Researchers find that certain types of drug-resistant leukemia stem cells are vulnerable to sabutoclax, a novel cancer stem cell-targeting drug based on Sanford-Burnham research.
New experiments show that sabutoclax, a novel cancer stem cell-targeting drug that grew out of research at Sanford-Burnham Medical Research Institute, in combination with other therapies, could effectively treat diseases like chronic myeloid leukemia (CML). Sabutoclax might also lower the chance of relapse.
“The demonstration of sabutoclax’s preclinical activity in mouse models of CML is exciting and encourages further evaluation of this promising drug candidate for aggressive leukemias. We look forward to continuing our collaborative studies of sabutoclax, as we move this drug closer to the clinic,” said John Reed, M.D., Ph.D., professor and Donald Bren Chief Executive Chair at Sanford-Burnham.
Sabutoclax was first discovered as a result of research in the laboratories of Reed and his Sanford-Burnham colleague, Maurizio Pellecchia, Ph.D. The pair is now working with biotechnology company Oncothyreon Inc to develop sabutoclax into a potential anti-cancer drug. This latest study of sabutoclax’s efficacy, published January 17 in the journal Cell Stem Cell, was led by Catriona Jamieson, M.D., Ph.D., at UC San Diego Moores Cancer Center, in collaboration with Reed, Pellecchia and others.
Convincing leukemia stem cells to die
In CML, some leukemia stem cells are tucked protectively within bone marrow. There, they elude destruction, develop resistance to current therapies and proliferate. Eventually, these stem cells can cause the leukemia to return.
In this study, the research team found that sabutoclax selectively targets a certain type of leukemia stem cell. Sabutoclax destroys cells by suppressing some members of the Bcl-2 protein family. Bcl-2 proteins are involved in apoptosis, the normal cellular process of programmed cell death. Sabutoclax blocks anti-apoptotic Bcl-2 proteins that would otherwise keep cancer cells from dying.
The team also discovered that when dormant white blood cell precursors process Bcl-2 genes in an abnormal manner, they transform into “blast crisis” leukemia stem cells. The blast crisis is the final phase of CML, when overabundant, abnormal white blood cells crowd out healthy cells.
In this study, sabutoclax rendered blast crisis leukemia stem cells sensitive—and thus more susceptible—to other therapeutics at doses that do not harm normal white blood cell precursors.
Future targets for sabutoclax
The findings of this study may have implications for treating solid tumor cancers, such as colon, prostate, breast, breast and brain cancers, noted Daniel 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 Bcl-2 family expression as well as isoform-switching may be crucial for the maintenance of cancer stem cells in these diseases as well,” he said. “If so, they may also be candidates for treatment with a Bcl-2 inhibitor like sabutoclax.”
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This research was funded by the California Institute for Regenerative Medicine (grants TR2-1789, DR1-01430 and TG2-01154), U.S. National Institutes of Health (National Cancer Institute grants CA-55164 and CA-149668), Ratner Family Foundation, Ontario Institute for Cancer Research, Genome Canada, Ontario Genomics Institute and Canadian Institute of Health Research.
UCSD press release: Drug Targets Hard-to-Reach Leukemia Stem Cells Responsible for Relapses
Original paper:
Goff, D., Recart, A., Sadarangani, A., Chun, H., Barrett, C., Krajewska, M., Leu, H., Low-Marchelli, J., Ma, W., Shih, A., Wei, J., Zhai, D., Geron, I., Pu, M., Bao, L., Chuang, R., Balaian, L., Gotlib, J., Minden, M., Martinelli, G., Rusert, J., Dao, K., Shazand, K., Wentworth, P., Smith, K., Jamieson, C., Morris, S., Messer, K., Goldstein, L., Hudson, T., Marra, M., Frazer, K., Pellecchia, M., Reed, J., & Jamieson, C. (2013). A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition Cell Stem Cell DOI: 10.1016/j.stem.2012.12.011
