Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Bcl-2 apoptosis’

New Orleans – Saturday at the annual meeting of the American Society of Hematology (ASH) is mainly focused on education and science, although there are also several hundred posters available for those in need of a data injection.

What I like about the ASH education and scientific program is the high quality of the presentations from thought leaders who not only share where things are at, but just as importantly, where they may be going.

Yesterday, I attended a scientific session on Targeting Apoptosis in Lymphoid Malignancies. Organized by the Scientific Committee on Lymphoid Neoplasia, it featured three world-class speakers:

  • Douglas Green, PhD (St Jude Children’s Research Hospital)
  • Andreas Strasser, PhD (Walter and Eliza Hall Institute of Medical Research)
  • Anthony Letai, MD, PhD (Dana Farber Cancer Institute).

Regular readers of this blog will know that I have been following the development of ABT-199/GDC-0199 a novel Bcl-2 inhibitor in development by Abbvie & Genentech for a while now.

It’s a drug with a lot of promise, notwithstanding the tumor lysis syndrome (TLS) deaths seen in the phase 1 CLL dose escalation trial.

In the ASH 2013 scientific session, Dr Letai shared his insights on potential new drug development targets for a small molecule inhibitor of Bcl-2 such as ABT-199 that have come about as a result of BH3 profiling.

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The Food and Drug Administration (FDA) today approved Roche/Genentech’s obinutuzumab (Gazyva), also known as GA101, for untreated Chronic Lymphocytic Leukemia (CLL) in combination with the chemotherapy chlorambucil. Updated CLL11 trial data will be presented at the 2013 annual meeting of the American Society of Hematology (twitter #ASH13) in New Orleans from December 7-10. Gazyva is the first drug with a Breakthrough Therapy Designation to be approved by the FDA.

“Gazyva is an important new medicine for people with newly diagnosed chronic lymphocytic leukemia as it more than doubled the time a person lived without their disease worsening compared to chlorambucil alone,” said Hal Barron, M.D., chief medical officer and head of Global Product Development in a press release this morning.

Blog readers who attended the Roche analyst event in Chicago during the ASCO annual meeting in June will have noted that Roche’s long-term corporate strategy is focused on combining cancer drugs to improve treatment outcomes; a theme echoed by Charles Sawyers, President of the American Association for Cancer Research (AACR) during his ASCO Science of Oncology award lecture on “Overcoming Resistance to Cancer Drug Therapy“.

One of the combinations that Roche COO Daniel O’Day highlighted in the analyst event at ASCO was obinutuzumab/GA101 (Gazyva) with GDC-0199 (ABT-199) for the treatment of B-cell hematological malignancies such as CLL & non Hodgkin’s lymphoma (NHL). Obinutuzumab is a glyco-engineered CD20 antibody, while GDC-0199 is a Bcl-2 inhibitor. Both cause apoptosis (cell death) through complementary mechanisms of action.

An abstract on the preclinical data for this combination will be presented at the ASH annual meeting in New Orleans. A phase 1 clinical trial in CLL with this combination is currently underway and recruiting patients (NCT01685892).

I had the great pleasure at the recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Boston to talk with Deepak Sampath, PhD the leader of Genentech’s Bcl-2 preclinical research about the rational for the obinutuzumab plus GDC-0199 combination.

In this SoundCloud, Dr Sampath introduces himself and what his lab does at Genentech: What he said during the interview makes for interesting reading, and suggests this combo could have blockbuster potential!
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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.

The New Drugs on the Horizon session at the recent annual American Association for Cancer Research (AACR) meeting in Chicago showcased several drugs that I expect we will be hearing more of in the future.  I previously wrote about AZD3514 in prostate cancer.

Another small molecule that particularly impressed me in this AACR session was ABT-199, a potent and selective inhibitor of Bcl-2. Steven Elmore from Abbott Laboratories presented impressive early data from an ongoing phase I trial in patients with chronic lymphocytic leukemia (CLL).

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