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Profiles of brain metastases: Prioritization of therapeutic targets.

ABSTRACT: We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

SUBMITTER: Ferguson SD

PROVIDER: S-EPMC6235694 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metastatic spine disease is a heterogeneous clinical condition commonly requiring surgical intervention. Despite this heterogeneity, all cases share the common theme of altered tumor metabolism, characterized by aerobic glycolysis and high lactate production. Here we review the existing literature on lactate metabolism as it pertains to tumor progression, metastasis, and the formation of painful bone lesions. We included articles from the English literature addressing the role of lactate metabolism in the following: (I) primary tumor aggressiveness, (II) local tissue invasion, (III) metastasis formation, and (IV) generation of oncologic pain. We also report current investigations into restoring normal lactate metabolism as a means of impeding tumor growth and the formation of bony metastases. Both in vivo and in vitro experiments suggest that high lactate levels may be necessary for tumor cell growth, as small molecules inhibitors of lactate dehydrogenase (LDH5/LDHA) decrease both the rate of tumor growth and formation of metastases. Additionally, in vitro evidence strongly implicates lactate in tumor cell migration by driving the amoeboid movements of these cells. Acidification of the local bony tissue by excess lactate production activates CGRP+ neurons in the bone marrow and periosteum to generate oncologic bone pain. High lactate may also increase expression of acid sensing receptors in these neurons to generate the neuropathic pain seen in some patients with metastatic disease. Lastly, investigation into lactate-directed therapeutics is still early in development. Initial preclinical trials looking at LDH5/LDHA inhibitors as well as inhibitors of lactate transporters (MCT1) have demonstrated promise, but clinical work has been restricted to a single phase I trial. Lactate appears to play a crucial role in the pathogenesis of metastatic spine disease. Efforts are ongoing to identify small molecules inhibitors of targets in the lactogenic pathway capable of preventing the formation of osseous metastatic disease.

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Profiles of brain metastases: Prioritization of therapeutic targets.

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