Improved Response to nab-Paclitaxel Compared with Cremophor-Solubilized Paclitaxel is Independent of Secreted Protein Acidic and Rich in Cysteine Expression in Non-Small Cell Lung Cancer
ABSTRACT The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is produced by tumor and/or neighboring stroma. SPARC expression is thought to facilitate the intracellular accumulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel, abraxane [ABX]). Gene hypermethylation is a common mechanism for loss of SPARC expression in non-small cell lung cancer (NSCLC). We aim to demonstrate the role of SPARC expression as biomarker for treatment selection using ABX in NSCLC and to evaluate the presence of synergistic antitumor effect when a demethylating agent is combined with ABX.
We analyzed the SPARC messenger RNA expression and SPARC gene methylation status in 13 NSCLC cell lines and 22 minimally passaged patient-derived (PD) NSCLC tumors using real-time (RT) polymerase chain reaction. The effect of ABX on tumor growth was compared with cremophor-solubilized paclitaxel (taxol) in severe combined immunodeficiency mice bearing SPARC-positive PD xenografts. The effect of pretreatment with a demethylating agent, 5-Aza-2'-deoxycytidine (DEC) in SPARC-negative tumors was assessed.
SPARC expression was weak to absent in 62% of established NSCLC cell lines and 68% of PD NSCLC tumor xenografts. SPARC expression could be up-regulated/restored by DEC treatment in both SPARC-negative cell lines and PD xenografts in vitro and in vivo. ABX demonstrated better antitumor efficacy than equitoxic dose of taxol in SPARC-expressing xenografts and some SPARC-negative xenografts. At equimolar doses in vitro, there was similar increased cytotoxicity on DEC pretreatment with either ABX or taxol in SPARC-negative cell lines. At equitoxic doses, there was similar additive antitumor activity of DEC with either ABX or taxol in SPARC-negative PD xenografts.
Endogenous SPARC status is somewhat uncorrelated with response to ABX in NSCLC. The greater antitumor effect of ABX compared with equitoxic dose of taxol observed in SPARC-expressing NSCLC tumors can also be seen in some SPARC-negative tumors. DEC pretreatment similarly enhanced antitumor activity with either ABX or taxol in SPARC-negative tumors.
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ABSTRACT: Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species-mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials. SIGNIFICANCE: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer.Cancer Discovery 03/2012; 2(3):260-9. DOI:10.1158/2159-8290.CD-11-0242 · 15.93 Impact Factor
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ABSTRACT: Anticancer drugs as well as nano-sized drug delivery systems face many barriers that hinder penetration deeply and evenly into solid tumors: a chaotic, tortuous vascular compartment resulting in tumor tissue distant from microvessels, a heterogeneous blood flow distribution with a concomitant defective microcirculatory exchange process, and a high interstitial fluid pressure. Furthermore, a resulting hostile tumor microenvironment characterized by hypoxia and/or extracellular acidosis can reduce the efficacy of anticancer drugs and confer drug resistance. Conversely, the enhanced permeation and retention effect has become the gold standard for developing macromolecular prodrugs and nano-sized drug delivery systems. Preclinically, there are meanwhile numerous in vivo proof-of-concepts that demonstrate not only a better tolerability of nano-sized drug delivery systems but also of enhanced antitumor efficacy compared to the conventional clinical standard. When faced with such a complex and heterogeneous disease as cancer in humans, it is more likely that a tailor-made combination of different therapeutic strategies will achieve the best results. In this respect, combining low-molecular weight cytostatic drugs with nano-sized drug delivery systems appears to be a natural choice for combination therapy that aims at distributing anticancer drugs at higher concentrations in the tumor in a more even manner. To date, such drug delivery approaches have been inadequately explored. In this review, we summarize the state-of-the-art of combination approaches with liposomal doxorubicin (Doxil™), the paclitaxel-albumin nanoparticle (Abraxane™) and the albumin-binding doxorubicin prodrug DOXO-EMCH (INNO-206), and discuss the insights obtained and perspectives for further research in this intriguing and promising field of drug delivery research.Journal of Controlled Release 06/2012; 164(2). DOI:10.1016/j.jconrel.2012.05.045 · 7.26 Impact Factor
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ABSTRACT: The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials.Advanced drug delivery reviews 08/2012; 64(13):1363-84. DOI:10.1016/j.addr.2012.08.005 · 12.71 Impact Factor