Dataset Information

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

ABSTRACT:

Background

Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies.

Scope of review

This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type.

Major conclusions

There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies.

General significance

The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.

SUBMITTER: Saletta F

PROVIDER: S-EPMC4633945 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

Saletta Federica F Wadham Carol C Ziegler David S DS Marshall Glenn M GM Haber Michelle M McCowage Geoffrey G Norris Murray D MD Byrne Jennifer A JA

BBA clinical 20140628

<h4>Background</h4>Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies.<h4>Scope of review</h4>This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clini ...[more]

PMID: 26675306

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Project description:Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery-namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex-correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

Dataset Information

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

Background

Scope of review

Major conclusions

General significance

Publications

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

Similar Datasets

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