Tumor SPARC microenvironment signature (SMS) and plasma levels in a phase II trial of unresectable stage IV melanoma treated with <i>nab</i>-paclitaxel and carboplatin: A translational study of NCCTG trial N057E.

Markovic, S. N.; Suman, Vera J.; Trieu, V.; Liu, X.; Yeh, William; Hwang, Larn; Treece, Tina; Motamed, Kouros; Pramanik, Priyanka; Desai, Neil

doi:10.1200/jco.2010.28.15_suppl.8578

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“…A putative mechanism for the tumor accumulation of nab-paclitaxel is the presence of albumin-binding proteins such as gp60 and secreted protein acidic and rich in cysteine (SPARC/ ostenectin) in the tumor proximity [88]. Although SPARC expression seems to correlate with worse outcomes in pancreatic cancer [89], treatment of SPARC expressing tumors with nab-paclitaxel may confer improved efficacy [16,90,91].…”

Section: First-line Therapy Metastatic Diseasementioning

confidence: 99%

Taxanes

Chiorean¹,

Hoff²

2014

Anti-Cancer Drugs

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Taxanes are core therapeutic components for several advanced malignancies, and have been studied extensively in pancreatic adenocarcinomas with mixed results. Although the triplet combination FOLFIRINOX improves outcomes for patients with metastatic disease, it is compounded by significant toxicity, and novel regimens, rationally designed and based on thorough mechanistic activity on the tumor targets, are clearly needed. Solvent-based taxanes, docetaxel and paclitaxel, have little activity as single agents, but combinations with fluoropyrimidines and gemcitabine show efficacy, albeit they have not undergone testing in phase III trials. Pancreatic cancer is characterized by an abundant desmoplastic, fibroinflammatory and hypoperfused stroma, which has been blamed for its overall chemoresistance. Nanoparticle bound paclitaxel (nab-paclitaxel) has been pharmacologically designed as a novel water-soluble agent, with improved therapeutic index compared with the cremophor-based formulation, capable of achieving higher systemic exposure. In preclinical systems, when combined with gemcitabine, nab-paclitaxel increased intratumoral gemcitabine delivery, possibly due to inducing stromal 'collapse' and through inhibition of the gemcitabine-catabolizing enzyme cytidine deaminase. Most recently, the combination of nab-paclitaxel and gemcitabine demonstrated significant survival benefit with good tolerability in metastatic pancreatic cancer in the phase III trial MPACT, and now represents one of the gold-standard regimens for this disease. Although taxanes are overall potent chemotherapeutics for various cancers, it is clear that for meaningful results in pancreatic adenocarcinomas, rationally designed combinations and novel technologies for drug delivery are likely to be most successful.

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