Associating retinal drug exposure and retention with the ocular toxicity profiles of Hsp90 inhibitors

• Published in: Journal of clinical oncology Vol. 30; no. 15_suppl; p. 3086
• Main Authors: Zhou, Dan, Teofilovici, Florentina, Liu, Yuan, Ye, Josephine, Ying, Weiwen, Shin Ogawa, Luisa, Inoue, Takayo, Lee, William, Adjiri-Awere, Alfred, Kolodzieyski, Lev, Tatsuta, Noriaki, Wada, Yumiko, Sonderfan, Andrew J
• Format: Journal Article
• Language: English
• Published: 20.05.2012
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2012.30.15_suppl.3086

Abstract only 3086 Background: In clinical trials certain Hsp90 inhibitors, including AUY922, SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal dysfunction; others, including ganetespib and 17-AAG, have not. Previous animal toxicology experiments have suggested that retinal changes may be linked to photoreceptor degeneration or cell death. Here histopathologic changes and/or exposure profiles of Hsp90 inhibitors with or without clinical reports of ocular toxicity were evaluated to understand the observed differences in toxicity profile between agents in this class. Methods: We reviewed visual symptoms among subjects administered ganetespib, a potent Hsp90 inhibitor currently in phase II trials; evaluated retinal morphology in rats and cyno monkeys given ganetespib; and compared TUNEL-positive photoreceptors and drug exposure profiles in the retina of rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing. Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both drugs induced marked photoreceptor cell death (increased TUNEL-positive cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min remained in the retina). In contrast, and consistent with an absence of clinical visual changes, 17-AAG at the maximum tolerated dose did not elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h post-dose, 94% of 17-AAG had been eliminated from the retina, resulting in a low R/P ratio). Ganetespib given by 1‑hour IV infusion on days 1 and 15 of four 21-day cycles did not cause histopathological changes in the retina of rats or cynos. This finding is consistent with very low rate (~3%) of drug-related visual symptoms observed among over 300 subjects to date that received ganetespib in the clinic. Conclusions: Unlike AUY922 and 17-DMAG, ganetespib is not associated with ocular toxicity in humans, primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit visual disorders when associated with high retina/plasma exposure ratio and lower retinal elimination rate.