Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type.

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.

Senescence-associated secretory proteins induced in lung adenocarcinoma by extended treatment with dexamethasone enhance migration and activation of lymphocytes.

There is a need to improve response rates of immunotherapies in lung adenocarcinoma (AC). Extended (7-14 days) treatment of high glucocorticoid receptor (GR) expressing lung AC cells with dexamethasone (Dex) induces an irreversible senescence phenotype through chronic induction of p27. As the senescence-associated secretory phenotype (SASP) may have either tumor supporting or antitumor immunomodulatory effects, it was interest to examine the effects of Dex-induced senescence of lung AC cells on immune cells. Dex-induced senescence resulted in sustained production of CCL2, CCL4, CXCL1 and CXCL2, both in vitro and in vivo. After Dex withdrawal, secretion of these chemokines by the senescent cells attracted peripheral blood monocytes, T-cells, and NK cells. Following treatment with Dex-induced SASP protein(s), the peripheral blood lymphocytes exhibited higher cell count and tumor cytolytic activity along with enhanced Ki67 and perforin expression in T and NK cells. This cytolytic activity was partially attributed to NKG2D, which was upregulated in NK cells by SASP while its ligand MICA/B was upregulated in the senescent cells. Enhanced infiltrations of T and NK cells were observed in human lung AC xenografts in humanized NSG mice, following treatment with Dex. The findings substantiate the idea that induction of irreversible senescence in high-GR expressing subpopulations of lung AC tumors using Dex pretreatment enhances tumor immune infiltration and may subsequently improve the clinical outcome of current immunotherapies.

Development of patient-derived xenograft models from a spontaneously immortal low-grade meningioma cell line, KCI-MENG1.

BACKGROUND: There is a paucity of effective therapies for recurrent/aggressive meningiomas. Establishment of improved in vitro and in vivo meningioma models will facilitate development and testing of novel therapeutic approaches. METHODS: A primary meningioma cell line was generated from a patient with an olfactory groove meningioma. The cell line was extensively characterized by performing analysis of growth kinetics, immunocytochemistry, telomerase activity, karyotype, and comparative genomic hybridization. Xenograft models using immunocompromised SCID mice were also developed. RESULTS: Histopathology of the patient tumor was consistent with a WHO grade I typical meningioma composed of meningothelial cells, whorls, and occasional psammoma bodies. The original tumor and the early passage primary cells shared the standard immunohistochemical profile consistent with low-grade, good prognosis meningioma. Low passage KCI-MENG1 cells were composed of two cell types with spindle and round morphologies, showed linear growth curve, had very low telomerase activity, and were composed of two distinct unrelated clones on cytogenetic analysis. In contrast, high passage cells were homogeneously round, rapidly growing, had high telomerase activity, and were composed of a single clone with a near triploid karyotype containing 64-66 chromosomes with numerous aberrations. Following subcutaneous and orthotopic transplantation of low passage cells into SCID mice, firm tumors positive for vimentin and progesterone receptor (PR) formed, while subcutaneous implant of high passage cells yielded vimentin-positive, PR-negative tumors, concordant with a high-grade meningioma. CONCLUSIONS: Although derived from a benign meningioma specimen, the newly-established spontaneously immortal KCI-MENG1 meningioma cell line can be utilized to generate xenograft tumor models with either low- or high-grade features, dependent on the cell passage number (likely due to the relative abundance of the round, near-triploid cells). These human meningioma mouse xenograft models will provide biologically relevant platforms from which to investigate differences in low- vs. high-grade meningioma tumor biology and disease progression as well as to develop novel therapies to improve treatment options for poor prognosis or recurrent meningiomas.

Novel quinoline substituted autophagy inhibitors attenuate Zika virus replication in ocular cells.

Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV.

Generation and immunologic functions of Th17 cells in malignant gliomas.

Th17 cells, a recently discovered inflammatory T cell subtype, have been implicated with autoimmune disorders. However, mechanism of generation or functions of intratumoral Th17 cells are still unclear. We have been investigating the mechanism of induction and role of Th17 cells in malignant gliomas using primary tumor as well as cell lines. We report here that: (1) a higher frequency of Th17 cells in gliomas were associated with higher number of myeloid (CD11b) cells as well as the expression of TGF-ß1 or IL-6; (2) conditioned medium from glioma cells (Gl CM) induced Th17 cell differentiation, which was inhibited by anti-TGF-ß1 and anti-IL-6; (3) glioma-associated monocytes secreted Th17-promoting cytokines IL-1ß and IL-23; (4) CM from glioma and monocyte co-culture (Gl+Mo CM) induced high frequency of Th17 cells in naïve T cell culture, which was abrogated by anti-IL-1ß and anti-IL-23 antibodies; (5) In vitro Gl+Mo CM-mediated Th17 generation was associated with a decrease in IFN-γ and a concomitant increase in IL-10 secretion. Anti-TGF-ß1, but not anti-IL-6, significantly reversed this cytokine profile. These results demonstrate prevalence of Th17 cells in gliomas and implicate the cytokines derived from the tumor as well as infiltrating myeloid cells in the induction of Th17 cells in glioma microenvironment. Moreover, the data also suggest that glioma-associated Th17 cells may contribute to immune-suppression via TGF-ß1-induced IL-10 secretion. Further studies on the mechanism of tumor-infiltration, developmental pathways, and pro-/anti-tumor functions of Th17 cells will provide rationale for developing novel adjuvant immunotherapeutic strategies for malignant gliomas.

Enzyme-Mediated Nerve Growth Factor Release from Nanofibers Using Gelatin Microspheres.

Spinal cord injury is a complex environment, with many conflicting growth factors present at different times throughout the injury timeline. Delivery of multiple growth factors has received mixed results, highlighting a need to consider the timing of delivery for possibly antagonistic growth factors. Cell-mediated degradation of delivery vehicles for delayed release of growth factors offers an attractive way to exploit the highly active immune response in the spinal cord injury environment. In this study, growth factor-loaded gelatin microspheres (GMS) combined with methacrylated hyaluronic acid (MeHA) were electrospun to create GMS fibers (GMSF) for delayed release of growth factors (GFs). GMS were successfully combined with MeHA while electrospinning, with an average fiber diameter of 365 ± 10 nm and 44% ± 8% fiber alignment. GMSF with nerve growth factor (NGF) was tested on dissociated chick dorsal root ganglia cells. We further tested the effect of M1 macrophage-conditioned media (M1CM) to simulate macrophage invasion after spinal cord injury for cell-mediated degradation. We hypothesized that neurons grown on GMSF with loaded NGF would exhibit longer neurites in M1CM, showing a release of functional NGF, as compared with controls. GMSF in M1CM was significantly different from MeHA in serum-free media (SFM) and M0-conditioned media (M0CM), as well as GMSF in M0CM (p < 0.05). Moreover, GMSF + NGF in all media conditions were significantly different from MeHA in SFM and M0CM (p < 0.05). The goal of this study was to develop a biomaterial system where drug delivery is triggered by immune response, allowing for more control and longer exposure to encapsulated drugs. The spinal cord injury microenvironment is known to have a robust immune response, making this immune-medicated drug release system particularly significant for directed repair.

Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model.

HER2-targeted therapy has improved breast cancer survival, but treatment resistance and disease prevention remain major challenges. Genes that enable HER2/Neu oncogenesis are the next intervention targets. A bioinformatics discovery platform of HER2/Neu-expressing Diversity Outbred (DO) F1 Mice was established to identify cancer-enabling genes. Quantitative Trait Loci (QTL) associated with onset ages and growth rates of spontaneous mammary tumors were sought. Twenty-six genes in 3 QTL contain sequence variations unique to the genetic backgrounds that are linked to aggressive tumors and 21 genes are associated with human breast cancer survival. Concurrent identification of TSC22D3, a transcription factor, and its target gene LILRB4, a myeloid cell checkpoint receptor, suggests an immune axis for regulation, or intervention, of disease. We also investigated TIEG1 gene that impedes tumor immunity but suppresses tumor growth. Although not an actionable target, TIEG1 study revealed genetic regulation of tumor progression, forming the basis of the genetics-based discovery platform.

Scutellaria extract and wogonin inhibit tumor-mediated induction of T(reg) cells via inhibition of TGF-ß1 activity.

A number of studies have implicated tumor-induced T(reg) cell activity in the sub-optimal response to therapeutic vaccines. Development of neo-adjuvant strategies targeting T(reg) cells is therefore imperative. Scutellaria extracts or constituent flavonoids have shown encouraging efficacy against various tumors, including gliomas, in both pre-clinical and clinical studies. We report here, for the first time, that Scutellaria ocmulgee leaf extract (SocL) and flavonoid wogonin could inhibit TGF-ß1-induced T(reg) activity in malignant gliomas. F344 rats, subcutaneously transplanted with F98 gliomas, were treated with SocL. There was a significant inhibition of intra-tumoral TGF-ß1 and T(reg) cell frequency as well as peripheral blood TGF-ß1 levels in SocL-treated animals compared to the controls. SocL extract and wogonin also inhibited glioma-induced, TGF-ß1-mediated T(reg) activity in vitro. SocL extract and wogonin also inhibited the secretion of IL-10 in T(reg) culture; whereas the level of IL-2 was either unchanged or marginally enhanced. We also observed an inhibition of Smad-3, GSK-3ß and ERK1/2 signaling by SocL and wogonin in T(reg) cells, while phosphorylation of P38 MAPK was considerably enhanced, indicating that SocL or wogonin could inhibit the T cells' response to TGF-ß1 via modulation of both Smad and non-Smad signaling pathways. Overall, this study suggests that Scutellaria can potentially reverse tumor-mediated immune suppression via inhibition of TGF-ß1 secretion as well as via inhibition of T cells' response to TGF-ß1. This may provide an opportunity for developing a novel adjuvant therapeutic strategy for malignant gliomas, combining Scutellaria with immunotherapy and chemo/radio-therapeutic regimen, which could potentially improve the disease outcome.

Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-κB signaling.

Plants of the genus Scutellaria constitute one of the common components of Eastern as well as traditional American medicine against various human diseases, including cancer. In this study, we examined the in vivo anti-glioma activity of a leaf extract of Scutellaria ocmulgee (SocL) while also exploring their potential molecular mechanisms of action. Oral administration of SocL extract delayed the growth of F98 glioma in F344 rats, both in intracranial and subcutaneous tumor models. Immunohistochemistry revealed inhibition of Akt, GSK-3α/ß and NF-κB phosphorylation in the subcutaneous tumors following treatment with Scutellaria. The SocL extract as well as the constituent flavonoid wogonin also showed dose- and time-dependent inhibition of Akt, GSK-3α/ß and NF-κB in F98 cell cultures in vitro, as determined by western blot analysis. Pharmacologic inhibitors of PI3K and NF-κB also significantly inhibited the in vitro proliferation of F98 glioma cells, indicating the key role of these signaling molecules in the growth of malignant gliomas. Transfection of F98 cells with constitutively active mutant of AKT (AKT/CA), however, did not significantly reverse Scutellaria-mediated inhibition of proliferation, indicating that Scutellaria flavonoids either directly inhibited Akt kinase activity or acted downstream of Akt. In vitro Akt kinase assay demonstrated that the SocL extract or wogonin could indeed bind to Akt and inhibit its kinase activity. This study provides the first in vivo evidence and mechanistic support for anti-glioma activity of Scutellaria flavonoids and has implications in potential usage of Scutellaria flavonoids in adjuvant therapy for malignant tumors, including gliomas.

Review of immune checkpoint inhibitors in immuno-oncology.

Tumor cells predominantly express self-antigens and overcoming self-tolerance is the primary challenge to effective immunotherapy. Tumors also express ligands for co-inhibitory molecules on immune cells, in order to suppress anti-tumor immunity. Over a decade ago, the first antibodies generated to block the co-inhibitory molecule CTLA-4 was tested in patients with metastatic melanoma. Results from this landmark trial have informed not only the current landscape of checkpoint blockade but also the way in which immunotherapy trial outcomes are determined. Antibodies targeting PD-1 and its ligand, PD-L1, soon followed and use of these checkpoint inhibitors (ICIs) have expanded exponentially. ICI treatment has shown long-lasting clinical benefit in several tumor types and patients refractory to other treatments can often respond to ICI therapy. On the other hand, in some tumor types, the response to ICI is short-lived and tumors eventually recur. Current clinical trials are focused on enhancing anti-tumor effects through combinations of multiple ICIs with agents which cause tumor death, particularly in solid tumors, in order to enhance antigen presentation. It is also important to define which patients will respond to therapy with ICIs as over half of all patients suffer from immune-related adverse events (irAE), some of which are severe and long-lasting.

Implications of the USP10-HDAC6 axis in lung cancer - A path to precision medicine.

Lung cancer is the leading cause of cancer death among both men and women in the United States. Because lung cancer is genetically heterogeneous, tailored therapy alone or in combination with chemotherapy would increase patient overall survival as compared with the one-size-fits-all chemotherapy. TP53-mutant lung cancer accounts for more than half of all lung cancer cases and is oftentimes more aggressive and resistant to chemotherapy. Directly targeting mutant p53 has not yet been successful, so identification of novel therapy targets and biomarkers in the TP53-mutant lung cancer is urgently needed to increase the overall survival in this subgroup. Deubiquitinating enzymes (DUBs) regulate a vast majority of proteins (DUBs' substrates) via removal of ubiquitin moieties or ubiquitin chains from these proteins, thereby altering the stability and/or functions of these substrates. In this review, we will focus on a DUB, referred to as ubiquitin-specific peptidase 10 (USP10) whose substrates include both oncogenic proteins and tumor suppressors. Therefore, targeting USP10 in cancer is highly context-dependent. Here, we will discuss USP10's functions in cancer by examining its various known substrates. In particular, we will elaborate our recent findings in the oncogenic role of USP10 in the TP53-mutant subgroup of lung cancer, focusing on USP10's function in the DNA damage response (DDR) via histone deacetylase 6 (HDAC6). Overall, these findings support the notion that targeting USP10 in the TP53-mutant subgroup of NSCLC would sensitize patients to cisplatin-based chemotherapy. Generating potent and specific clinically relevant USP10 inhibitors would benefit the TP53-mutant subgroup of NSCLC patients.

Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs.

Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand-receptor-mediated delivery of drug carriers.

Application of Bioactive Compounds from Scutellaria in Neurologic Disorders.

Inflammation of the brain is one of the most highly researched yet mysterious areas in modern day neurology. The process of inflammation is a normal mechanism of wound healing that can result from acute injuries such as traumas or can be caused by genetic/environmental factors. After the initial insult, the immune system defenses, specifically microglial cells, are activated in order to combat the infection or injury. However, prolonged or chronic inflammation is often deleterious due mainly to accumulation of free reactive oxygen species (ROS) and other pro-inflammatory cytokines in the brain FADDIN EN.CITE. Plant-derived natural compounds have the potential to ameliorate the causes and symptoms of neuroinflammation, due to their various anti-oxidant and anti-inflammatory activities, without completely muting the immune defenses. Scutellaria is a perennial plant in the mint family that has been used to treat diseases in Asia and Eastern Europe throughout history. This chapter reviews the active components of various Scutellaria species and their mechanisms of action to prevent chronic neurologic disorders involving neuroinflammation and neurodegeneration.

Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal.

Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17-IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2-19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17-IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs.

Flt3 ligand augmentation of T cell mitogenesis and expansion of type 1 effector/memory T cells.

Herein we report mechanisms whereby Flt3 ligand (FL) augments steady state T cell activity in addition to the expansion of dendritic cells (DCs). We demonstrate that in vivo administration of FL increases the frequency and absolute number of effector/memory T cells and preferentially expands T cells that express a type-1 cytokine phenotype. In addition, FL enhances T cell proliferative responses to Concanavalin A that directly correlated with increased frequencies in effector/memory T cells and expansion of lymphoid-derived (type 1) DCs (DC1s). Together, these data demonstrate that mechanisms of FL-induced T cell regulation include not only the expansion of DC subsets, but also the preferential expansion of type 1 -effector/memory T cell populations, and suggest multiple mechanisms of action for FL as a vaccine adjuvant and as a therapeutic modality.

Role of IL-17 in Glioma Progression.

There is increasing evidence in the literature pointing to an important role of inflammation during initiation and progression of cancer. Glioblastoma is the most common malignant primary brain tumor with approximately 23,000 newly-diagnosed cases each year in the United States, and has a dismal median survival of only 15 months. Although the blood-brain barrier maintains an immune-privileged status of the brain under steady state, intracranial tumors including gliomas are invariably infiltrated with various types of immune cells. The T helper 17 (Th17) cells, a recently discovered interleukin (IL)-17-producing T cell subtype, have been reported in several extracranial and some intracranial tumors, where they have been implicated in either pro- or antitumor activity depending on the tumor type. Here, we present a succinct review of the current literature on the prevalence and potential role of IL-17 in malignant gliomas. Further mechanistic studies on IL-17 mediated inflammatory pathway in gliomas may provide with opportunities for novel immunotherapeutic interventions.

In vitro antitumor mechanisms of various Scutellaria extracts and constituent flavonoids.

Scutellaria is a traditional herbal remedy with potential anti-cancer activity. The purpose of this study was to evaluate anticancer mechanisms of thirteen Scutellaria species and analyze their leaf, stem and root extracts for levels of common biologically active flavonoids: apigenin, baicalein, baicalin, chrysin, scutellarein, and wogonin. Malignant glioma, breast carcinoma and prostate cancer cells were used to determine tumor-specific effects of Scutellaria on cell proliferation, apoptosis and cell cycle progression, via the MTT assay and flow cytometry-based apoptosis and cell cycle analysis. The extracts and individual flavonoids inhibited the proliferation of malignant glioma and breast carcinoma cells without affecting primary or non-malignant cells. The flavonoids exhibited different mechanisms of anti-tumor activity as well as positive interactions. The antitumor mechanisms involved induction of apoptosis and cell cycle arrest at G1/G2. Of the extracts tested, leaf extracts of S. angulosa, S. integrifolia, S. ocmulgee and S. scandens were found to have strong anticancer activity. This study provides basis for further mechanistic and translational studies into adjuvant therapy of malignant tumors using Scutellaria leaf tissues.

Dendritic cell-based active specific immunotherapy for malignant glioma.

Immunotherapy is an appealing therapeutic modality for malignant gliomas because of its potential to selectively target residual tumor cells that have invaded the normal brain. Most immunotherapeutic studies are designed to exploit the capacity of dendritic cells for inducing cell-mediated effects as well as immune memory responses for destroying residual tumor cells and preventing recurrence. Although initial clinical studies on dendritic cell-based immunotherapy resulted in very limited success, they have prompted many new studies on exploring strategies to induce a more robust antitumor immune response by using novel adjuvants for maturation and activation of dendritic cells. More studies have focused on the mechanisms of immune suppression by tumor cells and the role of regulatory T cells in tumor growth and progression. In this article, the authors review the evolution of dendritic cell-based immunotherapeutic strategies for adjuvant treatment of malignant gliomas. The authors also discuss how new knowledge on tumor-intrinsic mechanisms of tolerance induction and immunosuppression are likely to shape the future of immunotherapy for high-grade gliomas.

Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis.

Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors. Primarily the result of altered isozyme expression, these adaptations enhance the survival and proliferation of the tumor at the expense of surrounding normal tissue. Consequently, they also expose a unique set of targets for tumor destruction while sparing healthy tissues. Despite this fact, development of drugs to directly target such altered metabolic pathways of malignant tumors has been under-investigated until recently. One such target is the ultimate step of glycolysis, which, as expected, presents itself as a metabolic aberration in most malignant tumors. Termed "aerobic glycolysis" due to abnormal conversion of pyruvic acid to lactic acid even under normoxia, the altered metabolism requires these tumors to rapidly efflux lactic acid to the microenvironment in order to prevent poisoning themselves. Thus, exposed is a prime "choke-point" to target these highly malignant, frequently chemo- and radio- resistant tumors. This review will focus on current outcomes in targeting lactate efflux in such tumors using glioma as a model, an ongoing project in our laboratory for the past half-decade, as well as supporting evidence from recent studies by others on targeting this "tail-end" of glycolysis in other tumor models.