In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1731-1731
Abstract:
Purpose/Objectives: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited, and in contrast to non-small cell lung cancer (NSCLC), few targetable oncogenes occur in SCLC. In this study, we tested new compound, STA-12-8666, which binds tumor-concentrated active form of shock protein 90 (HSP90) and has cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed issue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting. Materials/Methods: Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to isomolar irinotecan in lung tumors. Results: In all three models, high dose (150 mg/kg) STA-12-8666 was well tolerated. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for & gt; 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. STA-12-8666 was also effective in limiting or eliminating tumors growth that had progressed following initial treatment on standard first and second line agents for SCLC. Low dose (50 mg/kg) STA-12-8666 controlled but did not eliminate tumors: however, it strongly enhanced the action of 30 mg/kg carboplatin, resulting in tumor elimination. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that strongly contrasted with the pattern induced by irinotecan. Conclusions: Together, these results indicate that STA-12-8666 may be a promising therapy in both frontline and second line settings for SCLC and strongly support the evaluation of this compound in Phase I/II clinical trials. Note: This abstract was not presented at the meeting. Citation Format: Anna Gaponova, AS Nikonova,A Deneka,BL Egleston,S Litwin,JS Duncan,K Duncan,H Borghaei,R Mehra,DA Proia,Y Boumber, Erica Golemis. Preclinical testing demonstrates strong activity of STA-12-8666, an HSP90 inhibitor-SN-38 conjugate, in small cell lung cancer (SCLC). [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 1731. doi:10.1158/1538-7445.AM2015-1731
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-1731
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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