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A quicker recovery
LOS ANGELES—While chemotherapy kills cancer cells, it also has an impact on the immune system. In addition to healthy regular cells that can get caught in the crossfire, blood stem cell activity is suppressed. These cells are found in the bone marrow, and are the source of all blood cells and immune cells such as white blood cells. A new study out of the University of California, Los Angeles (UCLA) could offer a way to help patients' immune systems recover more rapidly after chemo or radiation. The work was published in Nature Communications in a paper titled “PTPσ inhibitors promote hematopoietic stem cell regeneration.”
The focus of this new research—led by Dr. John Chute, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA—is a protein called receptor type protein tyrosine phosphatase-sigma, or PTP-sigma. Tyrosine phosphatases are somewhat infamous for being difficult to target therapeutically.
“PTPs have been recognized as important potential drug targets due to their involvement in the pathogenesis of numerous diseases,” the authors explain in their paper. “However, active site-directed PTP inhibitors frequently lack target specificity due to the high degree of homology between PTP active sites40,41. Negatively charged phospho-tyrosine mimetics also have poor bioavailability, as they are typically cell impermeable40. These barriers have hindered the development of PTP active site inhibitors for clinical use. A recent analysis of non-receptor and receptor PTPs for “druggability” suggested that the majority of PTPs were poor drug targets due to the hydrophilic or shallow nature of their catalytic pockets.”
As noted in a UCLA press release by Sarah C.P. Williams, active sites are the part of the protein that interacts with other molecules; a drug that blocks the active site on one of these proteins often ends up blocking sites on others as well, which leads to unwanted off-target effects.
Chute and colleagues have worked with PTP-sigma before. Back in 2014, they found that the protein was present on blood stem cells and has a similar role in those cells as it does in neurons. PTP-sigma is primarily found in the nervous system and plays a role in the regeneration of neurons; its activation impedes neuronal regeneration, while its absence allows easier nerve regeneration after injury. This work also marked when the team discovered that mice with a PTP-sigma gene deficiency were able to regenerate blood stem cells more rapidly after radiation, according to Williams' piece.
In this latest research, Chute linked up with Michael Jung and his colleagues. Jung is the UC Presidential Chair in Medicinal Chemistry and UCLA distinguished professor of chemistry and biochemistry, and an expert in drug development. Jung’s team worked to design and synthesize more than 100 candidate drugs capable of blocking PTP-sigma, which Chute and his team evaluated.
After testing a variety of compounds, they identified DJ009 as the best candidate; it allowed human blood stem cells to recover in vitro, and when those cells were transplanted into immune-deficient mice, the cells survived and functioned normally. When tested in mice exposed to radiation, those that did not receive DJ009 presented with dangerously low levels of white blood cells and neutrophils after two weeks; mice who did receive DJ009 had already had their white blood cell counts return to normal levels by that time. In terms of mortality, nearly all mice who received DJ009 survived, but more than half of those that did not died within three weeks. These results, according to Chute, indicate that this drug has potential in humans as well, and the research team is working to optimize DJ009 and similar candidates to be advanced toward human trials.
“The potency of this compound in animal models was very high,” remarked Chute, who is also a professor of medicine and radiation oncology in the division of hematology/oncology at the David Geffen School of Medicine at UCLA, and a member of the UCLA Jonsson Comprehensive Cancer Center. “It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”
“The paucity of therapeutics capable of accelerating HSC [hematopoietic stem cells] regeneration and hematopoietic reconstitution in myelosuppressed patients highlights an unmet medical need. Here we describe a class of selective, allosteric PTPσ inhibitors that promote the regeneration of murine and human HSCs capable of long-term hematopoietic reconstitution. Our results provide the mechanistic foundation for the development of selective PTPσ inhibitors to promote hematopoietic regeneration in patients receiving myelosuppressive chemotherapy, radiotherapy, and those undergoing myeloablative hematopoietic cell transplantation,” the authors concluded.
SOURCE: UCLA press release authored by Sarah C.P. Williams