfather of the cancer mafia, lets execute the family. What are all of the proteins that Myc needs to work with and lets one-by-one develop chemical strategies for them. Dr. Bradner focused on a protein called BRD4. It turns out that for Myc to function in myeloma, it really needs this BRD4 protein to be nearby like a drinking buddy to function, he said. A chemist in Dr. Bradners lab, Jun Qi, created a BRD4 inhibitor, which he named JQ1. When JQ1 was tested on myeloma cells in the lab, the Myc gene turned off. And when it did that, Dr. Bradner said, the myeloma cells forgot they were myeloma and they went to sleep, something we call cellular senescence, and they died. When the drug was tested on mice, some of them had near-complete remissions within a week or two of taking the drug. But now theres a problem, Dr. Bradner said. This JQ1 molecule from our lab is not a drug. This molecule is not super-soluble. Its a molecule that we use in the lab like a prototype. Its not the iPhone 5; its not even the iPhone 1. Its like a Texas Instruments computer. I mean, this is something that we made for mice and for laboratory science. We didnt make it for humans. Because Dana-Farber is a charity and has an open-source philosophy, the lab made the JQ1 molecule freely available to any chemist worldwide. Drug companies were then able to show that the compound could work in treating myeloma, lymphoma, types of leukemia, and even HIV. Over about two years, the lab created a molecule called TEN-101, ten times more potent than JQ1. The molecule is now with a company called Tensha Therapeutics. The update there is that about, I suppose six to eight months ago, the molecule was first used in phase 1 clinical trials to establish the dose that is safe in humans, Dr. Bradner said. Its not a foregone conclusion that a new drug will be tolerated by humans. In the meantime, Dr. Bradner and his team are in the lab working on ways to drug Myc and its partners, and to create the next generation of prototypes for the pharmaceutical industry. How can you guys help? he said. Its a team effort, and my lab and I are genuinely honored by your interest. I get these emails from people that are so uplifting, and we put them right up on the bulletin board to make sure these young chemists and biochemists, who arent doctors and dont spend time with patients, know how much this community supports their science. So thank you for that. It means quite a lot to us.