Kura Oncology reported new findings regarding the mechanism of action of the company’s lead drug candidate tipifarnib and its potential clinical applications. These findings are being presented at the American Association for Cancer Research, or AACR. Tipifarnib is a potent and selective farnesyl transferase inhibitor currently in a registration-directed clinical trial in patients with head and neck squamous cell carcinoma, or HNSCC, that carry mutations in HRAS, an exclusively farnesylated oncogene. Tipifarnib has also been shown to downregulate production of the chemokine CXCL12 in tumor models and cancer patients. New findings suggest that gene expression of the exclusively farnesylated proteins RHOE, or RND3, and PRICKLE2 is associated with CXCL12 expression in bone marrow stroma, which may provide a mechanistic rationale for why the CXCL12 pathway is a therapeutic target of tipifarnib and other farnesyl transferase inhibitors. In addition, an analysis of a subset of patients from a previously conducted Phase 2 trial of tipifarnib in patients with relapsed and refractory lymphomas identified pre-treatment tumor CXCL12 expression as a potential biomarker of clinical benefit in patients with diffuse large B-cell lymphoma, or DLBCL, and mycosis fungoides, the most common form of cutaneous T-cell lymphoma, or CTCL. This observation is consistent with similar findings from Kura in other indications such as peripheral T-cell lymphoma, acute myeloid leukemia and pancreatic cancer. CXCL12 and its receptors, CXCR4 and CXCR7, have been implicated in cancer progression and poor prognosis across a large spectrum of solid tumor and hematologic indications.
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