Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Kelly, Michael G.; Mor, Gil; Husband, Alan J.; O’Malley, David M.; Baker, Lynda M.; Azodi, Masoud; Schwartz, Peter E.; Rutherford, Thomas J.

doi:10.1097/igc.0b013e3182126f05

Cited by 40 publications

(28 citation statements)

References 19 publications

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“…Sphingosine kinase 1 (SPHK1), which generates S1P, is also increased in cancer and shows oncogenic effects [83]. Phenoxodiol, an isoflavone-derivative SPHK1 inhibitor, is under clinical trial in patients with advanced cancer [84]. Therefore, simultaneous inhibition of both receptor-ligand interaction and ligand production may provide an effective approach to blocking LPA and S1P actions, thereby inhibiting tumors with elevated signaling of these pathways.…”

Section: Targeting Hippo-yap/taz Pathway For Drug Developmentmentioning

confidence: 99%

Regulation of the Hippo pathway and implications for anticancer drug development

Park

Guan

2013

Trends in Pharmacological Sciences

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Research in the past decade has revealed key components of the Hippo tumour-suppressor pathway and its critical role in organ size regulation and tumorigenesis. Recent progress has identified a wide range of upstream factors that control the Hippo pathway, which include cell-cell contact, various diffusible signals, and cognate receptors. Dysregulation of the Hippo pathway, caused by gene mutation or aberrant expression, promotes cell proliferation and tumorigenesis. Here, we discuss the current state of Hippo pathway research, primarily focusing on upstream regulators and protein-protein interactions as potential therapeutic targets. Consideration of pharmacological intervention of the Hippo pathway may provide novel avenues for future therapeutic treatment of human diseases, particularly in cancer.

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Section: Targeting Hippo-yap/taz Pathway For Drug Developmentmentioning

confidence: 99%

Regulation of the Hippo pathway and implications for anticancer drug development

Park

Guan

2013

Trends in Pharmacological Sciences

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“…Among 15 taxane-resistant patients, one patient had a complete response, 2 had PR and 8 had SD. These results, particularly the result from the cisplatin-phenoxodiol combination, are quite encouraging and warrant further investigation [104]. …”

Section: Clinical Trials Using Polyphenols and Chemotherapymentioning

confidence: 99%

Targeting Tumor Ubiquitin-Proteasome Pathway with Polyphenols for Chemosensitization

Shen¹,

Chan²,

Dou³

2012

ACAMC

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The development of tumor drug resistance is one of the biggest obstacles on the way to achieve a favorable outcome of chemotherapy. Among various strategies that have been explored to overcome drug resistance, the combination of current chemotherapy with plant polyphenols as a chemosensitizer has emerged as a promising one. Plant polyphenols are a group of phytochemicals characterized by the presence of more than one phenolic group. Mechanistic studies suggest that polyphenols have multiple intracellular targets, one of which is the proteasome complex. The proteasome is a proteolytic enzyme complex responsible for intracellular protein degradation and has been shown to play an important role in tumor growth and the development of drug resistance. Therefore, proteasome inhibition by plant polyphenols could be one of the mechanisms contributing to their chemosensitizing effect. Plant polyphenols that have been identified to possess proteasome-inhibitory activity include (−)-epigallocatechins-3-gallate (EGCG), genistein, luteolin, apigenin, chrysin, quercetin, curcumin and tannic acid. These polyphenols have exhibited an appreciable effect on overcoming resistance to various chemotherapeutic drugs as well as multidrug resistance in a broad spectrum of tumors ranging from carcinoma and sarcoma to hematological malignances. The in vitro and in vivo studies on polyphenols with proteasome-inhibitory activity have built a solid foundation to support the idea that they could serve as a chemosensitizer for the treatment of cancer. In-depth mechanistic studies and identification of optimal regimen are needed in order to eventually translate this laboratory concept into clinical trials to actually benefit current chemotherapy.

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“…No dose-limiting toxicities were observed when given intravenously, however diarrhea is limiting with the oral administration [2]. In a phase II study of intravenous phenoxodiol in combination with cisplatin or paclitaxel for women with epithelial ovarian, fallopian tube, or primary peritoneal cancers, three of 16 (19 %) platinum-refractory ovarian cancer patients had a partial response with 9 (56 %) patients achieving stable disease [3]. A subsequent phase III study evaluating an oral formulation of phenoxodiol in combination with carboplatin in patients with platinum-refractory ovarian cancer did not meet its primary endpoint of improved progression-free survival (clinicaltrials.gov, NCT00382811; MEI Pharma, Inc, data on file); however, these results may be confounded by bioavailability issues with the oral formulation.…”

Section: Introductionmentioning

confidence: 99%

A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors

et al. 2013

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SummaryBackground ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities (DLTs), pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. Methods Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. Results Eighteen patients were treated: 2.5 mg/kg (n = 3); 5 mg/kg (n = 3); 10 mg/kg (n = 3); 20 mg/kg (n = 6); 20 mg/kg twice-weekly (n = 3). There were no DLTs observed. Nearly all treatment-related toxicities were grade 1/2, specifically (all grades) nausea (22 %) and fatigue (17 %). Two patients experienced infusion reactions at the 20 mg/kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. Conclusions ME-143 was well-tolerated when administered intravenously at the maximally administered/recommended phase 2 dose of 20 mg/kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.

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Phase II Evaluation of Phenoxodiol in Combination With Cisplatin or Paclitaxel in Women With Platinum/Taxane-Refractory/Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Abstract: The combination of IV phenoxodiol with cisplatin or paclitaxel was well tolerated in this study. Cisplatin-phenoxodiol was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

Cited by 40 publications

References 19 publications

Regulation of the Hippo pathway and implications for anticancer drug development

Regulation of the Hippo pathway and implications for anticancer drug development

Targeting Tumor Ubiquitin-Proteasome Pathway with Polyphenols for Chemosensitization

A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors

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