Teaching an Old Drug New Tricks to Fight Prostate Cancer
A class of drugs commonly used to treat mental health conditions are good prostate cancer cell killers to boot. Prostate Cancer Foundation Young Investigator, Dr. Matthew Galsky, and colleagues are in the process of modifying these drugs, maximizing their anti-cancer effects while uncoupling certain unpleasant side effects. Lab studies show these novel drugs attack the androgen receptor—a key driver of prostate cancer progression.
November 04, 2013 -- Researchers have noted that men with schizophrenia taking drugs known as tricyclic neuroleptics (such as Thorazine) to treat their mental illness have a significantly lower likelihood of developing prostate cancer. Additionally, laboratory studies show that tricyclic neuroleptic drugs can kill prostate cancer cells. Yet because certain psychotropic drugs in this class can have significant side effects, such as fatigue, lethargy, and abnormal muscle function, their potential as an anti-cancer treatment had not been fully explored.
Dr. Galsky and colleagues Drs. Goutham Narla and Michael Ohlmeyer are in progress of unlocking the unknowns about why these drugs show anti-cancer effects and have developed a new class of drugs related to tricyclic neuroleptics that retain the anti-cancer properties of the original drug class but lack many of the unpleasant side effects. The researchers concocted their new drugs by performing relatively minor chemical modifications to existing tricyclic neuroleptics—drugs such as Thorazine that have been used in patients for decades. Because the novel drugs are so similar to existing drugs, the likelihood of unforeseen side effects or toxicities when introduced into humans is less. And that means faster time from the lab bench to the bedside.
Their novel drug candidates kill tumor cells by activating an enzyme (protein phosphatase 2A, PP2A) that turns off key cancer-promoting proteins. (Specifically, PP2A removes chemical groups known as phosphates from other proteins; when stripped of their phosphate groups, the cancer-causing proteins, such as androgen receptor protein, are deactivated.) “This deactivation is akin to turning off a light switch,” says Galsky.
Because the PP2A enzyme is most often not functioning in prostate cancer cells, a drug that kick starts PP2A function may work nicely to squash prostate cancer cell growth. In his presentation at the 20th Annual Prostate Cancer Foundation Scientific Retreat in Maryland, Galsky said that their novel class of drugs (re-purposed tricyclic neuroleptics) did just that in pre-clinical laboratory studies.
Dr. Matthew Galsky, MD
Mount Sinai School of Medicine
Galsky also pointed out that to their knowledge this is the first clinically feasible disease treatment that works by activating a phosphatase enzyme. He also postulates that activating this enzyme may help combat resistance to drug therapies currently in use in patients. Also quite promising, said Galsky is that the androgen receptor protein—a key driver of prostate cancer progression—is degraded or broken down by their novel drug candidates in laboratory experiments. Their working hypothesis is that by dephosphorylating AR, their lead drug candidate TRC-794, targets AR for degradation. To date, the researchers have just begun to dose mice with TRC-794. And while no formal toxicity studies have been done, at 28 days of dosing, no serious impact has been noted in chemical panels or the behavior of the mice dosed.
PCF Funding: Dr. Galsky is a recipient of the 2012 Mortimer Sackler – PCF Young Investigator Award. Read more about his Young Investigator award and prior research on the FOX01 protein that led Galsky to better understanding of mechanism of action on how neuroleptic drugs fight cancer. (The FOX01 protein functions downstream of the PP2A protein, so modifying the action of PP2A also modifies the FOX01 protein.