Kura Oncology Identifies Farnesylated Proteins Associated with CXCL12 Expression, Potential Biomarker of Clinical Benefit from Tipifarnib in Lymphoma Indications
– Tipifarnib is a farnesyl transferase inhibitor that downregulates CXCL12 –
– Gene expression of the exclusively farnesylated RHOE and PRICKLE2 proteins associated with CXCL12 expression –
– Pre-treatment tumor CXCL12 expression identified as a potential biomarker of clinical benefit in patients with DLBCL and CTCL –
– CXCL12 pathway biomarkers could enable multiple registrational strategies for tipifarnib –
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 (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, presented today, suggest that gene expression of the exclusively farnesylated proteins RHOE (RND3) and PRICKLE2 is strongly 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 (DLBCL) and mycosis fungoides, the most common form of cutaneous T-cell lymphoma (CTCL). This observation is consistent with similar findings from Kura in other indications such as peripheral T-cell lymphoma (PTCL), acute myeloid leukemia (AML) 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.
“The target of farnesyl transferase inhibitors has been elusive for several decades. These findings provide key evidence supporting the inhibition of the CXCL12 pathway as a mechanism of action mediating the activity of tipifarnib in the clinic,” said
Kura Oncology’s lead drug candidate, tipifarnib, is a potent and highly selective inhibitor of farnesylation, a key cell signaling process implicated in cancer initiation and development. Tipifarnib was previously studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets, however no molecular mechanism of action had previously been determined that could explain its activity across a range of diverse clinical indications, including squamous tumors that carry mutant HRAS, as well as in lymphoid, myeloid and solid tumors that do not carry HRAS mutations. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib.
This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of tipifarnib, the conduct, results and timing of clinical trials of tipifarnib, including Kura Oncology’s Phase 2 clinical trial of tipifarnib in patients with PTCL, plans regarding future clinical trials and development and commercial activities, the regulatory approval path for tipifarnib and expectations regarding biomarkers related to tipifarnib. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that
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Source: Kura Oncology, Inc.