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Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H). Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis. Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild-type tumors. Recognition of the high frequency of IDH mutations in glioma [and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma] have led to the development of a number of targeted agents that can inhibit these enzymes. Enasidenib and ivosidenib have both gained regulatory approval for IDH mutant AML. Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG-881, BAY1436032, and DS1001). A marked clinical problem in the development of these agents is overcoming the blood-brain barrier. An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target poly (ADP-ribose) polymerase (PARP), glutamine metabolism, and the Bcl-2 family of proteins. We conclude that within the last decade, several approaches have been devised to therapeutically target the IDH1 mutation, and that, potentially, both IDH1 inhibitors and synthetic lethal approaches might be relevant for future therapies. [ABSTRACT FROM AUTHOR]

A 71-year-old woman presented to our institution with a 2-week history of concentric bilateral left accentuated visual field loss. Examination of her eyes including funduscopy was normal. A gadolinium-enhanced magnetic resonance tomography showed contrast enhancement of the optic pathway in the T1-weighted sequence that included both optic nerves, the optic chiasm, and the left optic tract. Differential diagnoses of this kind of lesion extending along the optic nerves include neurosarcoidosis, lymphoma, and glioma. The patient was treated with high-dose corticosteroids under the suspicion of neurosarcoidosis. During that time her vision deteriorated, resulting in amaurosis on her left eye and marginal peripheral vision on the right. A biopsy of the left optic nerve revealed a pilocytic astrocytoma, which to some extent contrasted the observed clinical course. After discussing the treatment options including radiotherapy and chemotherapy, the patient opted for supportive care and died 3 months later. [ABSTRACT FROM AUTHOR]

The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2-D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2-D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti-glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach. [ABSTRACT FROM AUTHOR]

Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. [ABSTRACT FROM AUTHOR]

Background: Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods: The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results: The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions: PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor's molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good in vitro and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII. [ABSTRACT FROM AUTHOR]

Abstract: The metabolic and hemodynamic processes in the edema surrounding spontaneous, supratentorial intracerebral hemorrhage (ICH) are poorly understood. Specifically, the local metabolic effects of autoregulatory failure have not been described previously. In the current observational pilot study, microdialysis and brain tissue oxygenation probes (PbrO2) were placed in the perihemorrhagic edema using neuronavigation in five non-surgically treated patients with deep ICH. The cerebrovascular pressure reactivity index (PRx, moving correlation between mean arterial and intracranial pressure) and PbrO2 reactivity index (ORx, correlation between PbrO2 and cerebral perfusion pressure) were used to characterize cerebral autoregulation. While all five patients had ORx values indicative for severely disturbed autoregulation, assessment of PRx only in one patient was consistent with sustained failure of cerebrovascular reactivity. This patient at the same time had the worst metabolic parameters and the poorest tissue oxygenation. We conclude that multimodality monitoring in the perihemorrhagic penumbra is feasible. A study in a larger population is needed to clarify the relationship between PRx and ORx in ICH patients, the local metabolic effects of autoregulatory failure and its relation to brain edema formation and clinical outcome. [Copyright &y& Elsevier]

The epidermal growth factor receptor (HER1/EGFR) is known to be disregulated in a large subgroup of glioblastoma multiforme cases. Disregulation of HER1/EGFR is related to malignant transformation and tumor growth in various human cancers, including malignant glioma. One mechanism that may lead to disregulated HER1/EGFR signaling is the intrinsic alteration of the receptor structure due to mutational changes. The most common mutant form of HER1/EGFR, named variant III (EGFRvIII), results from an 801 bp in-frame deletion in the DNA sequence encoding the extracellular ligand-binding domain. Independent of ligand-binding, EGFRvIII is constitutively activated and beyond external control. Since its cellular expression was shown to relate nhanced tumorigenicity, various therapeutic strategies were developed to target EGFRvIII, including monoclonal antibodies, vaccination therapies and small-molecule tyrosine kinase inhibitors. In this review, we focus on ribozyme-mediated inhibition of EGFRvIII messenger RNA expression as a gene therapeutic approach for EGFRvIIIexpressing glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

: BackgroundComplement activation contributes to ischemia and reperfusion (IR)-initiated organ injury. C1 inhibitor (C1 Inh) inhibits the earliest steps of the classical and the mannose binding lectin pathways.: Materials and methodsTo determine whether C1 Inh prevented tissue injury, we performed intestinal IR experiments in BALB/c and C57BL/6 mice.: ResultsWe found that C1 Inh limits mucosal injury in the two strains in a dose dependent manner. Tissue damage was associated with the accumulation of functional polymorphonuclear cells, which was reduced following C1 Inh treatment. Constitutive nitric oxide synthase activity correlated with the development of injury in the C57BL/6 but not in the BALB/c mouse.: ConclusionsThese findings emphasize the importance of complement activation in ischemia/reperfusionand highlight the potential therapeutic use of C1 Inh in limiting or preventing damage caused by IR. [Copyright &y& Elsevier]

Background: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease. Methods: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models. Results: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced. Conclusion: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: Intraoperative magnetic resonance imaging (iMRI) improves the intraoperative detection of adenoma remnants in transsphenoidal surgery. iMRI might be redundant in endoscopic pituitary surgery in non-invasive tumors (Knosp 0–2) due to a superior visualization of anatomical structures in the periphery of the sella turcica compared to the microscopic technique. We identified the anatomical location of tumor remnants in iMRI and evaluated risk factors for secondary resection after iMRI and hereby selected patients with pituitary adenomas who may benefit from iMRI-assisted resection. Methods: We conducted a retrospective monocenter study of patients who underwent iMRI-assisted transsphenoidal surgical resection of pituitary adenomas at our department between 2012 and 2020. A total number of 190 consecutive iMRI-assisted transsphenoidal surgeries of pituitary adenomas graded as Knosp 0–2 were selected for analysis. Exclusion criteria were missing iMRI availability or pathologies other than adenomas. Of these 190 cases, 46.3% (N = 88) were treated with microscopic, 48.4% (N = 92) with endoscopic, and 5.3% (N = 10) with endoscopic-assisted technique. Volumetric measurement of preoperative, intraoperative, and postoperative tumor extension was performed. Demographic data, tumor characteristics, and MRI features were evaluated. Additionally, analysis of adenoma remnants identified by iMRI was performed. Results: An additional resection after iMRI was performed in 16.3% (N = 31). iMRI helped to reach gross total resection (GTR) in 83.9% (26/31) of these cases. False-positive resection was found in 1 patient (0.5%). Multivariable logistic analysis identified tumor volume (OR = 1.2, p = 0.007) recurrence (OR = 11.3, p = 0.002) and microscopic technique (OR = 2.8, p = 0.029) as independent risk factors for additional resection. Simultaneously, the endoscopic technique was significantly associated with GTR as evaluated by iMRI (OR = 2.8, p = 0.011) and postoperative MRI (OR = 5.8, p = 0.027). The detailed analysis of adenoma remnants on iMRI revealed the suprasellar location in a diaphragm fold, penetrating tumor above the diaphragm, or undetected invasion of cavernous sinus as well as in case of microscopic resection tumor location outside the line of sight as the main reasons for incomplete resections. Conclusion: Tumor volume, recurrence, and microscopic technique were identified as independent predictors for additional resection in patients with Knosp 0–2 adenomas. iMRI might increase the extent of resection (EOR) safely even after the endoscopic visualization of the sella with very low risk for false-positive findings. Remnants of tumors hidden within the diaphragmic folds, intrathecally, or behind the infiltrated wall of cavernous sinus not recognized on preoperative MRI were the most common findings in iMRI. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma.Experimental Approach: We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT-PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action.Key Results: Bcl-2/Bcl-xL inhibition exerted synergistic anti-proliferative effects across established, primary cultured, and stem-like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9-LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9-LD counteracted ABT263-mediated up-regulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis which indicates that down-regulation of Mcl-1 is crucial for the induction of cell death by the combination treatment.Conclusion and Implications: These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP. [ABSTRACT FROM AUTHOR]

Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids. [ABSTRACT FROM AUTHOR]

Intramuscular or infiltrating lipomas are rare. We present a 58-year-old man with an intramuscular lipoma developing after decompression surgery for lumbar spinal canal stenosis. One year after macroscopically complete lipoma resection, an even bigger recurrent tumor had to be removed. The lumbar paraspinal musculature is a very uncommon site for an intramuscular lipoma. A relation between surgery and the growth and recurrence of an intramuscular lipoma has not been described previously in the literature. [ABSTRACT FROM AUTHOR]

Simple Summary: We present eight core attributes of cancer growth that we must address for a more effective treatment than we currently have. To do this we outline why a regimen simultaneously using many different drugs will be needed. At our current state of knowledge, even adding two or three drugs will not counter all the growth attributes of a currently incurable cancer. We show in this paper, the details of how an example six drug regimen, when added alongside of current traditional treatments, might inhibit enough of the eight core growth driving elements to allow those standard treatments to be more effective. We further show how medicines from general medical practice used to treat pain, fungal infections, psychosis, leprosy and other non-cancer related illnesses can be repurposed to block cancer cells' survival pathways and growth drives. In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs. [ABSTRACT FROM AUTHOR]

The surgical treatment of recurrent adenomas can be challenging. Intraoperative magnetic resonance imaging (iMRI) can improve the orientation and increase the safe extent of resection. We conducted a quantitative and qualitative retrospective analysis of recurrent adenomas treated by endoscopic or microscopic iMRI-assisted transsphenoidal surgery. A total number of 59 resections were selected. Detailed volumetric measurements, tumor characteristics, and MRI features of intraoperative remnants were evaluated. Intraoperative MRI increased the gross total resection (GTR) rate from 33.9% to 49.2%. Common locations of tumor remnants after iMRI were the clivus, the wall of the cavernous sinus or the perforation of the diaphragm. Increasing tumor volume and the microscopic technique were significantly associated with further resection after iMRI in the univariate analysis (p = 0.004, OR 1.6; p = 0.009, OR 4.4). Only the increasing tumor volume was an independent predictor for further resection (p = 0.007, OR 1.5). A significantly higher proportion of GTRs was achieved with the endoscopic technique (p = 0.001). Patients with a large recurrent pituitary adenoma who underwent microscopic transsphenoidal resection were the most likely to benefit from iMRI regarding the extent of resection. Occult invasions of the cavernous sinus and/or the clivus were the most common findings leading to further resection of tumor remnants after iMRI. [ABSTRACT FROM AUTHOR]

Objective To determine the effectiveness of cervical transforaminal injection of steroids ( CTFIS) and to explore possible determinants of response in patients with cervical disc herniation. Design Retrospective practice audit covering a time period of 6 months. Setting Single spine center in which the patients underwent CTFIS, surgery, and subsequent treatment. Magnetic resonance images were reviewed independently by a radiologist and two neurosurgeons. Interventions Consecutive patients with cervical radicular pain and a magnetic resonance imaging demonstrating nerve root affection received CTFIS. Evaluation in terms of pain reduction and in relation to the level and side of the affected nerve root, the duration of pain, neck or radicular pain, and the presence of sensory or motor deficits. The radiological features assessed were the location, grading, and cause of the impingement. Results Forty-eight patients were included. Only 35.4% of patients achieved at least 50% reduction in pain 1 month after treatment. The initial pain on the numeric rating scale was reduced from 6.8 to 1.8. None of the clinical or radiological features was associated with a successful outcome. 22.9% of the included patients had to undergo an operation. The duration of these patients' symptoms was significantly shorter ( P = 0.01) than in patients without operation. Conclusion Only a minority of patients with disc herniation or spondylosis and a proven nerve root compression benefits from CTFIS. The potential advantage for the patient must be compared with the risk of the procedure. Even with the combination of clinical and radiological findings, the prediction of a favorable outcome of CTFIS was not possible. [ABSTRACT FROM AUTHOR]

Abstract: Since phosphatidylinositol-3-kinase (PI3K) inhibitors are primarily cytostatic against glioblastoma, we searched for new drug combinations. Here, we discover that the PI3K inhibitor GDC-0941 acts in concert with the natural compound B10, a glycosylated derivative of betulinic acid, to induce cell death in glioblastoma cells. Importantly, parallel experiments in primary glioblastoma cultures similarly show that GDC-0941 and B10 cooperate to trigger cell death, underscoring the clinical relevance of this finding. Molecular studies revealed that treatment with GDC-0941 stimulates the expression and nuclear translocation of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, the lysosomal membrane marker LAMP-1 and the mature form of cathepsin B. Also, GDC-0941 triggers a time-dependent increase of the lysosomal compartment in a TFEB-dependent manner, since knockdown of TFEB significantly reduces this GDC-0941-stimulated lysosomal enhancement. Importantly, GDC-0941 cooperates with B10 to trigger lysosomal membrane permeabilization, leading to increased activation of Bax, loss of mitochondrial membrane potential (MMP), caspase-3 activation and cell death. Addition of the cathepsin B inhibitor CA-074me reduces Bax activation, loss of MMP, caspase-3 activation and cell death upon treatment with GDC-0941/B10. By comparison, knockdown of caspase-3 or the broad-range caspase inhibitor zVAD.fmk inhibits GDC-0941/B10-induced DNA fragmentation, but does not prevent cell death, thus pointing to both caspase-dependent and -independent pathways. By identifying the combination of GDC-0941 and B10 as a new, potent strategy to trigger cell death in glioblastoma cells, our findings have important implications for the development of novel treatment approaches for glioblastoma. [Copyright &y& Elsevier]

C5 is critical in the development of local mucosal damage and inflammation as well as in the development of remote organ injury after mesenteric ischemia/reperfusion (IR). To define the role of C5a in tissue injury, we treated wild-type mice with a cyclic hexapeptide C5a receptor antagonist (C5aRa) and administered recombinant C5a to C5 deficient (C5−/−) mice subjected to mesenteric IR. We demonstrate that at 2-h postreperfusion, C5a administered to C5−/− mice during IR induces limited intestinal mucosal injury but failed to cause remote lung injury despite the fact that it upregulated adhesion molecule expression. C5aRa treatment of C5+/+ mice undergoing IR limited local injury and prevented distant organ injury. We conclude that although C5a can trigger certain components of the IR induced injury, other mediators such as C5b-9 and local factors are needed for the complete expression of IR tissue damage. [Copyright &y& Elsevier]

Malignant gliomas are still extremely difficult to treat because complete surgical resection is biologically not feasible due to the invasive nature of these diseases and the proximity of tumors to functionally sensitive areas. Moreover, adjuvant therapies are facing a strong therapeutic resistance since the central nervous system is a highly protected environment and the tumor cells display a vast intra-tumoral genetic and epigenetic variation. As a consequence, new therapeutics are urgently needed but the process of developing novel compounds that finally reach clinical application is highly time-consuming and expensive. Drug repurposing is an approach to facilitate and accelerate the discovery of new cancer treatments. In malignant glioma, like in other cancers, pre-existing physiological pathways that regulate cell growth, cell death or cell migration are dysregulated causing malignant transformation. A wide variety of drugs are clinically used to treat non-cancerous diseases interfering with these malignancy-associated pathways. Repurposed drugs have key advantages: They already have approval for clinical use by national regulatory authorities. Moreover, they are for the most part inexpensive and their side effect and safety profiles are well characterized. In this work, we provide an overview on current repurposing strategies for the treatment of malignant glioma. [ABSTRACT FROM AUTHOR]

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cell-substrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.Methods: Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).Results: ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.Conclusion: Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy. [ABSTRACT FROM AUTHOR]

Purpose: Anti-apoptotic and pro-migratory phenotypes are hallmarks of neoplastic diseases, including primary brain malignancies. In this work, we examined whether reprogramming of the apoptotic and migratory machineries through a multi-targeting approach would induce enhanced cell death and enhanced inhibition of the migratory capacity of glioblastoma cells. Methods: Preclinical testing and molecular analyses of combined inhibition of Bcl-2/Bcl-xL and RAC1 were performed in established, primary cultured and stem-like glioblastoma cell systems. Results: We found that the combined inhibition of Bcl-2/Bcl-xL and RAC1 resulted in synergistic pro-apoptotic and anti-migratory effects in a broad range of different glioblastoma cells. At the molecular level, we found that RAC1 inhibition led to a decreased expression of the deubiquitinase Usp9X, followed by a decreased stability of Mcl-1. We also found that the combined inhibition led to a significantly decreased migratory activity and that tumor formation of glioblastoma cells on chorion allantoic membranes of chicken embryos was markedly impaired following the combined inhibition. Conclusions: Our data indicate that concomitant inhibition of RAC1 and Bcl-2/Bcl-xL induces pro-apoptotic and anti-migratory glioblastoma phenotypes as well as synergistic anti-neoplastic activities. The clinical efficacy of this inhibitory therapeutic strategy warrants further evaluation. [ABSTRACT FROM AUTHOR]

Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM. [Display omitted] • Lactate is metabolized in glioblastoma, which is dependent on cellular respiration • Lactate provides carbons to acetyl-residues of histones • Lactate modifies the enhancer and super-enhancer landscape of GBM cells Torrini and Nguyen et al. reveal an important role of lactate in a broad range of glioblastoma (GBM). They demonstrate that lactate is actively metabolized in a manner reliant on cellular respiration and that lactate affects gene expression through modulation of the epigenome. Thus, targeting oxidative metabolism and lactate metabolism may be a novel therapeutic approach for GBM. [ABSTRACT FROM AUTHOR]

To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant mono-cyte lineage cells (MLCs) (monocyte, macrophage, microglia, dendritic cells) that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%-30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic - minocycline, an antihypertensive drug - telmisartan, and a bisphosphonate - zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocyc line, telmisartan, and zoledronic acid - the MTZ Regimen - have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low drug cost. Four core observations support this approach: 1) malignant glioblastoma cells require a reciprocal trophic relationship with nonmalignant macrophages or microglia to thrive; 2) glioblastoma cells secrete MCP-1 to start the cycle, attracting MLCs, which subsequently also secrete MCP-1 perpetuating the recruitment cycle; 3) increasing cytokine levels in the tumor environment generate further immunosuppression and tumor growth; and 4) MTZ regimen may impede MCP-1-driven processes, thereby interfering with glioblastoma growth. [ABSTRACT FROM AUTHOR]

Aims: Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc− imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system xc− and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy. Results: PI3Ks induce system xc− through glycogen synthase kinase 3β (GSK-3β) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2α phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4. This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts. Moreover, the pathway is active in human glioblastoma cells. In addition, it is induced in primary cortical neurons in response to robust neuronal activity and in hippocampi from patients with temporal lobe epilepsy. Innovation: Our findings further extend the concepts of how growth factors and PI3Ks induce neuroprotection and cell growth by adding a new branch to the signaling network downstream of GSK-3β, which, ultimately, leads to the induction of the cystine/glutamate antiporter system xc−. Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy. Conclusion: PI3K-regulated system xc− activity is not only involved in the stress resistance of neuronal cells and in cell growth by increasing the cysteine supply and glutathione synthesis, but also plays a role in the pathophysiology of tumor- and non-tumor-associated epilepsy by up-regulating extracellular cerebral glutamate. Antioxid. Redox Signal. 20: 2907-2922. [ABSTRACT FROM AUTHOR]

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the complexity of combination therapy is elucidated using the PI3-K-mediated signaling network as a specific example. Here we show that the current clinical approach to sensitize malignancies to apoptosis by maximal, prolonged inhibition of so-called survival pathways can actually be counter productive. Third, we propose that under certain conditions which will need to be clearly defined in future, chronification of a tumor might be preferable to the attempt at a cure. Finally, we discuss further problems with utilizing apoptosis induction in cancer therapy and propose a novel potential therapeutic approach that combines the previously discussed features. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells' migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378). [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma represents one of the most common malignant brain tumors in adults and is associated with a poor clinical outcome despite current therapeutic measures. Therefore, novel strategies for the treatment of this disease are urgently needed. In this work, we examined the antineoplastic effects of a combined treatment with photodynamic therapy and ABT-263 on different glioblastoma cells. Photodynamic therapy uses the selective uptake of a photosensitive molecule followed by activation by light of a specific wavelength to kill cancer cells. ABT-263 is a small molecule inhibitor that targets cancer cells by facilitating programmed cell death. This novel combinatorial therapeutic strategy synergistically killed glioblastoma cells. These results indicate that a combination of the two treatment modalities may be of benefit for the treatment of glioblastoma supporting further studies. The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device emitting light of 405 nm wavelength in combination with exposure to 5-ALA (PDT) and the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) was performed in human established and primary cultured glioblastoma cells as well as glioma stem-like cells. We applied cell count analyses to assess cellular proliferation and Annexin V/PI staining to examine pro-apoptotic effects. Western blot analyses and specific knockdown experiments using siRNA were used to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition synergistically enhanced apoptosis in combination with PDT. This effect was caspase-dependent. On the molecular level, PDT caused an increased Noxa/Mcl-1 ratio, which was even more pronounced when combined with ABT-263 in a Usp9X-independent manner. Our data showed that Bcl-2/Bcl-xL inhibition increases the response of glioblastoma cells toward photodynamic therapy. This effect can be partly attributed to cytotoxicity and is likely related to a pro-apoptotic shift because of an increased Noxa/Mcl-1 ratio. The results of this study warrant further investigation. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a poor prognosis. Complex genetic alterations and the protective effect of the blood–brain barrier (BBB) have so far hampered effective treatment. Here, we investigated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors, geldanamycin (GDN) and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), in a panel of glioma tumor cell lines with various genetic alterations. We also assessed the ability of the main drug transporters, ABCB1 and ABCG2, to efflux GDN and 17-AAG. We found that GDN and 17-AAG induced extensive cell death with the morphological and biochemical hallmarks of apoptosis in all studied glioma cell lines at sub-micro-molar and nanomolar concentrations. Moderate efflux efficacy of GDN and 17-AAG mediated by ABCB1 was observed. There was an insignificant and low efflux efficacy of GDN and 17-AAG mediated by ABCG2. Conclusion: GDN and 17-AAG, in particular, exhibited strong proapoptotic effects in glioma tumor cell lines irrespective of genetic alterations. GDN and 17-AAG appeared to be weak substrates of ABCB1 and ABCG2. Therefore, the BBB would compromise their cytotoxic effects only partially. We hypothesize that GBM patients may benefit from 17-AAG either as a single agent or in combination with other drugs. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12–18 months. New and emerging treatments include the application of a physical device, non-invasive 'tumor treating fields' (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use. [ABSTRACT FROM AUTHOR]

Apoptotic resistance remains a hallmark of glioblastoma (GBM), the most common primary brain tumor in adults, and a better understanding of this process may result in more efficient treatments. By utilizing chromatin immunoprecipitation with next-generation sequencing (CHIP-seq), we discovered that GBMs harbor a super enhancer around the Mcl-1 locus, a gene that has been known to confer cell death resistance in GBM. We utilized THZ1, a known super-enhancer blocker, and BH3-mimetics, including ABT263, WEHI-539, and ABT199. Combined treatment with BH3-mimetics and THZ1 led to synergistic growth reduction in GBM models. Reduction in cellular viability was accompanied by significant cell death induction with features of apoptosis, including disruption of mitochondrial membrane potential followed by activation of caspases. Mechanistically, THZ1 elicited a profound disruption of the Mcl-1 enhancer region, leading to a sustained suppression of Mcl-1 transcript and protein levels, respectively. Mechanism experiments suggest involvement of Mcl-1 in the cell death elicited by the combination treatment. Finally, the combination treatment of ABT263 and THZ1 resulted in enhanced growth reduction of tumors without induction of detectable toxicity in two patient-derived xenograft models of GBM in vivo. Taken together, these findings suggest that combined epigenetic targeting of Mcl-1 along with Bcl-2/Bcl-xL is potentially therapeutically feasible. [ABSTRACT FROM AUTHOR]

The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma. [ABSTRACT FROM AUTHOR]

Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX's transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session—the 5aai regimen—is warranted. [ABSTRACT FROM AUTHOR]

Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated LXR agonist, LXR623, along with the TRAP1 inhibitor, gamitrinib (GTPP), results in synergistic reduction of tumor growth and cell death induction in a broad range of solid tumors, which is rescued by exogenous cholesterol. The LXR agonist and TRAP1 inhibitor mediated cell death is regulated at the level of Bcl-2 family proteins with an elevation of pro-apoptotic Noxa. Silencing of Noxa and its effector BAK attenuates cell death mediated by the combination treatment of LXR agonists and TRAP1 inhibition. Combined inhibition of TRAP1 and LXR agonists elicits a synergistic activation of the integrated stress response with an increase in activating transcription factor 4 (ATF4) driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK). Silencing of ATF4 attenuates the increase of Noxa by using the combination treatment. Lastly, we demonstrate in patient-derived xenografts that the combination treatment of LXR623 and gamitrinib reduces tumor growth more potent than each compound. Taken together, these results suggest that TRAP1 inhibition and simultaneous activation of LXR might be a potent novel treatment strategy for solid malignancies. [ABSTRACT FROM AUTHOR]

The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs—the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat—that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial. [ABSTRACT FROM AUTHOR]

XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors. [ABSTRACT FROM AUTHOR]