Taxanes

Abstract

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.

Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin

“…Additional efficacy studies were completed in HT-29 (human colorectal adenocarcinoma) 3 and PANC-1 (human pancreas ductal carcinoma) models, both known targets of taxane therapy (Figure 4). 3,42 The trends in efficacy from the HT-1080 model were also observed in these models, where VTX at 250 mg/kg was well-tolerated and flat-lined tumor growth (Figure 4, Figure S26). Abraxane showed no significant therapeutic effect at 15 mg/kg in the PANC-1 model.…”

Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds

“…Bendamustine is being recognized as the drug of choice in the treatment of chronic lymphocytic leukemia and Non-Hodgkin lymphoma [15,16]. Gemcitabine and paclitaxel are used in the treatment of pancreatic cancer [17,18]. Irinotecan and 5-fluoro uracil have been used in a combination regimen for the treatment of colorectal and pancreatic cancers [19,20].…”

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

“…In addition to surgical resection, current therapeutic strategies to treat pancreatic cancer include radiation and chemotherapeutics like gemcitabine, 5-fluorouracil, oxaliplatin, nab-paclitaxel, and irinotecan1516. The identification of reliable biomarkers is needed to both prognosticate and potentially predict effective therapy for patients according to their tumor’s molecular profile.…”