Abstract C38: CRLX101 shows significant tumor penetration and superior activity compared to first- and second-line agents in NSCLC xenograft tumor models
| Autor: | Scott Eliasof, Sujan Kabir, Douglas Lazarus |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 10:C38-C38 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Introduction: CRLX101 is a tumor-targeted nanopharmaceutical designed to localize and accumulate in tumors. A randomized Phase 2 study is ongoing evaluating safety and efficacy of CRLX101 as a second- and third-line single agent therapy for the treatment of advanced non-small cell lung cancer (NSCLC). CRLX101 has previously demonstrated broad spectrum anti-tumor activity in xenograft tumor models of lung, ovarian, colorectal, pancreatic, breast and lymphoma. Here we present efficacy data of CRLX101 in NSCLC tumor models representative of clinical subgroups with limited therapeutic options, including squamous cell, and KRAS and EGFR mutants. Additionally, we present microscopy data illustrating that CRLX101 penetrates tumor tissues and is taken up by cancer cells. Experimental procedures: CRLX101 is composed of camptothecin, a highly potent topoisomerase 1 inhibitor, conjugated to a cyclodextrin-poly(ethylene glycol) co-polymer and self-assembles into nanoparticles of 20–50 nm in diameter. For in vivo efficacy, tumor-bearing mice were administered either CRLX101 or a comparator at their respective maximum-tolerated dose (MTD) and schedule, and tumor growth inhibition and survival were measured. For tumor localization studies, xenograft tumors were excised and CRLX101 was visualized with standard staining methods. Summary of data: In H1299 NSCLC model, CRLX101 showed superior activity over approved 1st and 2nd line agents resulting in 100% (10/10) cures. Gemcitabine and topotecan achieved 50% (5/10) or 10% (1/10) cures, respectively; and no cure (0/10) was observed with docetaxel, erlotinib or pemetrexed. In H520 squamous-type NSCLC model, CRLX101 showed a greater median survival and tumor growth delay than carboplatin, docetaxel or gemcitabine. Finally, CRLX101 showed significant tumor growth delay activity and survival improvements in G12C and G12S KRAS mutation models (H2122 and A549 respectively) and in a T790M EGFR mutation model (H1975). BrdU staining of tumor sections from H1299 NSCLC xenografts treated with CRLX101 demonstrated that the nanoparticle penetrated deep and uniformly in the tumor tissues and inhibited cell proliferation. Conclusions: CRLX101 is a novel nanopharmaceutical that has shown encouraging activity in advanced NSCLC patients in a Phase 1/2b clinical trial. Our preclinical data suggests that CRLX101 may be efficacious in patient population harboring mutations and drug resistance that render them refractory to currently approved agents. Our imaging data further support that CRLX101 can potentially achieve superior anti-tumor activity by localizing and penetrating deep into tumor tissues and releasing camptothecin inside tumor cells. In sum, our pre-clinical and clinical data together support that CRLX101 is potentially a versatile therapeutic option for the management of advanced NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C38. |
| Databáze: | OpenAIRE |
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