Translational Research in Chronic Lymphocytic Leukemia (CLL) Therapeutics
Dr. Jian YU
Moores Cancer Center, University of California, San Diego
Dr. Yu was engaged in developing therapeutic strategies against leukemia, and published 4 papers as the first author in prestigious journals such as PNAS, J Clin Invest and Leukemia. As a lead researcher, Dr. Yu was involved in generating a first-in-class humanized mAb, cirmtuzumab, which is being evaluated in a phase I clinical trials for the treatment of Chronic Lymphocytic Leukemia patients.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) was considered as a novel therapeutic target for CLL, which is an onco-embryonic antigen that is exclusively expressed on CLL cells, but not on normal postpartum tissues. My study focused on investigation of the mechanism of ROR1 signaling and development of monoclonal antibodies (mAbs) against ROR1 for the treatment of CLL patients. Cirmtuzumab could inhibit Wnt5a-induced RhoA and Rac1 activation, and impair the capacity of ROR1 to enhance migration and proliferation of leukemia cells in vitro and in vivo, providing rationale for the ongoing clinical evaluation of cirmtuzumab in CLL patients or other ROR1-dependent malignancies. Also, we demonstrated that cirmtuzumab and ibrutinib may have synergistic activity in the treatment of patients with CLL, providing the rationale for clinical trials using cirmtuzumab in combination with ibrutinib, or another inhibitor of BTK, such as acalabrutinib, for treatment of patients with CLL or other B-cell malignancies dependent on non-canonical Wnt5a/ROR1 signaling.
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