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Profile of trebananib (AMG386) and its potential in the treatment of ovarian cancer.

ABSTRACT: Angiogenesis has been implicated in ovarian cancer pathogenesis. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been incorporated in ovarian cancer treatment in combination with chemotherapy both in a frontline setting and in disease recurrence. However, resistance eventually develops and treatment with bevacizumab is associated with increased risk for toxicities such as thromboembolic and hemorrhagic events, gastrointestinal perforation, and impaired wound healing, suggesting the need for new therapeutic approaches. Targeting of the angiopoietins/Tie2 pathway has gained accumulating interest during the last few years as a strategy to overcome bevacizumab resistance and toxicities. Trebananib is a first-in-class peptibody that inhibits angiopoietin 1 and 2 interaction with their receptor Tie2. The molecular profile of this agent, the preclinical data, and clinical studies demonstrating its efficacy in ovarian cancer are discussed in this review.

SUBMITTER: Liontos M

PROVIDER: S-EPMC4199819 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Profile of trebananib (AMG386) and its potential in the treatment of ovarian cancer.

Liontos Michalis M Lykka Maria M Dimopoulos Meletios-Athanasios MA Bamias Aristotle A

OncoTargets and therapy 20141004

Angiogenesis has been implicated in ovarian cancer pathogenesis. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been incorporated in ovarian cancer treatment in combination with chemotherapy both in a frontline setting and in disease recurrence. However, resistance eventually develops and treatment with bevacizumab is associated with increased risk for toxicities such as thromboembolic and hemorrhagic events, gastrointestinal perforation, and impaired w ...[more]

PMID: 25336975

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Project description:Our aim was to review the profile of vintafolide (EC145) and its rationale for use in platinum-resistant ovarian cancer. First we investigated the folate receptors (FRs), folate's pathway into cells, and its expression in normal and cancerous cells, before detailing the mechanism of action of vintafolide, its clinical applications, and the results of different study phases.A literature search was conducted through PubMed/Medline, Google, ClinicalTrials.gov and websites of pharmaceutical companies. Only articles in English were selected. All articles investigating folate receptor expression in ovarian cancer were selected first, than articles reviewing platinum resistance. Papers about vintafolide were collected, while those talking about synthesis and biochemistry concerns were excluded. The different Phase I and II studies were read, and an update on the website of pharmaceuticals companies were added.FR is a bundle-membrane receptor that is expressed normally in some normal tissues on the apical surface of cells, but highly expressed in ovarian cancer cells (>80%). It collects folate through endocytosis. Chemotherapy does not modify its expression in ovarian cancer cells, and its expression appears to be mostly associated with a poor prognosis and platinum resistance. Vintafolide is a folate-desacetylvinblastine monohydrazide conjugate, allowing a liberation of the drug into the cytoplasm of cancerous cells via the FR-? (FR?) and endocytosis, with high specificity. Phase I studies showed a 2.5 mg bolus dose to be nontoxic, with moderately adverse events. Phase II clinical trials for the first time demonstrated a statistically significant improvement in disease-free survival in patients with platinum-resistant ovarian cancer, and in those with a very poor prognosis who had already received three to four lines of systemic chemotherapy. The greater benefits were observed in patients with highly expressed FR?.Vintafolide is a promising targeted agent for recurrent platinum-resistant ovarian cancer, first, thanks to its mechanism of action and the characteristics of FR? in ovarian cancer, and, second, because of the favorable results observed in the first clinical trials on platinum-resistant ovarian cancer. Phase III clinical trials are currently ongoing and are expected to confirm these results.

Dataset Information

Profile of trebananib (AMG386) and its potential in the treatment of ovarian cancer.

Publications

Profile of trebananib (AMG386) and its potential in the treatment of ovarian cancer.

Similar Datasets

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