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Molecularly targeted therapies for p53-mutant cancers.

ABSTRACT: The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

SUBMITTER: Zhao D

PROVIDER: S-EPMC5664959 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Molecularly targeted therapies for p53-mutant cancers.

Zhao Dekuang D Tahaney William M WM Mazumdar Abhijit A Savage Michelle I MI Brown Powel H PH

Cellular and molecular life sciences : CMLS 20170622 22

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with muta ...[more]

PMID: 28643165

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Project description:ObjectivesCancer is increasingly classified according to biomarkers that drive tumour growth and therapies developed to target them. In rare biomarker-defined cancers, randomised controlled trials to adequately assess targeted therapies may be infeasible. Extrapolating existing evidence of targeted therapy from common cancers to rare cancers sharing the same biomarker may reduce evidence requirements for regulatory approval in rare cancers. It is unclear whether guidelines exist for extrapolation. We sought to identify methodological guidance for extrapolating evidence from targeted therapies used for common cancers to rare biomarker-defined cancers.DesignScoping review.Data sourcesWebsites of health technology assessment agencies, regulatory bodies, research groups, scientific societies and industry. EBM Reviews-Cochrane Methodology Register and Health Technology Assessment, Embase and MEDLINE databases (1946 to 11 May 2022).Eligibility criteriaPapers proposing a framework or recommendations for extrapolating evidence for rare cancers, small populations and biomarker-defined cancers.Data extraction and synthesisWe extracted framework details where available and guidance for components of extrapolation. We used these components to structure and summarise recommendations.ResultsWe identified 23 papers. One paper provided an extrapolation framework but was not cancer specific. Extrapolation recommendations addressed six distinct components: strategies for grouping cancers as the same biomarker-defined disease; analytical validation requirements of a biomarker test to use across cancer types; strategies to generate control data when a randomised concurrent control arm is infeasible; sources to inform biomarker clinical utility assessment in the absence of prospective clinical evidence; requirements for surrogate endpoints chosen for the rare cancer; and assessing and augmenting safety data in the rare cancer.ConclusionsIn the absence of an established framework, our recommendations for components of extrapolation can be used to guide discussions about interpreting evidence to support extrapolation. The review can inform the development of an extrapolation framework for biomarker-targeted therapies in rare cancers.

Dataset Information

Molecularly targeted therapies for p53-mutant cancers.

Publications

Molecularly targeted therapies for p53-mutant cancers.

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