Synergistic activity of the Hsp90 inhibitor ganete

Authors: David A Proia Jim Sang Suqin He Donald L Smith Manuel Sequeira Chaohua Zhang Yuan Liu Shuxia Ye Dan Zhou Ronald K Blackman Kevin P Foley Keizo Koya Yumiko Wada

Publish Date: 2012/01/10

Volume: 30, Issue: 6, Pages: 2201-2209

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Abstract

Systemic chemotherapy using twodrug platinumbased regimens for the treatment of advanced stage nonsmall cell lung cancer NSCLC has largely reached a plateau of effectiveness Accordingly efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents either alone or in combination with standard of care therapies such as taxanes The molecular chaperone heat shock protein 90 Hsp90 represents an attractive candidate for therapeutic intervention as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades Ganetespib is a nonansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies including NSCLC Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models The combination of ganetespib with paclitaxel docetaxel or another microtubuletargeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro These benefits translated to improved efficacy in H1975 xenografts in vivo with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel Notably concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial including loss of prosurvival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib Taken together these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLCNonsmall cell lung cancer NSCLC accounts for 85 of all cases of lung cancer the leading cause of cancerrelated deaths worldwide 1 This high mortality is associated in part to the fact that a majority of patients present with advanced disease at the time of diagnosis with treatment options limited to systemic therapy Combination chemotherapy with a platinumbased regimen is the foundation of current treatment for patients with advanced NSCLC 2 Twodrug combinations consisting of either cisplatin or carboplatin with an additional ‘thirdgeneration’ cytotoxic agent paclitaxel docetaxel gemcitabine vinorelabine or pemetrexed represent the current standard of care for most patients 3 Paclitaxel and docetaxel comprise the taxane family of microtubule stabilizers widely used in the treatment of advanced NSCLC Docetaxel the only agent that is approved for both first and secondline treatment of NSCLC 4 was also the first drug to establish superior efficacy and tolerability over other thirdgeneration agents when used in combination with platinum compounds 3 Unfortunately however conventional chemotherapy has largely reached a plateau of effectiveness in improving survival rates for lung cancer patients 3 4In recent years the advent of new molecularlytargeted agents and refinements to existing systemic therapies such as the addition of the vascular endothelial growth factor VEGFbinding monoclonal antibody bevacizumab to platinum doublets the epidermal growth factor receptor EGFRbinding monoclonal antibody cetuximab or the use of EGFR inhibitors erlotinib and gefitinib as well as ELM4ALK inhibitors such as crizotinib have improved the therapeutic options for treating this disease 5 6 7 resulting in modest improvements in overall survival and quality of life for certain patient populations Despite this progress treatment outcomes are still considered disappointing 8 Clearly the development and use of novel therapeutic strategies to effectively combat NSCLC represents an urgent unmet medical needHeat shock protein 90 Hsp90 is a molecular chaperone required for the posttranslational stability and function of numerous key signal transduction proteins termed ‘client’ proteins many of which play critical roles in cell growth differentiation and survival 9 10 Importantly it is now recognized that the chaperoning activity of Hsp90 can become subverted during tumorigenesis to help facilitate malignant progression 9 Since multiple signaling cascades are regulated by this molecule the effects of pharmacological blockade of Hsp90 are transmitted to a variety of client proteins and biochemical pathways Because of this unique characteristic inhibition of Hsp90 can overcome signaling redundancies and mechanisms of drug resistance commonly observed in many cancers 11 12 13 In addition because tumor cells contain elevated levels of the active form of the chaperone complex relative to normal cells tumor cells have been shown to be selectively sensitive to Hsp90 inhibition 14 Thus Hsp90 provides an attractive molecular target for the development of novel anticancer agents 13 15 16Ganetespib formerly STA9090 is a potent and selective small molecule Hsp90 inhibitor 17 currently being evaluated in multiple clinical trials in solid tumor and hematological malignancies Recently a Phase 2b/3 trial was initiated in which it is being combined with docetaxel to treat patients with advanced NSCLC This indication is considered promising for the application of Hsp90 inhibitors 18 and importantly has provided a compelling rationale for the feasibility of combining Hsp90 inhibitors with other therapeutic agents For example mutated EGFR a known Hsp90 client protein is an important oncogenic driver in a subset of NSCLC patients 19 Accordingly Hsp90 inhibitors have demonstrated clinical efficacy when used in combination with EGFR tyrosine kinase inhibitors TKIs even in individuals who had progressed on TKI therapy 20 Of relevance here Hsp90 inhibitors have also been shown to potentiate the cytotoxic effects of paclitaxel in multiple tumor models including NSCLC 21 22 23 24These considerations therefore prompted a more comprehensive evaluation of ganetespib activity in combination with taxanes in preclinical models of NSCLC In the present study we show that combinatorial treatment results in synergistic antiproliferative and antitumor effects both in vitro and in vivo Our findings support the potential therapeutic value of ganetespib particularly in combination with docetaxel for the treatment of patients with NSCLCAll cell lines were obtained from the ATCC Rockville MD and were maintained according to standard techniques at 37°C in 5 v/v CO2 using culture medium recommended by the supplier All primary antibodies were purchased from Cell Signaling Technology CST Beverly MA Ganetespib 324dihydroxy5isopropylphenyl41methyl1Hindol5yl1H124triazol54Hone was synthesized by Synta Pharmaceuticals Corp Paclitaxel docetaxel and vincristine were purchased from LC Laboratories Woburn MA

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