The “Hallmarks of Cancer” paper by Douglas Hanahan and Robert Weinberg is a classic, and a must read (allow plenty of time) for anyone interested in cancer drug development.
The original 2000 paper, updated in 2011, identified six hallmarks of cancer, “distinctive and complementary capabilities that enable tumour growth and metastatic dissemination:”
- Sustaining Proliferative Signaling
- Evading Growth Suppressors
- Activating Invasion and Metastasis
- Enabling Replicative Immortality
- Inducing Angiogenesis
- Resisting Cell Death
Apoptosis or programmed cell death according to Hanahan and Weinberg is “a natural barrier to cancer development.” One of the ways cancer cells survive is by resisting cell death and disrupting the apoptosis signaling pathway; in other words the normal signals that trigger cell death don’t get through.
Researchers have shown that apoptosis is controlled at the cellular level, in the mitochondrion, by the Bcl-2 family of regulatory proteins (BCL-2, BCL-XL). Targeting BCL-2 (a protein that prevents apoptosis) could induce cell death and be a potentially successful anti-cancer strategy.
The result of our increased understanding of cancer biology has been the development of novel targeted drugs such as ABT-199, a potent and selective BCL-2 inhibitor. This is in early clinical development by AbbVie ($ABBV), a new biopharmaceutical company spun off from Abbott Laboratores ($ABT) last week.
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The data presented at AACR has now been published in Nature Medicine, online ahead of print (AOP) on 6 January 2013: “ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.”
Andrew Souers and colleagues from AbbVie and other institutions discuss how they re-engineered the since-discontinued navitoclax (ABT-263) to create a different and less toxic BCL-2 inhibitor. This new compound, unlike navitoclax, does not cause the thrombocytopenia associated with BCL-2-like1 (BCL-XL) inhibition. It’s a compelling story of science-based cancer drug development.
At the December 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta interim data was available from the phase 1 clinical trial of ABT-199 in Non-Hodgkin Lymphoma (abstract #304).
Matthew S. Davids, MD, Instructor in Medicine at Harvard Medical School & attending physician at the Dana Farber Cancer Institute, presented the results from the first-in-human phase 1, open-label, dose escalation, multicenter international trial in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL).
Of the 30 NHL patients enrolled, Dr Davids told the audience that 20 remained active, with a median time on study of 80 days (range 7 to 413).
ABT-199 particularly active in CLL & MCL
In 7 patients who had mantle cell lymphoma (MCL) in the 30 subject NHL trial, all seven (100%) obtained a partial remission. A 72 year old man with stage IV MCL obtained complete clinical resolution of auxiliary node clinically and 2 x 1 cm neck nodes by day 8.
ABT-199 is also active in CLL. Dr Davids briefly shared data previously presented at the 2012 Congress of the European Hematology Association (EHA) last year. The waterfall plot was quite impressive, unfortunately I could not obtain permission to share an iPhone photograph here. However, by my eye, the plot appeared to show that 30 of the 37 evaluable patients had a greater than 50% reduction in nodal size!
Dr Davids shared by email some additional commentary on the potential of ABT-199 in CLL:
“ABT-199 appears to be very active in patients with relapsed refractory CLL irrespective of high risk features such as del(17p).
Given its distinct mechanism of action from the BCR pathway antagonists, it has the potential to become an important additional treatment option in the armamentarium of CLL therapies.
Whether ABT-199 will be most useful as a signal agent, in combination with chemotherapy, or in combination with other novel agents will be an important question moving forward.”
ABT-199 has an acceptable safety profile
ABT-199 related grade 3 / 4 neutropenia was experienced in 3 of the 30 NHL phase 1 trial participants (10%). Dr Davids noted there were:
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No discontinuations due to adverse events
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No dose limiting toxicities observed in NHL patients
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No evidence of dose-dependent thrombocytopenia
He concluded that ABT-199 had an acceptable safety profile and further research is ongoing in NHL, both as a single agent and in combination with bendamustine/rituximab. The lack of severe thrombocytopenia is a definite improvement on its predecessor navitoclax.
Overall, ABT-199 is an exciting new agent in development with potential as a new treatment option for CLL & MCL. I look forward to hearing more about it at future scientific meetings.
In his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.