are many proposed “magic bullets” since the 1940s to combat cancer, more than
90% of these drug candidates fail during clinical trials.
Part of the reason for this failure is because many drugs are often effective in eliminating only the bulk of the tumor without even touching the root of the disease. With the discovery of cancer stem cells as the root of cancer in the 1970s, scientists began developing therapeutics against cancer stem cells with hopes to eliminate cancer for good.
Scientists are now a step closer to this feat. In a recent global collaborative effort lead by Dr. Catriona Jamieson at the Moores Cancer Research Center UCSD, scientists have recently identified a new drug that can effectively eradicate the root of chronic myeloid leukemia (CML).
The drug is called sabutoclax (ONT-701), a preclinical pan-Bcl-2 inhibitor licensed to Oncothyreon Inc.
CML is often characterized by its progression towards blast crisis; a condition identified by the uncontrolled growth and accumulation of immature white blood cells in the bone marrow and blood. This process is driven by a population of cancer cells dubbed the leukemia stem cells (LSCs), a cancer stem cell population defined by their capacity to regenerate the entire cellular profile of CML in vivo. These cells often demonstrate profound resistance to standard therapy such as the BCR-ABL-targeted tyrosine kinase inhibition (TKI), and are considered the root cause of CML relapse.
In the January 17th Cell Stem Cell online edition, Dr. Jamieson and colleagues reported that the root of CML lies is the aberrant elevation of Bcl-2 in leukemia stem cells (LSCs). Specifically, they discovered that Bcl-2 overexpression can render LSCs resistant to standard TKI treatment, and that the spared LSCs are the initiator of CML relapse. Jamieson and colleagues further found that pan-Bcl-2 inhibition with sabutoclax can render LSCs sensitive to TKI treatment, and successfully suppress CML relapse. Importantly, sabutoblax appeared to be effective against a broad panel of CML samples from patients in Canada, USA, and Italy. Based on these results, Jamieson concluded the sabutoclax may be the first drug that can successfully eradicate leukemia stem cells: the root of CML relapse.
Dr. John Reed from the Sanford-Burnham Medical Center stated that “Bcl-2 is the first anti-death protein to be discovered in cancer, and is one of the milestone discoveries that soon had widespread implications in cancer biology”. Bcl-2 overexpression is a key survival mechanism in cancer stem cells (CSCs): a subpopulation of cancer defined by their capacity to regenerate the tumor in which they reside.
According to Dr. Edward Chow at the University of Singapore,” the Bcl-2 protein family has been identified as critical primary or secondary oncogenic events during tumorigenesis”. In his recent review article published in the Clinical&Translational Medicine, Chow cited a series of studies showing that Bcl-2 elevation is a functional feature of CSCs in a wide range of cancers including breast cancer, colon cancer, and leukemia. The higher expression of Bcl-2 confers chemoresistance in CSCs, enabling these cells to survive and initiate cancer relapse following chemotherapy.
Interestingly, in a recent Cell Stem Cell paper, Dr. Craig T. Jordan at the University of Rochester Medical School found that the elevation of Bcl-2 in leukemia stem cells is “central” to their energy production, an “Achilles heel” that can be exploited in anti-cancer drugs to combat cancer stem cells and eliminate the root of cancer.
Jamieson shares the same conclusion. “Elimination of CSC
contributing to therapeutic resistance, the primary cause of cancer death, is
of high clinical importance”, said Jamieson. “The development of a small
molecule pan-BCL2 inhibitor would fulfill a vital unmet medical need.” With
generous support from the California Institute of Regenerative Medicine,
Jamieson is currently working on the preclinical development of Bcl-2
inhibitors for directed cancer stem cell therapy.
One of the
most potent pan-Bcl-2 inhibitors is sabutoclax (ONT-701), a compound discovered
by Dr. Maurizio Pellichia at the Sanford-Burnham Medical Institute at La Jolla,
CA. This drug is an early stage preclinical drug that is licensed exclusively
to Oncothyreon, Inc. a Seattle-based biotechnology company specializing in
Jamieson’s preclinical work with sabutoclax is a milestone in the preclinical development of cancer stem cell directed therapy, showing that Bcl-2 inhibition can indeed eliminate the root of recurring CML. As the most potent pan-BCL-2 inhibitor in the market, sabutoclax has the potential to be the next curative drug to combat the root of cancer: a “magic bullet” like no other.