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SAN DIEGO—While it's well known that aberrant mutations of genes leads to cancer, the actions of proteins aren't generally highlighted as being at fault in the disease. However, the latest study in years of research out of University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center has revealed that the protein Wnt5a—specifically, its interactions with tumor-surface proteins ROR1 and ROR2—is guilty of speeding the proliferation of chronic lymphocytic leukemia cells (CLL), the most common form of blood cancer in adults. This work appeared in The Journal of Clinical Investigation.
Wnt5a, as noted on GeneCards.org, is short for “Wingless-Type MMTV Integration Site Family, Member 5A.” The site reports that the protein “plays an essential role in regulating developmental pathways during embryogenesis” and “may also play a role in oncogenesis.” ROR1 and ROR2 are what are considered “orphan receptors,” in that they're expressed primarily during embryonic development. Their expression is suppressed during fetal development, especially ROR1's, and is negligible in normal adult tissues, but CLL and other solid tissue cancers re-express both proteins.
Low levels of ROR2 are found in some adult tissues, but ROR1 is only present in cancer cells. When Wnt5a signals, ROR1 and ROR2 come together to signal the growth and migration of cancer cells, which in turns leads to metastasis.
However, treating mouse models of CLL with cirmtuzumab interrupted this process, inhibiting the engraftment of leukemia cells and either slowing or stopping the cancer's spread.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears over-expressed in patients with CLL and can act as a survival/growth factor for leukemia cells. By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells,” senior author Dr. Thomas J. Kipps, Evelyn and Edwin Tasch Chair in Cancer Research and deputy director for research at Moores Cancer Center, said in a press release. “We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a Phase 1 clinical trial for patients with CLL.”
Cirmtuzumab is a humanized monoclonal antibody specific for ROR1, and proved capable of inhibiting the growth and spread of CLL cells in cell lines and mouse models of leukemia. The Phase 1 trial will assess cirmtuzumab's safety and tolerability in patients with relapsed or refractory CLL who are ineligible for chemotherapy.
Based on the team's previous work, there's plenty of potential left to explore in this area. In 2012, the team noted that ROR1 was found on a number of different types of cancer, especially those that are less differentiated and more likely to spread. In November 2014, cellular experiments seemed to indicate that cirmtuzumab could also prove effective against cancer stem cells, a leading cause of relapse in patients of many cancer types even after treatment.
This research was funded in part by the California Institute for Regenerative Medicine, the UC San Diego Foundation Blood Cancer Research Fund, the Leukemia and Lymphoma Society and the National Institutes of Health.