Drug targets hard-to-reach leukemia stem cells responsible for relapses

Chronic myeloid leukemia leads to production of many abnormal white blood cells, which do not fight infection as well as normal white blood cells. As these abnormal cells accumulate in blood and bone marrow, they crowd out healthy white blood cells, red blood cells and platelets, impairing normal functions. Credit: UC San Diego School of Medicine

Researchers at the University of California, San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive – and thus vulnerable – to a novel cancer stem cell-targeting drug currently under development.

The findings, published in the January 17 online issue of Cell Stem Cell, open the possibility that diseases like (CML) and some solid tumor cancers might – in combination with other therapies – be more effectively treated with this drug, and with a lower chance of relapse.

Led by principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine and director of at UC San Diego Moores Cancer Center, the researchers found that a compound called sabutoclax appears to selectively target LSCs that express particular protein isoforms through alternatively splicing, a fundamental process in which a gene is able to code for multiple proteins.

An emerging class of drugs called (TKI) – such as imitinib (Gleevec), gifitinib (Iressa) and sunitinib () – has become a popular anti-cancer treatment. However, current TKIs are not 100 percent effective. In cases of CML, for example, some LSCs tucked protectively within bone marrow elude destruction, develop resistance to therapy, self-renew and eventually cause the leukemia to dramatically return.

Jamieson and colleagues found that alternative splicing of BCL2 genes, which code for proteins involved in apoptosis or , specifically promoted of dormant white blood cell precursors into "blast crisis" LSCs. The blast crisis is the final phase of CML when overabundant, abnormal crowd out healthy cells, causing serious dysfunction.

Of clinical importance, they noted that sabutoclax, which suppresses all BCL2 anti-apoptotic proteins, renders these marrow-dwelling blast crisis LSCs sensitive – and more susceptible – to TKI-based therapeutics at doses that do not harm normal progenitor cells.

"Our findings show that pan-BCL2 inhibition will be critical for the eradication of cancer stem cells in CML and that there is an essential link between cancer stem cell dormancy, pro-survival BCL2 isoform expression and therapeutic resistance," Jamieson said. "By using a novel pan-BCL2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs."

The findings may have implications for treating solid tumor cancers, such as colon, prostate, breast, and brain cancers, noted Daniel J. Goff, the study's first author.

"With many of these tumor types being shown to harbor cancer stem cells, it raises the question of whether BCL2 family expression as well as isoform-switching may be crucial for the maintenance of cancer in these diseases as well," he said. "If so, they may also be candidates for treatment with a BCL2 inhibitor like sabutoclax."

Related Stories

Therapy targets leukemia stem cells

Feb 13, 2012

New research takes aim at stubborn cancer stem cells that are thought to be responsible for treatment resistance and relapse. The study, published by Cell Press in the February 14 issue of the journal Cancer Cell, provid ...

To prevent leukemia's dreaded return, go for the stem cells

Apr 05, 2012

Researchers reporting in the April Cell Stem Cell, a Cell Press publication, have found a way to stop leukemia stem cells in their tracks. The advance in mice suggests that a combination approach to therapy might stamp out ch ...

Combination therapy targets stubborn leukemia stem cells

May 17, 2010

New research discovers a combination of drugs that may prove to be a more effective treatment for a lethal form of leukemia. The study, published by Cell Press in the May issue of the journal Cancer Cell, reports that the ne ...

Recommended for you

Aspirin may lower the risk for aggressive prostate cancer

4 hours ago

Use of aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) was associated with a reduced risk for aggressive prostate cancer in men who had elevated prostate specific antigen (PSA) and a negative biopsy prior ...

User comments