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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
MINI37.02 - The Novel HSP90 Inhibitor-SN-38 Conjugate (STA-12-8666), Is Highly Active in Preclinical Models of Small Cell Lung Cancer (SCLC) (ID 911)
18:30 - 20:00 | Author(s): J.S. Duncan
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. In contrast to non-small cell lung cancer, few targetable oncogenes have been identified in SCLC. STA-12-8666 is a small molecule drug, which binds the tumor-concentrated active form of heat shock protein 90 (HSP90), with a 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 tissue. 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 for SCLC.
Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, cisplatin 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 irinotecan in lung tumors.
In all four models, high dose (150 mg/kg) STA-12-8666 was tolerated without side effects. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for > 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. Further, STA-12-8666 induced complete or partial regression of tumors that progressed following first or second line treatment with standard of care agents for SCLC. Low dose (50 mg/kg) STA-12-8666 inhibited tumor growth and enhanced the anti-tumor activity of 30 mg/kg carboplatin, resulting in complete tumor regression. 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 is different from that induced by irinotecan.
The findings that HSP90i-drug conjugate STA-12-8666 is highly active in preclinical models of SCLC (in both frontline and second line settings) support the evaluation of this novel compound in clinical trials.
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