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The potential complementary role of targeted alpha therapy in the management of metastatic melanoma.

ABSTRACT: Standard treatments for metastatic melanoma have recently extended survival although many patients still succumb. Targeted alpha therapy (TAT) is a new therapeutic approach in which a cancer-targeting vector is labeled with an alpha-emitting radioisotope. Alpha-particles have the shortest range and highest energy transfer, and produce localized, high-density and lethal ionization damage to DNA. Thus, the targeted radiation can kill isolated cancer cells circulating in blood and lymphatic vessels, regress metastatic cancer cell clusters, and disrupt the vasculature of solid tumors. Preclinical and clinical studies of TAT for metastatic melanoma demonstrate its safety and anti-tumor activity. We recommend ways in which TAT can be used to treat small-volume disease sometimes in conjunction with cytoreductive anti-melanoma therapies.

SUBMITTER: Brown MP

PROVIDER: S-EPMC6094593 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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The potential complementary role of targeted alpha therapy in the management of metastatic melanoma.

Brown Michael P MP Bezak Eva E Allen Barry J BJ

Melanoma management 20151124 4

Standard treatments for metastatic melanoma have recently extended survival although many patients still succumb. Targeted alpha therapy (TAT) is a new therapeutic approach in which a cancer-targeting vector is labeled with an alpha-emitting radioisotope. Alpha-particles have the shortest range and highest energy transfer, and produce localized, high-density and lethal ionization damage to DNA. Thus, the targeted radiation can kill isolated cancer cells circulating in blood and lymphatic vessels ...[more]

PMID: 30190863

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Project description:Therapies that target oncogenes and immune checkpoint molecules constitute a major group of treatments for metastatic melanoma. A mutation in BRAF (BRAF V600E) affects various signaling pathways, including mitogen activated protein kinase (MAPK) and PI3K/AKT/mammalian target of rapamycin (mTOR) in melanoma. Target-specific agents, such as MAPK inhibitors improve progression-free survival. However, BRAFV600E mutant melanomas treated with BRAF kinase inhibitors develop resistance. Immune checkpoint molecules, such as programmed death-1 (PD-1) and programmed death ligand-1(PD-L1), induce immune evasion of cancer cells. MAPK inhibitor resistance results from the increased expression of PD-L1. Immune checkpoint inhibitors, such as anti-PD-L1 or anti-PD-1, are main players in immune therapies designed to target metastatic melanoma. However, melanoma patients show low response rate and resistance to these inhibitors develops within 6-8 months of treatment. Epigenetic reprogramming, such as DNA methylaion and histone modification, regulates the expression of genes involved in cellular proliferation, immune checkpoints and the response to anti-cancer drugs. Histone deacetylases (HDACs) remove acetyl groups from histone and non-histone proteins and act as transcriptional repressors. HDACs are often dysregulated in melanomas, and regulate MAPK signaling, cancer progression, and responses to various anti-cancer drugs. HDACs have been shown to regulate the expression of PD-1/PD-L1 and genes involved in immune evasion. These reports make HDACs ideal targets for the development of anti-melanoma therapeutics. We review the mechanisms of resistance to anti-melanoma therapies, including MAPK inhibitors and immune checkpoint inhibitors. We address the effects of HDAC inhibitors on the response to MAPK inhibitors and immune checkpoint inhibitors in melanoma. In addition, we discuss current progress in anti-melanoma therapies involving a combination of HDAC inhibitors, immune checkpoint inhibitors, and MAPK inhibitors.

Dataset Information

The potential complementary role of targeted alpha therapy in the management of metastatic melanoma.

Publications

The potential complementary role of targeted alpha therapy in the management of metastatic melanoma.

Similar Datasets

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