San Diego, CA, United States
San Diego, CA, United States

Time filter

Source Type

Reckamp K.,City of Hope Comprehensive Cancer Center | Gitlitz B.,University of Southern California | Chen L.-C.,Nevada Cancer Institute | Patel R.,Comprehensive Blood and Cancer Center | And 4 more authors.
Cancer | Year: 2011

BACKGROUND: Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose-limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E2 metabolite (PGE-M). METHODS: Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE-M was used to assess biologic activity and inform the optimal biologic dose. RESULTS: Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2-14 cycles); 8 patients (40%) received prior EGFR-directed therapies. No dose-limiting toxicity was observed. Study drug-related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade ≥3 drug-related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE-M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE-M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control. CONCLUSIONS: Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M. © 2010 American Cancer Society.


Kirane A.,University of Texas Southwestern Medical Center | Toombs J.E.,University of Texas Southwestern Medical Center | Larsen J.E.,University of Texas Southwestern Medical Center | Ostapoff K.T.,University of Texas Southwestern Medical Center | And 4 more authors.
Carcinogenesis | Year: 2012

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 μM and remained sufficient to completely inhibit prostaglandin E 2 production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity. © The Author 2012. Published by Oxford University Press. All rights reserved.


Kirane A.,University of Texas Southwestern Medical Center | Toombs J.E.,University of Texas Southwestern Medical Center | Ostapoff K.,University of Texas Southwestern Medical Center | Carbon J.G.,University of Texas Southwestern Medical Center | And 5 more authors.
Clinical Cancer Research | Year: 2012

Purpose: COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/ erlotinib in preclinical models of pancreatic cancer. Experimental Design: Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined. Results: COX-2 inhibition reduced the IC50 of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression. Conclusions: Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer. ©2012 AACR.


Trademark
Tragara Inc. | Date: 2011-10-13

Pharmaceutical preparations for use in oncology, pain, inflammation, cachexia and related disorders.


Trademark
Tragara Inc. | Date: 2011-09-26

Pharmaceutical preparations for use in oncology, pain, inflammation, cachexia and related disorders.


Described herein are compositions and methods for using these compositions in the treatment of cancer, tumors, and tumor-related disorders in a subject.


Tragara Inc. | Entity website

Website Currently Being Updated Tragara is a pharmaceutical company based in San Diego, California focused on the clinical and commercial development of proprietary drugs for the treatment of various cancers. Tragara is managed by a team of entrepreneurs with both Big Pharma and Biotech experience in the development and commercialization of oncology therapeutics


Tragara Inc. | Entity website

Privacy Policy Tragara Pharmaceuticals, Inc respects the privacy of visitors to its Web site and recognizes the need for appropriate protection and management of personally identifiable information you share with us. However, any communication you send to Tragara Pharmaceuticals, Inc via this Web site or other electronic means is transmitted by you on a non-confidential basis ...


Tragara Inc. | Entity website

Terms of Use This Web site is designed to provide general information about Tragara Pharmaceuticals, Inv. It is not intended to provide medical advice ...


Loading Tragara Inc. collaborators
Loading Tragara Inc. collaborators