Survival vs. Longevity
Perhaps the best characterized downstream effector of PI3K is AKT/PKB (protein kinase B), which interacts with PIP3 through its PH domain. AKT is known to foster cell growth—a good thing when you want to protect cells against things like neurodegenerative disorders, but “obviously during cancer it’s a target that you’d want to limit,” pointed out Kenneth Maiese, M.D., chair of the department of neurology and neurosciences at the University of Medicine and Dentistry of New Jersey.
Dr. Maiese is interested in finding treatment strategies that balance the sometimes competing goals of increasing cellular protection in acute situations with preserving cell longevity. To that end, his lab looks at novel pathways that include transcription factors such as wingless, forkhead, and the sirtuins, and the role they may play in illnesses like Alzheimer disease, stroke, diabetes, and cancer.
Take, for example, the cytokine and growth factor erythropoietin (EPO), which is FDA approved to treat anemia. EPO stimulates AKT, and Dr. Maiese has shown that many of the sub-pathways from EPO lead to wingless and forkhead.
“What we’re trying to do, in a nutshell, is to either design new drugs or, using current drugs like EPO, to use better compounds or derivatives of these compounds that may increase intended efficacy (such as the treatment of anemia) but limit any complications (such as the growth of cancer).”
The pathways Dr. Maiese works on are very complex. Although they traditionally may have been thought to only do one thing, it may surprise people to learn of newly discovered, more novel, connections, he said. “It’s very important to understand how these pathways may function in certain environments, whether they affect acute cell survival, and whether they also affect long-term cell longevity.”
Kill the Chaperone
Many cancers are the result of constitutively active JAK-STAT signaling, and attempts to control that pathway are proceeding apace. Incyte’s JAK inhibitor, ruxolitinib, is under fast-track review by the FDA, and other compounds are currently in clinical trials. These ATP-competitive inhibitors target the protein’s kinase activity.
“But, oftentimes, these kinases will mutate and no longer be responsive to their inhibitor,” said David Proia, Ph.D., senior scientist at Synta Pharmaceuticals.
The Boston-based company uses a different strategy to target JAK. Ganetespib is an inhibitor of Hsp90, a chaperone protein essential for the folding of hundreds of client proteins including JAK2. By inhibiting the activity of Hsp90, JAK2 is unable to adapt its active conformation and is subsequently targeted for degradation by the proteasome.
“Regardless of the mutations that develop in a client kinase like JAK they still require Hsp90 for their maturation, and so they’re still candidates of Hsp90 inhibitors,” Dr. Proia pointed out.
Leukemic cell lines driven by JAK2 mutations are highly sensitive to ganetespib, due in part to the degradation of JAK2 and subsequent inhibition of its substrates, STAT3 and STAT5, transcription factors linked to tumor cell survival, proliferation, and metastasis.
Yet, it is its effect on Hsp90’s other clients that intrigues Dr. Proia so much about ganetespib—most specifically the “overwhelming effect that Hsp90 inhibitors have on cell division and DNA replication. It’s the coordinated insult on kinases like JAK, AKT, as well as cyclins like CDC2 and other checkpoint proteins: the culmination of inhibition of those targets I think is what really gives such great potency to ganetespib.”
Despite this, ganetespib doesn’t seem to have the toxicity issues that earlier-generation Hsp90 inhibitors had. Over 400 cancer patients have been treated in the clinic so far—ganetespib is currently in Phase IIB/III trials—and it is generally well tolerated, according to Dr. Proia.
Treating Alcoholism Like Cancer
The neurobiology of alcohol addiction is much more complicated than that of other drugs of abuse because it doesn’t have a well-defined site of action—alcohol is “not something that works on GPCRs or on dopamine transporters, for example, as cocaine does,” remarked Dorit Ron, Ph.D., professor of neurology at University of California San Francisco.
Although the mechanisms are different, the end result is the same—all drugs of abuse increase the levels of dopamine in the nucleus accumbens (NAc), a key component of the reward circuit—and “if you study addiction that’s usually the pathway where you start.”
Dr. Ron and her colleagues found that the PI3K/AKT/mTOR complex 1 (mTORC1) signaling pathway in the NAc is activated in response to alcohol, leading to translation of new synaptic proteins. “So we think this is a mechanism that can either lead to or maintain these phenotypes such as binge drinking, relapse, or seeking of alcohol.”
There are three drugs that the FDA has approved for treating phenotypes such as craving and relapse, “and they don’t work well,” Dr. Ron explained. “The problem with the drugs that we have now is that they basically shut off the reward pathway, so people don’t feel good; they basically don’t have the desire to do anything.”
But what if the same drugs that big pharma is developing for cancer could be used to treat alcohol abuse? As a proof of concept, Dr. Ron’s team showed that various inhibitors of the PI3K/AKT/mTORC1 pathway in the NAc decrease excessive alcohol intake and lessen other behaviors seen in preclinical rodent models of alcohol abuse.
In terms of anticancer agents for alcohol abuse, Dr. Ron pointed to Rapamycin, for example. “It does all the things that we want, but it really is very selective.” Although it’s an FDA-approved drug, because rapamycin is an immunosuppressant it won’t be used to treat alcohol abuse. But like many researchers at the conference, Dr. Ron is keeping her eye out for its derivatives, as well as other ways to interfere with intracellular signaling pathway, with fewer side effects.