Seymour on the BCL-2 Pathway and Novel Therapeutic Strategies in CLL

John Seymour, MBBS, FRACP, PhD, director of hematology at the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne, Australia, explains why BCL-2 was considered an undruggable target for so long and what led to the development of effective BCL-2 inhibitors.

For years, BCL-2 was deemed an "undruggable" target in oncology. According to Seymour, the challenge lay in its unique mechanism of action. Unlike typical drug targets involving enzymatic catalysis, BCL-2 functions by protein-protein interaction, which occupies a binding site and prevents apoptosis. Ultimately, this created a hurdle in developing specific inhibitors.

“The vast majority of drugs that were developed work by binding to a catalytic or an enzymatic issue. Drugs like tyrosine kinase inhibitors in [chronic myeloid leukemia], imatinib [Gleevec], dasatinib [Sprycel], ponatinib [Iclusig], or the BTK inhibitors in other lymphoid malignancies, all prevent an enzymatic action,” explains Seymour.

Traditional cancer drugs, such as tyrosine kinase inhibitors, work by blocking enzymatic activity. However, BCL-2's role in simply binding and sequestering pro-apoptotic proteins required a different approach. The BCL-2 family is made up of multiple proteins with subtle structural differences that require extreme specificity to avoid off-target effects, like BCL-XL inhibition, which could lead to thrombocytopenia.

The development of venetoclax (Venclexta) marked a pivotal breakthrough. This BCL-2 inhibitor functions by displacing apoptotic activators, re-initiating programmed cell death. Seymour emphasizes that venetoclax's efficacy isn't solely dependent on BCL-2 levels; the presence and displacement of apoptotic activators, along with factors like MCL-1 interference, play crucial roles.

The drug's potent and rapid induction of apoptosis necessitates careful management. Seymour also highlights the importance of a gradual dose ramp-up to mitigate the risk of cytoreduction-related morbidity. This strategic approach ensures patient safety while maximizing the therapeutic benefits of targeting this once "undruggable" protein. The successful development of BCL-2 inhibitors underscores the evolving landscape of targeted cancer therapies, specifically for the treatment of hematologic malignancies.