Abstract 4409: STA-12-8666: a first-in-class HSP90 inhibitor drug conjugate (HDC) designed to selectively deliver chemotherapy to tumors

Chemotherapeutic drugs have been a mainstay of cancer therapy for decades; however, their effectiveness is often hampered by inefficient drug exposures and undesirable toxicity to normal tissues. Here we report on a novel drug delivery system, termed heat shock protein 90 (HSP90) inhibitor-drug conjugates (HDC), based on the property that small molecule inhibitors of HSP90 are preferentially retained in tumors cells in contrast to their rapid clearance from the circulation and normal tissues. By attaching chemotherapeutic drugs to HSP90 inhibitor backbones, HDC technology exploits this inherent retention property to efficiently deliver cytotoxic payloads directly into tumor tissues and provide extended drug exposure. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to the topoisomerase inhibitor SN-38 (active metabolite of irinotecan). In vivo modeling showed that the HSP90 inhibitor moiety was required for tumor-selective retention of STA-12-8666. Prolonged exposure of STA-12-8666 provided extended release of active SN-38 within the tumor compartment, generating up to two weeks of biomarker engagement (γ-H2AX) in contrast to 3-4 days with irinotecan. The broad therapeutic window exhibited by STA-12-8666 conferred superior efficacy and durability over irinotecan treatment alone - resulting in complete or near complete responses (CR) across a broad spectrum of solid tumor models, including an irinotecan-insensitive bladder cancer model and an aggressive lung cancer model where biweekly treatment of STA-12-8666 was initiated at a starting tumor volume 5-times greater that of typical studies. CRs were also observed in a human pancreatic PDX model following 3 doses of STA-12-8666, which were maintained for more than a month. Of note, recurrent PDX tumors remained sensitive to subsequent therapeutic challenge with STA-12-8666 suggesting HDC delivery may circumvent common mechanisms of resistance to irinotecan. Preliminary findings from an ongoing Phase 1 dose escalation study in dogs with spontaneous tumors suggest a well-managed safety profile and encouraging tumor responses. Overall, STA-12-8666 is a promising investigational agent prototypical of a platform technology that can be applied to other cytotoxic payloads to improve therapeutic indices as well as generating new pharmaceutical entities for evaluation as novel anticancer drugs. Citation Format: David A. Proia, Donald L. Smith, Junyi Zhang, Dan Zhou, John-Paul Jimenez, Jim Sang, Sarah Rippy, Cheryl London, Luisa S. Ogawa, Jun Jiang, Teresa Przewloka, Manuel Sequeira, Jaime Acquaviva, Suqin He, John Chu, Chaohua Zhang, Yuan Liu, Josephine Ye, Vladimir Khazak, Igor Astsaturov, Takayo Inoue, Noriaki Tatsuta, Richard C. Bates, Andrew Sonderfan, Dinesh Chimmanamada, Weiwen Ying. STA-12-8666: a first-in-class HSP90 inhibitor drug conjugate (HDC) designed to selectively deliver chemotherapy to tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4409. doi:10.1158/1538-7445.AM2015-4409