Melanoma brain metastases: Biological basis and novel therapeutic strategies

Abstract

Cutaneous melanoma is the deadliest form of skin cancer, with a propensity to aggressively metastasize to multiple organs. 1 One common site of melanoma metastasis development is the brain, with 40-60% of patients with advanced melanoma showing evidence of CNS involvement. 2,3 Left untreated, MBMs progress rapidly, with most patients dying within 3 months. 4 As such, MBMs development accounts for 54% of melanoma deaths. 5 Melanoma cells disseminate to the brain through the circulatory system, with MBMs most commonly forming in areas of the brain with the highest blood flow. Around 80% of melanoma brain metastases (MBM) are located in the cerebral hemispheres, with a further 5% and 15% of MBM being located in the brain stem and cerebellum, respectively. 6 Initial clinical presentation of MBM includes headache, neurological impairment and seizures. 7 Risk factors for MBM development are male gender, head or neck as a primary disease site, the presence of visceral or nodal metastases, metastases at three or more visceral sites, high serum lactate dehydrogenase (LDH: which is a marker of higher disease burden) and high Clark's level/Breslow thickness of the primary melanomas. 7,8 For many years, MBM development had a dismal prognosis with no systemic therapies demonstrated to alter the natural history of the disease. Radiation therapy and surgery were the mainstays of treatment. The recent development of effective systemic therapies for advanced melanoma including immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) and the BRAF-MEK inhibitor-based targeted therapies has dramatically improved outcomes and overall

HSP70 Inhibition Blocks Adaptive Resistance and Synergizes with MEK Inhibition for the Treatment of NRAS-Mutant Melanoma

“…These data suggest that MEKi, and potentially also the BRAF/MEKi combination, might show enhanced efficacy in melanoma brain metastases. However, in general, MAPK inhibitors have shown poorer response rates for intracranial metastases compared with extracranial ones (37). To date, it has been unclear whether this is due to protection afforded from the brain microenvironment, or due to physical constraints, such as impaired ability of inhibitors to penetrate the blood-brain barrier and/or diffuse into tumors (38,39).…”

“…Overexpression of ID family members has been observed in multiple tumor types and can be associated with poor prognosis (44). Recently, ID3 was found to be upregulated in response to BRAFi, and to play a role in resistance to BRAF inhibition (37,38). ID3 expression in normal tissues is typically low or undetectable, making this protein an attractive therapeutic target in cancer.…”

How I treat brain metastases of melanoma

“…Patients without treatment of brain metastases generally have progression and die within 3 months. 3 …”

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

“…Metastasis of cancer cells to the brain is a complex, multi-step process [24, 26]. Although our studies did not recapitulate the entire brain metastatic cascade, we did model many key steps including 1) survival of the cells in the general circulation, 2) infiltration of the cells into the brain parenchyma and 3) the establishment of macrometastases.…”

“…Cells that metastasize to the brain must overcome multiple obstacles including survival under the high shear stress conditions of the circulatory system, extravasation through the bloodbrain-barrier and growth in the protease-rich environment of the brain parenchyma [24][25][26]. We hypothesized that the increased invasive capacity/stress tolerance of the HDAC8-driven cell state could increase MBM development.…”