While there
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
cancer therapeutics.
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.
