RXDX-107, A Dodecanol Alkyl Ester of Bendamustine, Demonstrates Greater Stability and Broad Antitumor Activity in Multiple Pre-Clinical Models of Solid Tumor Martin L, Johnson M, Patel R, Walsh C, Chua P, Tindall E, Shoemaker R, Oliver J, Lin R and Li G* Department of Translational Oncology, Ignyta, Inc 11111 Flintkote Avenue, San Diego, CA-92121, USA * Corresponding author: Li G, Department of Translational Oncology, Ignyta, Inc 11111 Flintkote Avenue, San Diego, CA-92121, USA, Tel: +858-255-5959; E-mail: gli@ignyta.com Received date: July 25, 2016; Accepted date: August 20, 2016; Published date: August 28, 2016 Copyright: © 2016 Martin L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Purpose: RXDX-107 is a dodecanol alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles. The anti-tumor activity of bendamustine in solid tumor malignancies has been less impressive, partially due to short half-life. RXDX-107 was designed to extend the half-life and improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. Experimental Design: The anti-tumor activity of RXDX-107 was measured in cellular anti-proliferation assay, cell-line derived xenograft (CDX) models and patient-derived xenograft (PDX) models. The mechanism of action and pharmacodynamics properties were measured by comet assay. The tumor accumulation was measured by a novel LC-MS/MS method. Results: In in vitro anti-proliferative studies, RXDX-107 displayed dose-dependent cytotoxicity against multiple solid tumor cell lines. While the IC50 of RXDX-107 were comparable to those of bendamustine, RXDX-107 displayed more complete cell killing. RXDX-107 exhibited enhanced pharmacodynamics properties, including stronger induction of pH2AX (a biomarker for DNA damage) and higher interstrand crosslinks (ICLs) formation. RXDX-107 significantly reduces tumor growth in human NSCLC xenograft models. RXDX-107 also showed single agent anti-tumor activities, including tumor regression in multiple PDX models of solid tumors including breast, lung, and ovarian cancer. Furthermore, the mode of action data exhibit slow and sustained release of bendamustine from RXDX-107, and high intratumoral accumulation of RXDX-107. Conclusions: Our preclinical data demonstrate potent and broad anti-tumor activity of RXDX-107 across a variety of solid tumor types, and support further clinical development of this novel drug candidate for the treatment of solid tumors. Keywords: Solid tumor; Breast; Hematological; Preclinical; Antimetabolic Statement of Translational Relevance Te bendamustine is an efective therapy in various hematological malignancies, but it has been less impressive in solid tumor setting, due to short half-life. Te manuscript provides a novel scientifc rationale and approach to improve half-life and bio-distribution properties of bendamustine, which may results in signifcant benefts for solid tumor patients. RXDX-107 showed enhanced pharmacokinetics and pharmacodynamics properties of RXDX-107 vs. bendamustine, including stronger induction of pH2AX, high interstrand crosslinks formation, extended half-life of bendamustine and high intratumoral enrichment of RXDX-107. Te manuscript demonstrates the superior anti-tumor property of RXDX-107 in preclinical models, including high tumor growth inhibition in cell line-derived xenograf (CDX) models of human NSCLC and multiple patient-derived xenograf (PDX) models of advanced solid tumors, such as breast, lung, and ovarian cancer. RXDX-107 is currently in Phase 1 clinical trial and capable of efectively targeting several solid tumor patients. Tus, the manuscript supports further clinical development of this novel compound in solid tumors. Introduction Bendamustine HCL is an alkylating agent that induces interstrand DNA crosslinks (ICLs) and causes cell death via several pathways, including intrinsic apoptosis. Bendamustine was originally developed in 1963 in the former East German Democratic Republic with the intent to produce an antitumor and antimetabolic agent with superior pharmacological properties compared to other nitrogen mustards. Unlike other alkylating agents, Bendamustine exhibits a unique structure and pattern of activity. Bendamustine contains three structural elements: 1) a chloroethylamine alkylating group, which is shared with other member of nitrogen mustard family, including cyclophosphamide, chlorambucil and melphalan; 2) a butyric acid side chain, which is shared with chlorambucil and melphalan; 3) a benzimidazole central ring system is unique to bendamustine [1-3]. Te complete mechanism of action of bendamustine in humans has not been fully characterized, but unique mechanisms of action include DNA damage stress response, inhibition of mitotic checkpoint, Martin, et al., Chemo Open Access 2016, 5:3 DOI: 10.4172/2167-7700.1000213 Research Article Open Access Chemo Open Access, an open access journal ISSN:2167-7700 Volume 5 • Issue 3 • 1000213 C h e m o t h er a p y : O p en A c c e s s ISSN: 2167-7700 Chemotherapy: Open Access