A New Class of Cancer Drug Moves Closer to Potential FDA Approval in Leukemia

Updated April 13, 2015

Venetoclax, a new type of cancer drug known as a Bcl-2 inhibitor, is showing great promise against a poor-prognosis form of chronic lymphocytic leukemia (CLL), and could work in other cancers as well.

Venetoclax, formerly known as ABT-199, attacks the protein molecule, Bcl-2, that allows cancer cells to survive despite signals from the body ordering damaged and abnormal cells to self-destruct.

If the oral pill wins Food and Drug Administration (FDA) approval, which many think it will in 2016, venetoclax will validate an approach conceived nearly 30 years ago – that cancer might be treated by forcing tumor cells to self-destruct. This was the vision of the late scientist Stanley Korsmeyer, MD, who along with colleagues at Washington University School of Medicine discovered the role of Bcl-2 in cancer. He subsequently joined Dana-Farber Cancer Institute and spent the years until his death in 2005 developing strategies for blocking Bcl-2 it as a novel cancer treatment.

Carrying the Research Forward

Anthony Letai, MD, PhD, a physician and scientist at Dana-Farber
Anthony Letai, MD, PhD, a physician and scientist at Dana-Farber

Anthony Letai, MD, PhD, a Dana-Farber investigator, was a post-doctoral protégé of Korsmeyer, and carried the important research forward after his mentor’s death. Matthew Davids, MD, MMSc, another Dana-Farber investigator, was a post-doctoral fellow in Letai’s lab and has led Dana-Farber’s clinical research effort that has moved venetoclax to the brink of FDA approval in CLL.

According to Davids, “Many CLL patients on venetoclax achieve a minimal residual disease (MRD) negative complete response, which means that even with highly sensitive techniques we cannot detect any leukemia in their body. Although this is not necessarily equivalent to cure, it does suggest that venetoclax has curative potential, particularly if used in combination with other drugs.”

Working in close collaboration with groups from Australia and other sites across the United States, the results for the CLL patients on this trial were recently published in the New England Journal of Medicine.

Matthew Davids, MD MMSc, a Dana-Farber physician-scientist
Matthew Davids, MD MMSc, a Dana-Farber physician-scientist

While still experimental, venetoclax has demonstrated an unprecedented response rate and some long-lasting remissions in patients with advanced CLL that carries a highly lethal genetic alteration called 17p. It’s also being tested in early trials in other types of leukemia, non-Hodgkin lymphoma, and multiple myeloma.

“I am very excited about venetoclax as a novel class of inhibitors that affects Bcl-2, particularly because some of its mode of action suggests that it may work well in combination with ibrutinib (another new CLL treatment)” says Jennifer Brown, MD, PhD, director of Dana-Farber’s CLL treatment center. “This could perhaps form the backbone for a potential combination therapy that is free of chemotherapy.”

Turning on Cell Death
Cancer cells, which are notorious escape artists, can be masters at cheating death. A process known as apoptosis, or programmed cell death, regulates the constant balance between our cells’ life and death. It’s evolution’s method of quality control — ordering unneeded or damaged cells to destroy themselves for the body’s greater good.

But cancer cells, concerned only with their own survival, can evade apoptosis. They commandeer an army of “pro-survival” proteins that intercept the molecular execution squad. It’s a strategy that helps explain why chemotherapy or radiation treatments don’t always eliminate cancer, and how even a few surviving cells can fuel its return.

Bcl-2 is one such pro-survival protein. Studying patients with follicular B-cell lymphoma, Korsmeyer concluded that when the Bcl-2 gene was overexpressed in cancer cells, it helped ward off cell death and enabled lymphoma cells to survive. A paper published in Cell in 1989 showed that introducing this abnormal gene in animal models prevented apoptosis, creating favorable conditions for cancer. This early work was considered a major insight that changed how researchers thought about cell death and survival, and eventually led Korsmeyer and colleagues at Dana-Farber to study manipulation of apoptosis molecules in an attempt to cause cancer cells to self-destruct.

What if a designer drug could disable the cancer’s survival signals, tipping the balance back once again to the self-destruct side? If it could be done without significantly injuring normal cells, it might open a new approach to fighting cancer. That was the proposal and the hope of Korsmeyer, Letai, and others at Dana-Farber for whom the success of venetoclax is a dramatic proof of principle.

After Korsmeyer joined Dana-Farber in 1998, he and his laboratory were acknowledged leaders of investigations into how Bcl-2 allows cancer cells to escape treatment, and how the pro-survival molecule might be targeted with designer compounds such as venetoclax. Dana-Farber physician-scientists, including Letai, had critical input into the prioritization of Bcl-2 inhibitors developed by Abbott Laboratories (now called AbbVie) in collaboration with Genentech, and guidance on which forms of cancer the inhibitors might target most effectively. These cancers have prominently included CLL, AML, and certain types of non-Hodgkin lymphoma.

Looking forward, researchers believe this class of agent will likely find broad application across a wide variety of cancers, likely in combination with existing or other novel therapeutics.

Ed. note: The U.S. Food and Drug Administration (FDA) announced on April 11, 2016, it approved Venclexta (venetoclax) for treatment of patients with a certain form of chronic lymphocytic leukemia who have been treated with at least one prior therapy. This is the first FDA-approved drug that targets the B-cell lymphoma 2 (Bcl-2) protein, which supports cancer cell growth and is over expressed in many patients with CLL.