Browsing by Subject "Nab-paclitaxel"

Now showing 1 - 7 of 7
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    Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models
    (Impact Journals, 2016-07-26) Awasthi, Niranjan; Scire, Emily; Monahan, Sheena; Grojean, Meghan; Zhang, Eric; Schwarz, Margaret A.; Schwarz, Roderich E.; Department of Surgery, IU School of Medicine
    Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.
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    Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using UGT1A1 Genotype–Guided Dosing
    (American Association for Cancer Research, 2020-01-01) Joshi, Smita S.; Catenacci, Daniel V. T.; Karrison, Theodore G.; Peterson, Jaclyn D.; Zalupski, Mark M.; Sehdev, Amikar; Wade, James; Sadiq, Ahad; Picozzi, Vincent J.; Amico, Andrea; Marsh, Robert; Kozloff, Mark F.; Polite, Blase N.; Kindler, Hedy L.; Sharma, Manish R.; Medicine, School of Medicine
    Purpose: 5-fluorouracil/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. Experimental Design: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Results: Fifty patients enrolled: 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5/23 (22%) *1/*1 patients, 1/19 (5%) *1/*28 patients, and 0/7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. Conclusion: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.
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    Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer
    (Impact Journals, 2017-12-25) Awasthi, Niranjan; Monahan, Sheena; Stefaniak, Alexis; Schwarz, Margaret A.; Schwarz, Roderich E.; Surgery, School of Medicine
    Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.
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    Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers—Improvements in Clinical Efficacy and Safety
    (MDPI, 2023-07-15) Hassan, Md Sazzad; Awasthi, Niranjan; Ponna, Saisantosh; von Holzen, Urs; Surgery, School of Medicine
    Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
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    Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma
    (Elsevier, 2018-04) Hassan, Md Sazzad; Awasthi, Niranjan; Li, Jun; Williams, Fiona; Schwarz, Margaret A.; Schwarz, Roderich E.; von Holzen, Urs; Surgery, School of Medicine
    Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20%. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of paclitaxel, and the potential role of nab-paclitaxel has not been tested yet in experimental EAC. Here we tested the antiproliferative and antitumor efficacy with survival advantage of nab-paclitaxel as monotherapy and in combinations in in-vitro, and in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Nab-paclitaxel significantly inhibited in-vitro cell proliferation with higher in-vivo antitumour efficacy and survival benefit compared to paclitaxel or carboplatin treatments both in mono- and combination therapies. Nab-paclitaxel treatment increased expression of mitotic-spindle associated phospho-stathmin, decreased expression of proliferative markers and enhanced apoptosis. This study demonstrates that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents which supports the rationale for its clinical use in EAC.
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    Targeted dual inhibition of c‐Met/VEGFR2 signalling by foretinib improves antitumour effects of nanoparticle paclitaxel in gastric cancer models
    (Wiley, 2021-06) Grojean, Meghan; Schwarz, Margaret A.; Schwarz, Johann R.; Hassan, Sazzad; U., von Holzen; Zhang, Changhua; Schwarz, Roderich E.; Awasthi, Niranjan; Surgery, School of Medicine
    Elevated expression of multiple growth factors and receptors including c-Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c-Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses. In c-Met overexpressing MKN-45 cell-derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c-Met low-expressing SNU-1 or patient-derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN-45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c-Met, ERK, AKT and p38. Foretinib led to a decrease in Bcl-2, and an increase in p27, Bax, Bim, cleaved PARP-1 and cleaved caspase-3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c-Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients' survival.
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    Targeted FGFR/VEGFR/PDGFR inhibition with dovitinib enhances the effects of nab-paclitaxel in preclinical gastric cancer models
    (Taylor & Francis, 2021) Crawford, Kate; Bontrager, Erin; Schwarz, Margaret A.; Chaturvedi, Apurva; Lee, Daniel D.; Sazzad, Hassan Md; von Holzen, Urs; Zhang, Changhua; Schwarz, Roderich E.; Awasthi, Niranjan; Surgery, School of Medicine
    Standard chemotherapy regimens for gastric adenocarcinoma (GAC) have limited efficacy and considerable toxicity profiles. Nab-paclitaxel has shown promising antitumor benefits in previous GAC preclinical studies. Dovitinib inhibits members of the receptor tyrosine kinase family including FGFR, VEGFR and PDGFR, and has exhibited antitumor effects in many solid tumors including GAC. Based on the antimitotic, antistromal and EPR effects of nab-paclitaxel, we investigated augmentation of nab-paclitaxel response by dovitinib in multiple GAC preclinical models. In MKN-45 subcutaneous xenografts, inhibition in tumor growth by nab-paclitaxel and dovitinib was 75% and 76%, respectively. Dovitinib plus nab-paclitaxel had an additive effect on tumor growth inhibition and resulted in tumor regression (85% of its original value). Dovitinib monotherapy resulted in minimal improvement in animal survival (25 days) compared to control (23 days), while nab-paclitaxel monotherapy or dovitinib plus nab-paclitaxel combination therapy led to a clinically significant lifespan extension of 83% (42 days) and 187% (66 days), respectively. IHC analysis of subcutaneous tumors exhibited reduced tumor cell proliferation and tumor vasculature by dovitinib. In vitro studies demonstrated that dovitinib and nab-paclitaxel individually reduced tumor cell proliferation, with an additive effect from combination therapy. Immunoblot analyses of MKN-45 and KATO-III cells revealed that dovitinib decreased phospho-FGFR, phospho-AKT, phospho-ERK, phospho-p70S6K, phospho-4EBP1, Bcl-2 and increased cleaved PARP-1, cleaved-caspase-3, p27, Bax, Bim, with an additive effect from combination therapy. These results demonstrate that the FGFR/VEGFR/PDGFR inhibitor, dovitinib, has the potential to augment the antitumor effects of nab-paclitaxel, with implications for use in the advancement of clinical GAC therapy.