Tuesday, February 23, 2016
Antibody-TKI Combination Impairs Leukemia Stem Cells
BY ROBERT H. CARLSON
A monoclonal antibody targeting chronic myeloid leukemia (CML) embryonic stem cells appears to potentiate tyrosine kinase inhibitor (TKI) therapy in CML mouse and tissue models.
Researchers at the University of California San Diego School of Medicine and the University of California San Diego Moores Cancer Center say the monoclonal antibody impairs the ability of cancer stem cells to regenerate, making them easier to eradicate with TKIs.
The findings were published in the Proceedings of the National Academy of Sciences (2015;112:15444–15449).
Novel Humanized CD44 Monoclonal Antibody-TKI Combo
The researchers found that targeting blast crisis leukemia stem cells with a humanized CD44 monoclonal antibody in combination with a targeted TKI impairs the leukemia stem cells' self-renewal, potentially leading to novel clinical combination strategies to eradicate the leukemia stem cell.
"Resistance in CML occurs because of mutations in the kinase domain, but also because other pathways are activated that would normally be activated only in an embryonic stem cell," said Catriona Jamieson, MD PhD, Associate Professor of Medicine and Chief of the Division of Regenerative Medicine at UC San Diego and senior author of the paper. "This [paper] is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival."
First author of the paper is Frida Holm, PhD, a Postdoctoral Fellow in Jamieson's lab.
When cancer co-ops embryonic signaling pathways they start to behave in a very primitive way, and that's a telltale sign the cancer is progressing and that there will be therapeutic resistance, Jamieson said.
"Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in CML switch to embryonic RNA splicing, which enhances their capacity to self-renew," Jamieson said. This embryonic patterning can be seen as a form of biomarker that could be used to predict progression and resistance to kinase inhibition, she added.
"When we see evidence of progression we should bring in a whole novel class of inhibitors that will block cancer's ability to clone itself," she said. "You can target cancer cells with a kinase inhibitor, but that's not getting at the embryonic stem cells that can self-renew or regenerate themselves, and that's what we really want to go after."
Embryonic stem cells can become dormant in protective microenvironments or niches, however, and that prevents them from responding to most therapies that target dividing cells, include TKIs, chemotherapy, and radiation therapy.
CD44 is a cell surface protein expressed by many tissues, and in this paper the researchers describe a very specific isoform, CD44 transcript variant 3, which is far more highly expressed by the leukemia stem cells.
"In essence this is very similar to what embryonic stem cells express, and that's the key—if we can see how leukemia and other cancers have co-opted the embryonic pathway, then we can target them," Jamieson said. "If we can detect and then prevent leukemia stem cells from cloning, that would be an important strategy to circumvent the therapeutic resistance that we see clinically."
Targeting Unique Cancer Stem Cell Vulnerabilities
She said research is moving towards targeted therapies used in combinations to eradicate cancer stem cell populations that promote relapse. One possible partner is the JAK inhibitor ruxolitinib, already approved by the Food and drug Administration, which could be partnered with a leukemia-stem cell targeting antibody.
"That's the game changer, it's not just throwing individually toxic chemicals together, it's actually coming up with therapies that target unique cancer stem cell vulnerabilities," she said.
Jamieson added that now is a very promising time for clinical development because there are quite a few agents available that work on different potential therapeutic liabilities of cancer.
"And if we can predict and prevent relapse by coming up with combination strategies, that's the really important part of this research," she said.