Lexington, Mass.-based Synta Pharmaceuticals has released results on the use of ganetespib, the most advanced heat shock protein 90 (Hsp90) inhibitor in clinical development, in melanoma and colorectal cancer.
The data, compiled from several studies, demonstrates that ganetespib is active in tumor cell lines with acquired resistance to BRAF inhibitors, suggesting that ganetespib may be a promising approach to BRAF-driven cancers, including melanoma, thyroid and colon cancers. It also supports earlier data showing ganetespib is active in other cancer models of acquired resistance, making a case for combining ganetespib with other therapies in trials going forward, according to Vojo Vukovic, M.D, chief medical officer, Synta.
In BRAF-driven cancer studies, Synta used ganetespib to overcome acquired resistance to BRAF inhibitors in melanoma. Ganetespib displayed strong anticancer activity in human melanoma, thyroid and colon cancer cells driven by mutant BRAF. Similar to BRAF and MEK inhibitors, ganetespib effectively suppressed the activity of ERK kinase in melanoma cells, a critical component in the BRAF signaling cascade. In vivo, combinations of ganetespib with either BRAF or MEK inhibitors resulted in greater activity than monotherapy. Melanoma cells with high levels of COT, implicated in resistance to BRAF inhibitors, were found to be resistant to both BRAF and MEK inhibitors yet extremely sensitive to ganetespib. Tumor response was associated with ganetespib-induced abrogation of ERK activity and degradation of CRAF, proteins responsible for BRAF-inhibitor resistance.
“Targeting Hsp90 with ganetespib is a promising approach to the treatment of BRAF-driven cancers such as melanoma,” noted David Proia, Ph.D., Synta. “BRAF inhibitors have a short disease control, as acquired resistance frequently develops within 7-9 months after start of treatment. By deactivating the cascade of events that underlie resistance, ganetespib could be potentially utilized as a single agent or as part of a combination for BRAF–driven diseases.”
The majority of malignant melanomas contain activated PI3K/mTOR. In an effort to maximize antitumor activity ganetespib was further combined with PI3K/mTOR inhibitors. As single agents, ganetespib effectively blocked both ERK and AKT/mTOR signaling; by contrast, PI3K/mTOR inhibitors blocked their targets while activating ERK. Combining ganetespib with PI3K/mTOR inhibitors led to enhanced cytotoxicity in melanoma cells in vitro and decreased tumor burden in human melanoma xenograft mouse models as compared to monotherapy.
Another study focused on the antiangiogenic effects associated with the inhibition of HSP90 in colorectal cancer. Ganetespib was found to significantly inhibit two proteins that stimulate angiogenesis, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), in colorectal cancer cell lines. The antiangiogenic effect of ganetespib was confirmed by data showing blockade of tube formation in human umbilical vein endothelial cells (HUVEC), and inhibition of blood vessel formation in chicken eggs.
“Ganetespib demonstrated significant antiangiogenic actions in preclinical models of colorectal cancer, an effect associated with inhibition of proteins that regulate the formation and growth of new blood vessels in tumor cells,” stated Bassel F. El-Rayes, M.D., Winship Cancer Institute, Emory University. “Combining ganetespib with chemotherapy may therefore be a rational approach for treatment of colorectal cancer.”
A third study explored how the functional inhibition of HSP90 potentiates the effects of ionizing radiation in colorectal cancer.
HSP90 expression was found to be elevated in human colorectal tumors in comparison to paired normal tissue suggesting that HSP90 contributes to colorectal tumorigenesis. In vitro, ganetespib decreased the proliferation and clonogenicity of human colorectal cancer cell lines in part through the loss of AKT survival signaling. These effects were enhanced by either chemotherapy or ionizing radiation. The findings were consistent with data Synta released in 2011, where ganetespib was shown to synergize with radiotherapy in human cervical cancer tumor xenografts. Taken together, the preclinical findings identify ganetespib as a novel agent to be combined with radiation therapy.