“We hypothesized that concomitant targeting of BCL-2 and BCR-ABL tyrosine kinase could overcome these limitations,” the authors wrote.

“We discovered, over the last few years, that BCL-2, a gene that prevents cell death, is very important for myeloid leukemic stem cells,” Dr Andreeff explained. “These are the dangerous cells, because they lead to relapse sooner or later.”


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They combined the BCR-ABL inhibitor nilotinib with venetoclax (ABT-199), which targets the BCL-2 protein in cancer cells. BCL-2 regulates so-called “programmed cell death,” or apoptosis, and is linked to drug resistance and tumor cell survival. The FDA gave accelerated approval to venetoclax in April 2016 for the treatment patients with chronic lymphocytic leukemia who have a specific, 17p deletion, form of genetic alteration.

The results are dramatic.

One study found that ABT-199 “inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in 3 patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 hours.”3

Dr Andreeff and Dr Carter’s study found similarly powerful results.

“When ABT-199 and TKIs were combined,” they wrote, “the enhanced anti-leukemia activity was reflected in reduced leukemia burden and increased survival of CML mice after only 23 days of treatment. The combination was highly effective in preventing secondary engraftment and reducing leukemia LT-HSC frequency, suggesting the eradication of leukemia stem cells and potential of curing CML with an optimized treatment schedule.”

The results may offer promise in combating other cancers.

“This combination strategy may also apply to other malignancies that depend on kinase signaling for progression and maintenance.”

Encouraged by the results in mice, Dr Andreeff is clamoring for human trials.

What really counts here is to do this in patients. We have pushed for these trials for now over one year. What we need is very clear. We need industry support,” he said. “I’m a clinician. I’m not doing this to cure mice.”

References

  1. Carter BZ, Mak PY, Mu H, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8(355):355ra117. doi: 10.1126/scitranslmed.aag1180
  2. Combination therapy shows promise for chronic myeloid leukemia. MD Anderson Cancer Center website. https://www.mdanderson.org/newsroom/2016/09/combination-therapy-.html. Updated September 7, 2016. Accessed September 2016.
  3. Souers AJ, Leverson JD, Boghaert ER. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-8. doi: 10.1038/nm.3048