Incidence of brain metastasis according to patient race and primary cancer origin: a systematic review.

PURPOSE: A systematic review was conducted to investigate differences in incidence and primary origin of synchronous brain metastasis (sBM) in varying racial groups with different primary cancers. METHODS: Adhering to PRISMA 2020 guidelines a search was conducted using PubMed and Ovid databases for publications from January 2000 to January 2023, with search terms including combinations of "brain metastasis," "race," "ethnicity," and "incidence." Three independent reviewers screened for inclusion criteria encompassing studies clearly reporting primary cancer sites, patient demographics including race, and synchronous BM (sBM) incidence. RESULTS: Of 806 articles, 10 studies comprised of mainly adult patients from the United States met final inclusion for data analysis. Higher sBM incidence proportions were observed in American Indian/Alaska native patients for primary breast (p < 0.001), colorectal (p = 0.015), and esophageal cancers (p = 0.024) as well as in Asian or Pacific islanders for primary stomach (p < 0.001), thyroid (p = 0.006), and lung/bronchus cancers (p < 0.001) yet higher proportions in White patients for malignant melanoma (p < 0.001). Compared to White patients, Black patients had higher sBM incidence likelihood in breast cancer (OR = 1.27, p = 0.01) but lower likelihood in renal (OR = 0.46, p < 0.001) and esophageal cancers (OR = 0.31, p = 0.005). American Indian/Alaska native patients had a higher sBM likelihood (OR = 3.78, p = 0.004) relative to White patients in esophageal cancer. CONCLUSIONS: These findings reveal several comparative racial differences in sBM incidence arising from different primary cancer origins, underscoring a need for further research to explain these variations. Identifying the factors contributing to these disparities holds the potential to promote greater equity in oncological care according to cancer type.

CRISPRi screen of long non-coding RNAs identifies LINC03045 regulating glioblastoma invasion.

INTRODUCTION: Glioblastoma (GBM) invasion studies have focused on coding genes, while few studies evaluate long non-coding RNAs (lncRNAs), transcripts without protein-coding potential, for role in GBM invasion. We leveraged CRISPR-interference (CRISPRi) to evaluate invasive function of GBM-associated lncRNAs in an unbiased functional screen, characterizing and exploring the mechanism of identified candidates. METHODS: We implemented a CRISPRi lncRNA loss-of-function screen evaluating association of lncRNA knockdown (KD) with invasion capacity in Matrigel. Top screen candidates were validated using CRISPRi and oligonucleotide(ASO)-mediated knockdown in three tumor lines. Clinical relevance of candidates was assessed via The Cancer Genome Atlas(TCGA) and Genotype-Tissue Expression(GTEx) survival analysis. Mediators of lncRNA effect were identified via differential expression analysis following lncRNA KD and assessed for tumor invasion using knockdown and rescue experiments. RESULTS: Forty-eight lncRNAs were significantly associated with 33-83% decrease in invasion (p<0.01) upon knockdown. The top candidate, LINC03045, identified from effect size and p-value, demonstrated 82.7% decrease in tumor cell invasion upon knockdown, while LINC03045 expression was significantly associated with patient survival and tumor grade(p<0.0001). RNAseq analysis of LINC03045 knockdown revealed that WASF3, previously implicated in tumor invasion studies, was highly correlated with lncRNA expression, while WASF3 KD was associated with significant decrease in invasion. Finally, WASF3 overexpression demonstrated rescue of invasive function lost with LINC03045 KD. CONCLUSION: CRISPRi screening identified LINC03045, a previously unannotated lncRNA, as critical to GBM invasion. Gene expression is significantly associated with tumor grade and survival. RNA-seq and mechanistic studies suggest that this novel lncRNA may regulate invasion via WASF3.

Comparative analysis of the spatial distribution of brain metastases across several primary cancers using machine learning and deep learning models.

OBJECTIVE: Brain metastases (BM) are associated with poor prognosis and increased mortality rates, making them a significant clinical challenge. Studying BMs can aid in improving early detection and monitoring. Systematic comparisons of anatomical distributions of BM from different primary cancers, however, remain largely unavailable. METHODS: To test the hypothesis that anatomical BM distributions differ based on primary cancer type, we analyze the spatial coordinates of BMs for five different primary cancer types along principal component (PC) axes. The dataset includes 3949 intracranial metastases, labeled by primary cancer types and with six features. We employ PC coordinates to highlight the distinctions between various cancer types. We utilized different Machine Learning (ML) algorithms (RF, SVM, TabNet DL) models to establish the relationship between primary cancer diagnosis, spatial coordinates of BMs, age, and target volume. RESULTS: Our findings revealed that PC1 aligns most with the Y axis, followed by the Z axis, and has minimal correlation with the X axis. Based on PC1 versus PC2 plots, we identified notable differences in anatomical spreading patterns between Breast and Lung cancer, as well as Breast and Renal cancer. In contrast, Renal and Lung cancer, as well as Lung and Melanoma, showed similar patterns. Our ML and DL results demonstrated high accuracy in distinguishing BM distribution for different primary cancers, with the SVM algorithm achieving 97% accuracy using a polynomial kernel and TabNet achieving 96%. The RF algorithm ranked PC1 as the most important discriminating feature. CONCLUSIONS: In summary, our results support accurate multiclass ML classification regarding brain metastases distribution.

SRRM4-mediated REST to REST4 dysregulation promotes tumor growth and neural adaptation in breast cancer leading to brain metastasis.

BACKGROUND: Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases (BBMs) has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Serine/Arginine Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells. METHODS: Utilizing pure neuronal cultures and brain-naive and patient-derived BM tumor cells, along with in vivo tumor modeling, we surveyed the early induction of mediators of neural acclimation in tumor cells. RESULTS: When SRRM4 is overexpressed in systemic breast cancer cells, there is enhanced BBM leading to poorer overall survival in vivo. Concomitantly, SRRM4 knockdown expression does not provide any advantage in central nervous system metastasis. In addition, reducing SRRM4 expression in breast cancer cells slows down proliferation and increases resistance to chemotherapy. Conversely, when SRRM4/REST4 levels are elevated, tumor cell growth is maintained even in nutrient-deprived conditions. In neuronal coculture, decreasing SRRM4 expression in breast cancer cells impairs their ability to adapt to the brain microenvironment, while increasing SRRM4/RE-1 Silencing Transcription Factor (REST4) levels leads to greater expression of neurotransmitter and synaptic signaling mediators and a significant colonization advantage. CONCLUSIONS: Collectively, our findings identify SRRM4 as a regulator of brain metastasis colonization, and a potential therapeutic target in breast cancer.

Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions.

Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters' role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based.

A quantitative characterization of the spatial distribution of brain metastases from breast cancer and respective molecular subtypes.

PURPOSE: Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. METHODS: We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. RESULTS: We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. CONCLUSIONS: We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

The abscopal effect: systematic review in patients with brain and spine metastases.

Background: The abscopal effect is a rare phenomenon whereby local radiation induces a proposed immune-mediated anti-tumor effect at distant sites. Given the growing use of immunotherapies and systemic immune checkpoint inhibitors in neuro-oncologic practice, we aimed to review prior studies pertaining to this phenomenon in the context of tumor shrinkage both within the central nervous system as well as distant disease sites. Methods: A systematic review in accordance with the PRISMA guidelines was conducted to identify all studies which assessed the abscopal effect in patients with treated metastatic cancer to the brain and/or spine. Articles were included if they reported the abscopal effect in patients (case studies) or if the abscopal effect was explicitly analyzed in case series with cohorts of patients with metastatic brain or spine tumors. Laboratory investigations and clinical trials investigating new therapies were excluded. Results: Twenty reports met inclusion criteria [16 case reports, 4 case series (n = 160), total n = 174]. Case reports of the abscopal effect were in relation to the following cancers: melanoma (6 patients), breast cancer (3), lung adenocarcinoma (2), non-small-cell lung cancer (2), hepatocellular carcinoma (1), and renal cell carcinoma (1). Eleven patients had irradiation to the brain and 2 to the spine. Patients undergoing whole brain radiotherapy (6) had an average dose of 33.6 Gy over 8-15 fractions, and those undergoing stereotactic radiosurgery (5) had an average dose of 21.5 Gy over 1-5 fractions. One patient had radiation to the body and an intracranial abscopal effect was observed. Most common sites of extracranial tumor reduction were lung and lymph nodes. Ten case studies (57%) showed complete resolution of extra-CNS tumor burden. Median progression-free survival was 13 months following radiation. Four papers investigated incidence of abscopal effects in patients with metastatic melanoma to the brain who received immune checkpoint inhibitor therapy (n = 160); two papers found an abscopal effect in 35% and 52% of patients (n = 16, 21 respectively), and two papers found no evidence of abscopal effects (n = 61, 62). Conclusions: Abscopal effects can occur following radiotherapy in patients with brain or spine metastases and is thought to be a result of increased anti-tumor immunity. The potential for immune checkpoint inhibitor therapy to be used in combination with radiotherapy to induce an abscopal effect is an area of active investigation.

Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.

The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.

Anatomical and topographical variations in the distribution of brain metastases based on primary cancer origin and molecular subtypes: a systematic review.

BACKGROUND: While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field. METHODS: A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines. RESULTS: Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes. CONCLUSION: The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.

Use of predictive spatial modeling to reveal that primary cancers have distinct central nervous system topography patterns of brain metastasis.

OBJECTIVE: Brain metastasis is the most common intracranial neoplasm. Although anatomical spatial distributions of brain metastasis may vary according to primary cancer subtype, these patterns are not understood and may have major implications for treatment. METHODS: To test the hypothesis that the spatial distribution of brain metastasis varies according to cancer origin in nonrandom patterns, the authors leveraged spatial 3D coordinate data derived from stereotactic Gamma Knife radiosurgery procedures performed to treat 2106 brain metastases arising from 5 common cancer types (melanoma, lung, breast, renal, and colorectal). Two predictive topographic models (regional brain metastasis echelon model [RBMEM] and brain region susceptibility model [BRSM]) were developed and independently validated. RESULTS: RBMEM assessed the hierarchical distribution of brain metastasis to specific brain regions relative to other primary cancers and showed that distinct regions were relatively susceptible to metastasis, as follows: bilateral temporal/parietal and left frontal lobes were susceptible to lung cancer; right frontal and occipital lobes to melanoma; cerebellum to breast cancer; and brainstem to renal cell carcinoma. BRSM provided probability estimates for each cancer subtype, independent of other subtypes, to metastasize to brain regions, as follows: lung cancer had a propensity to metastasize to bilateral temporal lobes; breast cancer to right cerebellar hemisphere; melanoma to left temporal lobe; renal cell carcinoma to brainstem; and colon cancer to right cerebellar hemisphere. Patient topographic data further revealed that brain metastasis demonstrated distinct spatial patterns when stratified by patient age and tumor volume. CONCLUSIONS: These data support the hypothesis that there is a nonuniform spatial distribution of brain metastasis to preferential brain regions that varies according to cancer subtype in patients treated with Gamma Knife radiosurgery. These topographic patterns may be indicative of the abilities of various cancers to adapt to regional neural microenvironments, facilitate colonization, and establish metastasis. Although the brain microenvironment likely modulates selective seeding of metastasis, it remains unknown how the anatomical spatial distribution of brain metastasis varies according to primary cancer subtype and contributes to diagnosis. For the first time, the authors have presented two predictive models to show that brain metastasis, depending on its origin, in fact demonstrates distinct geographic spread within the central nervous system. These findings could be used as a predictive diagnostic tool and could also potentially result in future translational and therapeutic work to disrupt growth of brain metastasis on the basis of anatomical region.

Cortisol promotes breast-to-brain metastasis through the blood-cerebrospinal fluid barrier.

BACKGROUND: Elevated basal cortisol levels are present in women with primary and metastatic breast cancer. Although cortisol's potential role in breast-to-brain metastasis has yet to be sufficiently studied, prior evidence indicates that it functions as a double-edged sword-cortisol induces breast cancer metastasis in vivo, but strengthens the blood-brain-barrier (BBB) to protect the brain from microbes and peripheral immune cells. AIMS: In this study, we provide a novel examination on whether cortisol's role in tumor invasiveness eclipses its supporting role in strengthening the CNS barriers. We expanded our study to include the blood-cerebrospinal fluid barrier (BCSFB), an underexamined site of tumor entry. METHODS AND RESULTS: Utilizing in vitro BBB and BCSFB models to measure barrier strength in the presence of hydrocortisone (HC). We established that lung tumor cells migrate through both CNS barriers equally while breast tumors cells preferentially migrate through the BCSFB. Furthermore, HC treatment increased breast-to-brain metastases (BBM) but not primary breast tumor migratory capacity. When examining the transmigration of breast cancer cells across the BCSFB, we demonstrate that HC induces increased traversal of BBM but not primary breast cancer. We provide evidence that HC increases tightness of the BCSFB akin to the BBB by upregulating claudin-5, a tight junction protein formerly acknowledged as exclusive to the BBB. CONCLUSION: Our findings indicate, for the first time that increased cortisol levels facilitate breast-to-brain metastasis through the BCSFB-a vulnerable point of entry which has been typically overlooked in brain metastasis. Our study suggests cortisol plays a pro-metastatic role in breast-to-brain metastasis and thus caution is needed when using glucocorticoids to treat breast cancer patients.

Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis.

BACKGROUND: Brain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization. METHODS: Utilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, we surveyed the early induction of mediators of neurotransmitter (NT) and synaptic signaling in breast and lung tumor cells. Reliance on microenvironmental GABA in breast-to-brain metastatic cells (BBMs) was assessed in vitro and in vivo. RESULTS: Coculture with neurons induces early expression of classical NT receptor genes (HTR4, GRIA2, GRIN2B, GRM4, GRM8, DRD1) and neuronal synaptic mediators (CNR1, EGR2, ARC, NGFR, NRXN1) in breast and lung cancer cells. NT-dependent classification of tumor cells within the neuronal niche shows breast cancer cells become GABAergic responsive brain metastases (GRBMs) and transition from relying on autocrine GABA, to paracrine GABA from adjacent neurons; while autocrine Dopaminergic breast and lung tumor cells persist. In vivo studies confirm reliance on paracrine GABA is an early CNS-acclimation strategy in breast cancer. Moreover, neuronal contact induces early resurgence in Reelin expression in tumor cells through epigenetic activation, facilitating CNS adaptation. CONCLUSION: Tumor-neuron interactions allow for CNS adaptation early in the course of brain metastasis.

The microenvironment of brain metastases from solid tumors.

Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood-brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.

Utilization of Discarded Surgical Tissue from Ultrasonic Aspirators to Establish Patient-Derived Metastatic Brain Tumor Cells: A Guide from the Operating Room to the Research Laboratory.

Patient-derived cells from surgical resections are of paramount importance to brain tumor research. It is well known that there is cellular and microenvironmental heterogeneity within a single tumor mass. Thus, current established protocols for propagating tumor cells in vitro are limiting because resections obtained from conventional singular samples limit the diversity in cell populations and do not accurately model the heterogeneous tumor. Utilization of discarded tissue obtained from cavitron ultrasonic surgical aspirator (CUSA) of the whole tumor mass allows for establishing novel cell lines in vitro from the entirety of the tumor, thereby creating an accurate representation of the heterogeneous population of cells originally present in the tumor. Furthermore, while others have described protocols for establishing patient tumor lines once tissue has arrived in the research lab, a primer from the operating room (OR) to the research lab has not been described before. This is integral, as basic research scientists need to understand the surgical environment of the OR, including the methods utilized to obtain a patient's tumor resection, in order to more accurately model cancer biology in laboratory. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Establishment of brain tumor cell lines from patient-derived CUSA samples: processing brain tumor sample from the OR to the lab Support Protocol 1: Sterilization of microsurgical tools in preparation for dissection Support Protocol 2: Collagen coating of tissue culture flasks Basic Protocol 2: Selection of tumor cells in vitro Support Protocol 3: FACS sorting tumor sample to isolate cancer cells from heterogeneous cell population.

Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.

Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.

Enhanced brain delivery and therapeutic activity of trastuzumab after blood-brain barrier opening by NEO100 in mouse models of brain-metastatic breast cancer.

BACKGROUND: The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity. METHODS: An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival. RESULTS: NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100. CONCLUSION: IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.

Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines.

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood-brain barrier, blood-tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model in vivo. These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.