The Evolving Landscape of Brain Metastasis

Abstract

Metastasis, involving the spread of systemic cancer to the brain, results in neurologic disability and death. Current treatments are largely palliative in nature; improved therapeutic approaches represent an unmet clinical need. However, recent experimental and clinical advances challenge the bleak long-term outcome of this disease. Encompassing key recent findings in epidemiology, genetics, microenvironment, leptomeningeal disease, neurocognition, targeted therapy, immunotherapy, and prophylaxis, we review preclinical and clinical studies to provide a comprehensive picture of contemporary research and the management of secondary brain tumors.

Keywords: brain metastasis; genomics; microenvironment; neurocognition; prevention; therapy.

Figure 1. Preclinical Strategies To Study Brain Metastasis.

(A) Cell line-derived xenotransplants (clDX) (human cancer cell lines implanted in immunosuppressed animals) have been extensively used [,,,–170]. clDX correspond to organotropic cell lines that target preferentially the brain. (B) The use of syngeneic mouse cell lines tropic to the brain allows using immunocompetent mice and to test them in genetically engineered mouse models (GEMMs) with an altered brain microenvironment [25,28,44]. (C) Few of the many GEMM or chemically induced cancer models result in brain metastases; three such models have been reported to generate brain metastasis. (D) Patient-derived brain metastasis xenotransplants (POX) reproduce the main histological and genomic findings in humans [39,42,140,171,172]. and are potential resources for investigation of targeted therapies. Abbreviation: BrM, brain metastasis.

Figure 2. The Complexity of the Brain Metastasis Microenvironment: Reactive Astrocytes.

(A) Reactive astrocytes initiate a defensive program aimed to eliminate recently extravasated metastatic cells. Astrocytes produce the plasminogen activators (PA) IPA and uPA that activate plasminogen into plasmin. The active enzyme eliminates many cancer cells. A limited number of metastatic cells block this response through anti-PA serpins (neuroserpin, NS; and serpin 82, S82). Serpins inhibit plasmin generation and thus prevent its deleterious effects on cancer cells. (8) Surviving cancer cells continue to interact with reactive astrocytes during brain colonization, establishing gap junctions with reactive astrocytes. Metastatic cells employ these C43 gap junctions to send calcium and cGAMP to astrocytes. Within astrocytes, cGAMP activates a signaling pathway leading to secretion of TNF and IFN-? to induce cancer cell proliferation. (C) Astrocytes are known secretory cells and also produce extracellular vesicles, including exosomes. In the context of brain metastasis, astrocyte-derived exosomes contain miR-19a. Once internalized by metastatic cells, miR-19a targets PTEN. Loss of PTEN increases cancer cell prolliferation and induces secretion of CCL2. Secreted CCL2 attracts prometastatic myeloid cells to favor metastatic brain colonization.

Figure 3. Experimental Models of Leptomeningeal Disease.

(A) Leptomeningeal disease has been established in immunocompetent and immunosuppressed mouse models. These models were generated by in vivo selection of cells proliferating in the cerebrospinal fluid (CSF) after inoculation into the cistema magna. After several rounds of in vivo selection, cell lines were inoculated intracardiacally. The subpopulation of cells targeting the leptomeninges after intracardiac inoculation was termed LeptoM. (B) Transcriptomic analysis of LeptoM and BrM (parenchymal brain metastasis) generated from the same parental cells revealed different profiles, indicating that leptomeningeal tropism constitutes a unique biological entity.

Figure 4. Pathophysiology of Radiation-Induced Damage.

Whole-brain radiation therapy (WBRT) induces secondary neurocognitive effects through two proposed mechanisms: destruction of neural stem cells located in the hippocampus, and/or damage to brain capillaries generating localized ischemic areas. By either mechanism, death of neuronal cells increases extracellular NMDA levels, resulting in toxicity for other cells. Abbreviation: H, hippocampus.

Figure 5. Patients with Brain Metastasis Eligible for Targeted Therapies.

Patients with lung cancer (A), breast cancer (B), or melanoma (C) brain metastasis may benefrt from targeted therapies. The main oncogenomic alterations that qualify these patients for this advanced treatment are shown, as well as the corresponding drugs that have shown efficacy in the brain. The percentage of patients harboring brain metastases that are susceptible to targeted therapy is very low (D).

Figure 6. Potential Approaches for lmmunotherapy in Brain Metastasis.

(A) Immune checkpoint inhibitors have been used in brain metastasis patients, and positive responses were reported. The potential mechanisms of action of this therapeutic approach include local and systemic effects. Locally derived effects include access of blocking antibodies to the brain parenchyma at therapeutic levels. In a complementary scenario, blocking antibodies would impair the checkpoint between antigen-presenting cells and lymphocytes in regional lymph nodes or other organs. Activated lymphocytes then access the brain to target cancer cells. (B,C) Experimental cell transfer immunotherapies that have been report for brain metastasis. (B) In a prevention setting, I FN- β-stimulated CD4⁺/CD8⁺. lymphocytes were induced in cancer-free mice into which metastatic cells were later inoculated, and T cells were able to prevent the development of brain metastasis. (C) After brain metastasis developed, a combined therapy including CDs⁺ Pmel-1 together with IL-2 and a gp-100 vaccine efficiently induced an initial expansion of T cells in the spleen and regional lymph nodes that later targeted cancer cells in the brain. Abbreviations: Ape, antigen-presenting cell; CC, cancer cell; TIL, tumor-infiltrating lymphocyte.

Figure 7. Potential Strategies To Prevent Brain Metastasis.

(A) Patients with HER2⁺ or triple-negative breast cancer, melanoma, small-cell lung cancer (SCLC), and stage IIV/IV non-scuamous non-small cell lung cancer (NSCLC) are at high risk for the development of brain metastasis during the progression of the disease. To guide clinical decisions in initiating brain metastasis-preventive trials, the discovery of biomarkers in preclinical models that could be translated to this group of patients will be a valuable resource. (B) Although clinically undetectable, brain micrometastasis might be present in asymptomatic patients with these high-risk tumors. Experimental findings suggest the importance of the interaction with the vasculature to allow metastasis-initiating cells to progress. Metastatic cells initially interact with pre-existing vessels (vascular cooption), and drugs targeting key mediators of this process will therefore impede their outgrowth. The efficacyof ALK inhibitors (iALK) that cross the blood-brain barrier (BBB) will allow targeting of cancer cells before they are detectable by imaging. Some micrometastases may have proliferated and started to influence the microenvironment, and at this point a VEGF-dependent switch from vascular cooption to angiogenesis is necessary to support the outgrowth of the metastatic lesion derived from lung cancer. Preventive trials with BBB-permeable Pl3K inhibitors might be considered because there is experimental evidence for their efficacy [41]. In addition, interaction with astrocytes could be targeted with blockers of gap junction communication (iGap junctions). (C) An alternative option will be to apply preventive therapies after neurosurgical resection, given the known ability of brain metastatic cells to infiltrate the tissue [57] and the likelihood that some cancer cells remain in surgical margins. In this sense the infiltrative phenotype of brain metastasis has been linked to reduced survval [167]. During reinitiation of local growth, the metastasis might follow the same principles and molecular regulation as during the inltial stages.