Abstract 2509: Hsp90-inhibitor drug conjugates (HDC): Novel tumor-selective drug delivery platform with unprecedented anticancer activity

Abstract

Abstract Background: Various strategies have been used to make chemotherapeutic compounds more tumor selective in order to increase their safety and efficacy, but they were met with only limited success. Antibody Drug Conjugates (ADCs) and folate receptor mediated drug delivery (FRDC) are the emerging concepts in the drug delivery field, but they are limited to high potent toxins and narrow sets of indications. We established a novel tumor-directed drug delivery platform technology based on the unique property of Hsp90 inhibitors. One prominent feature of Hsp90 inhibitors is their ability to be retained selectively in tumor cells for a prolonged period of time. The difference in residency time in tumor against plasma and normal tissues is 10-25 fold. Moreover, the chaperone protein Hsp90 is overexpressed 2-3 fold in tumor compared to normal tissues. Combining the overexpression Hsp90 and longer residency of its inhibitors in tumor, a strategy to link anticancer drugs to an Hsp90 inhibitor, where the attached “payload” is released in the tumor selectively for prolonged periods, was conceived. Results: Though the HDC concept is applicable to most small molecule anticancer drugs, we chose a common topoisomerase-1 inhibitor (SN-38) for proof-of-concept studies. More than 100 Hsp90 inhibitor/SN38 conjugates were synthesized; we chose STA-12-8666 as our lead molecule based on its in vitro and in vivo pharmacokinetic properties. The conjugate binds strongly to Hsp90 as determined by client protein degradation assays and has good stability in plasma of several species (human>rat>mouse). In xenograft tumor tissue distribution studies, we demonstrate that mice dosed once weekly with 50 mg/kg STA-12-8666 clear the parental HDC and its cleavage products, SN-38 and the Hsp90 inhibitor, from plasma and normal tissue within 24 hr. However, we detected 0.6 µM and 0.3 µM SN-38 in tumor at 24h and 48h, respectively. SN-38 was not detected in tumor at 24h or 48h with an equivalent dose of the SN-38 prodrug, irinotecan. Xenograft studies using multiple cell lines demonstrated superior efficacy for STA-12-8666 compared to irinotecan. For example, in MCF-7 breast cancer xenografts, STA-12-8666 produced 70% regression in tumor volume compared to moderate tumor growth inhibition by irinotecan with no regression. Similar results were observed in in colon, SCLC, ovarian, bladder, NSCLC, melanoma models. Preliminary toxicological evaluation of STA-12-8666 resulted in better or comparable toxicities to that of irinotecan. Conclusion: We designed a novel tumor-directed drug delivery platform by conjugating previously validated small molecule chemotherapeutics to HSP90 inhibitors. Our lead candidate STA-12-8666, has great tissue distribution profile, superior in vivo antitumor activity and better safety profile than the active control irinotecan, warranting its clinical evaluation. Citation Format: Dinesh Chimmanamada, David Proia, Takayo Inoue, Luisa Shin Ogawa, Suqin He, Manuel Sequeira, Donald Smith, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Jaime Acquaviva, Masazumi Nagai, Yuan Liu, Josephine Ye, Dan Zhou, Andrew Sonderfan, Ritu Singh, Noriaki Tatsuta, Teresa Przewloka, Jun Jiang, Junyi Zhang, Weiwen Ying. Hsp90-inhibitor drug conjugates (HDC): Novel tumor-selective drug delivery platform with unprecedented anticancer activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2509. doi:10.1158/1538-7445.AM2014-2509