Dr. Kipps on Signal Blockers, Venetoclax, ROR1 Antibodies and the Importance of More Research

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Thomas Kipps, MD, PhD, Deputy Director of Research Operations at the Moores Cancer Center at UCSD is not only a top researcher, but also a brilliant educator that is capable of explaining difficult concepts with colorful analogies. Picture BIM (pro cancer programmed cell death or cell suicide) and BCL-2 (pro cancer cell survival) as sumo wrestlers. Inhibit BCL-2 and the powerful BIM quickly brings down the cancer.

Take Away Points

• It is only by understanding the biology of the cancer cell, and how it is different from normal cells, that we can make progress in treating CLL.
• Because of this increased understanding, we are now able to target cancer cells much more specifically, rather than by just taking aim at rapidly dividing cells with traditional chemotherapy.
• By blocking homing and survival pathways with signal blockers such as ibrutinib or idelalisib, we make our CLL cells an easier target to kill.
• The RESONATE 2 trial demonstrated superior survival with this approach for CLL patients over 65 years old, leading to the FDA approval of frontline use of ibrutinib.
• The pro-survival BCL-2 is overexpressed in CLL and blocking it with venetoclax can lead to dramatic results, including some patients that have no detectable traces of their cancer (MRD negative).
• Rapid cell death can lead to the dangerous problem of tumor lysis syndrome (explained here) but now that the risk is mitigated with a new slower ramp up in dosing.

Venetoclax was recently approved in the USA for patients with 17p deletion who have had at least one prior treatment based on some of the research we discussed.

Here is a link to one of the many ASH 2015 abstracts on venetoclax in CLL where Dr. Kipps was one of the researchers.

Here is a link to my interview with Dr. Stephan Stilgenbauer from that same ASH meeting where we discuss his late-breaking powerful abstract on venetoclax.

Next we discussed ROR1, an embryonic antibody that we no longer need as adults, but that cancer cells including malignant B-cells appropriate to use to spread throughout the body.

Here is a link to one of our earlier discussions on ROR1.

In a recent development, I bet there will be a real push to commercialize cirmtuzumab, the first-in-class anti-ROR1 monoclonal antibody based on this press release.

Finally, Dr. Kipps reminds us that if we are smart in blocking multiple pathways, we can put our CLL cells into a death spiral. Our research work is not done. We have to close the deal and cure CLL.

Please enjoy our wide ranging discussion on transformative research from ASH 2015 where some of the research Dr. Kipps references helped lead to new approved indications for Imbruvica and the FDA approval of Venclexta in the USA.

Brian Koffman, MD  6/6/16