–Ganetespib highly effective in models of multiple oncogene addicted tumors–
–Ocular toxicities common in 2nd generation Hsp90 inhibitors associated with drug distribution properties–
–Results from a Phase 1 canine clinical trial of ganetespib pro-drug published in PLoS ONE–
“The results presented today and published in PLoS support the potential
of ganetespib activity in a broad range of tumor types, including
erlotinib-resistant non-small cell lung cancer,” said
The study showed that the retina/plasma exposure ratio and drug elimination rate profile play crucial roles in ocular toxicity seen with many 2nd generation Hsp90 inhibitors. These results suggest that drug distribution properties may explain the differences in level of ocular toxicity observed in the clinic with different Hsp90 inhibitors.
Ganetespib is a potent inhibitor of heat shock protein 90 (Hsp90) that is structurally unrelated to first-generation, ansamycin-family Hsp90 inhibitors such as 17-AAG or IPI-504, and has shown superior activity to these agents in preclinical studies. Ganetespib is currently being evaluated in a broad range of cancer clinical trials, including the global Phase 2b/3 GALAXY TrialTM in non-small cell lung cancer. In these trials ganetespib has shown anti-tumor activity in heavily pretreated patients with lung cancer, breast cancer, and other tumor types and has been well tolerated without severe liver or common ocular toxicities seen with other Hsp90 inhibitors.
Ganetespib highly effective in multiple oncogene addicted tumors
Title: Ganetespib, a unique resorcinolic Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile in preclinical models.
Permanent Abstract Number: B105
In in vitro studies ganetespib displays potent activity against drug resistant non-small cell lung cancer (NSCLC) cells. HCC827 NSCLC cells express the EGFR receptor and are highly sensitive to the EGFR inhibitor erlotinib. Activation of the c-MET receptor by its ligand hepatocyte growth factor (HGF) or amplification of the receptor by sustained exposure to erlotinib renders cells resistant to erlotinib. By inducing the degradation of EGFR and c-MET simultaneously ganetespib displays equipotent anticancer activity in both erlotinib sensitive and resistant NSCLC cells.
To determine whether these effects of ganetespib in vitro translated to antitumor efficacy in vivo, the activity of ganetespib was evaluated using a variety of doses and schedules in a series of xenograft models. Ganetespib exhibited potent antitumor efficacy in oncogene-driven xenograft models of solid and hematological malignancies.
Tumor penetration and the microregional activity of ganetespib were also assessed and showed that in vivo, ganetespib penetrates hypoxic regions of tumors and provides strong evidence that ganetespib efficiently distributed within the extravacular compartment, resulting in the sustained inhibition of proliferation and induction of apoptosis throughout the tumors.
Additional results showed ganetespib has a favorable hepatic and cardiac safety profile in vivo.
Ocular toxicities common in 2nd generation Hsp90 inhibitors may be successfully minimized
Title: A critical role for the tissue distribution profile in heat shock protein (Hsp) 90 inhibitor-induced ocular toxicity in rats.
Permanent Abstract Number: C212
The Hsp90 molecular chaperone controls the folding of key signaling molecules required to maintain normal cell function in many organs, including the retina. Ocular toxicities, including blurred vision, flashes, delayed light/dark accommodation, and photophobia have emerged as commonly-occurring adverse events in human clinical trials of certain second-generation Hsp90 inhibitors, observed in the majority of patients. These adverse retinal effects are believed to be due to drug-induced photoreceptor degeneration and cell death.
This study examined the relationship between retinal drug distribution profiles and photoreceptor degeneration in common Hsp90 inhibitors. 17-DMAG, 17-AAG, and STA-9056 (an Hsp90 inhibitor with comparable in vitro activity to 17-DMAG) were compared for retinal tissue exposure and plasma and cerebrospinal fluid levels. In contrast, both ganetespib and 17-AAG have shown clinical activity with a much lower incidence of ocular toxicity. 17-DMAG, for which visual changes have been reported in clinical subjects, produced marked photoreceptor cell death and was associated with a slow elimination rate and a high retina/plasma (R/P) ratio. In contrast, and consistent with the absence of clinically-reported visual changes, 17-AAG did not produce detectable photoreceptor injury. 17-AAG showed 94% drug elimination from the retina within 6 hours and a low R/P ratio. STA-9056 exhibited a drug distribution profile more comparable to 17-AAG than 17-DMAG: a moderately low R/P ratio, 79% retinal elimination within 6 hours and minimal degenerative effects within the eye.
These findings suggest that the retina/plasma exposure ratio and elimination rate profiles play important roles in ocular toxicity observed with certain Hsp90 inhibitors.
Phase I Evaluation of STA-1474, a Prodrug of the Novel HSP90 Inhibitor Ganetespib, in Dogs with Spontaneous Cancer
In addition to the data presented at the
Hsp90 is a chaperone protein required for the proper folding and activation of cellular proteins, particularly kinases. Many of these “client proteins” of Hsp90 – such as ALK, AKT, BCR-ABL, BRAF, KIT, MET, EGFR, FLT3, HER2, PDGFRA, VEGFR – have been shown to be critical to cancer cell growth, proliferation, and survival and are the targets of clinically validated cancer drugs. In preclinical studies, inhibiting Hsp90 causes the degradation of multiple client proteins and leads to cancer cell death.
Ganetespib (formerly STA-9090) is a potent, synthetic, small-molecule inhibitor of heat shock protein 90 (Hsp90). Hsp90 is a molecular chaperone required for the proper folding and activation of many cancer-promoting proteins, and is recognized as a key facilitator of cancer cell growth and survival. In preclinical experiments, ganetespib has shown activity in multiple tumor models both as a single agent and in combination with certain widely used cancer agents. Ganetespib is currently being evaluated in a broad range of cancer clinical trials, including the global Phase 2b/3 GALAXY trial in non-small cell lung cancer. In these trials, ganetespib has shown anti-tumor activity in heavily pretreated patients with lung cancer, breast cancer, and other tumor types and has been well tolerated with no evidence of severe liver or common ocular toxicities seen with other Hsp90 inhibitors. The most common adverse event seen to date has been diarrhea, which has been manageable with standard supportive care. Information on clinical trials with ganetespib can be found at www.clinicaltrials.gov.
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Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125