Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models.

Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small 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 non-ansamycin 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 microtubule-targeted 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 pro-survival 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 NSCLC.

Dynamic output feedback H∞ control for 2D fuzzy systems.

In this paper, the dynamic output feedback H∞ control problem is considered for two-dimensional discrete fuzzy systems described by the second Fornasini-Marchesini state-space model. By introducing novel slacked matrices, sufficient criteria are established to guarantee an H∞ noise attenuation of the resulting closed-loop system. Then the proposed output feedback H∞ controller design method is applied to one-dimensional discrete-time fuzzy systems. It is worth mentioning that there is no rank constraints to system matrices. Moreover, the sufficient criteria are expressed as strict linear matrix inequalities, which can be effectively solved via MATLAB LMI toolbox. Finally, the effectiveness and advantage of the proposed approach are shown through two simulation examples.

Robust H(∞) control for a class of 2-D discrete delayed systems.

In this paper, we deal with the problem of robust H∞ control for a class of 2-D discrete uncertain systems with delayed perturbations described by the Roesser state-space model (RM). The problem to be addressed is the design of robust controllers via state feedback such that the stability of the resulting closed-loop system is guaranteed and a prescribed H∞ performance level is ensured for all delayed perturbations. By utilizing the Lyapunov method and some results, H∞ controllers are given. The results are delay-dependent and can be expressed in terms of linear matrix inequalities (LMIs). Finally, some numerical examples are given to illustrate the effectiveness of the proposed results.

Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy.

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 µm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.