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Purpose: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo., Experimental Design: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures., Results: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebrafish and a mouse xenograft model of GBM compared with the standard of care (radiation and TMZ) or onalespib with radiation., Conclusions: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in patients with GBM., (©2022 American Association for Cancer Research.)

Background: Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial., Objective: This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms., Methods: Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1-4 μg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation., Results: A total of 10 patients have completed treatment with infusion doses of carboplatin of 1μg, 2μg, and 4μg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure)., Conclusions: IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4μg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy., Competing Interests: The authors have declared that no competing interests exist.

Introduction : Gliomas are highly heterogeneous primary brain tumors which result in a disproportionately high degree of morbidity and mortality despite their locoregional occurrence. Advances in the understanding of the biological makeup of these malignancies have yielded a number of potential tumor-driving pathways which have been identified as rational targets for therapy. However, early trials of agents that target these pathways have uniformly failed to yield improvement in outcomes in patients with malignant gliomas. Areas covered : This review provides an overview of the most common biological features of gliomas and the strategies to target the same; in addition, the current status of immunotherapy and biological therapies are outlined and the future directions to tackle the challenges of therapy for gliomas are examined. Expert opinion : The limitations of current treatments are attributed to the inability of most of these agents to cross the blood-brain barrier and to the intrinsic heterogeneity of the tumors that result in treatment resistance. The recent emergence of immune-mediated and biological therapies and of agents that target metabolic pathways in gliomas have provided strategies that may overcome tumor heterogeneity and ongoing trials of such agents are anticipated to yield improved outcomes.

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood-brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non-tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models. Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts. Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215-26. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

Primary meningeal gliomas are rare tumors composed of a heterogeneous group of neoplasms. We present 2 clinically aggressive cases of primary meningeal pleomorphic xanthoastrocytoma that clinically mimicked meningioma. One case presented in the posterior fossa of a 56-year-old woman; the other centered on the left operculum of a 35-year-old woman. These cases showed many of the classic features of pleomorphic xanthoastrocytoma, except that xanthomatous cells were rare and eosinophilic granular bodies were inconspicuous. Both cases exhibited high proliferative indices and superficially invaded the brain. One case harboring a BRAF mutation disseminated to the thecal sac and showed a clinical response to the targeted BRAF inhibitor dabrafenib. These cases seem to represent an unusual primarily extra-axial presentation of pleomorphic xanthoastrocytoma and may account for at least some of the previously reported cases of primary meningeal glioma and/or glial fibrillary acidic protein-immunoreactive meningioma variants. We suggest that BRAF mutation analysis be considered in all meningeal lesions showing atypical histologic or immunohistochemical profiles, particularly those exhibiting glial differentiation, as a diagnostic aid and possible indication for targeted therapy.

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib., Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response., Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages., Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

Fenretinide, a synthetic retinoid that induces apoptosis in tumor cells in vitro, is being evaluated in clinical trials as a chemotherapeutic agent against several malignancies. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining its efficacy in vitro against such cells in primary culture. Cells, cultured from freshly resected benign, atypical, or malignant meningiomas, were exposed to fenretinide (10 mumol/L). Treatment effects were assessed using flow cytometry, Western blot analysis, semiquantitative reverse transcription-PCR for retinoid receptor expression, and changes in insulin-like growth factor-I (IGF-I)-induced proliferation. Fenretinide induced apoptosis in the three grades of meningioma primary cells tested, as shown by the appearance of a sub-G(1) fraction in flow cytometric analysis and by the detection of poly-adenosyl ribonucleotidyl phosphorylase cleavage indicating caspase activation. Fenretinide treatment also increased levels of the death receptor DR5 and caused mitochondrial membrane depolarization. The levels of the retinoid receptors, retinoic acid receptor alpha and retinoid X receptor gamma, were up-regulated in response to fenretinide, suggestive of ligand-induced receptor up-regulation. IGF-I-induced proliferation in the meningioma cells was abolished by fenretinide. We conclude that fenretinide induces apoptosis in all three histologic subtypes of meningioma and exerts diverse cellular effects, including DR5 up-regulation, modulation of retinoid receptor levels, and inhibition of IGF-I-induced proliferation. These results provide preliminary evidence that fenretinide has activity against meningiomas and suggest that further studies are warranted to explore its potential as a therapeutic agent against meningiomas.

Purpose: Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas., Patients and Methods: Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m(2) bid., Results: Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m(2) bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma C(max) for fenretinide was 832 +/- 360 ng/mL at the 600 mg/m(2) bid dosage and 1,213 +/- 261 ng/mL at the 900 mg/m(2) bid dosage., Conclusion: Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.

Purpose: Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.Experimental Design: Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml x min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml x min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.Results: The administered regimen of paclitaxel (225 mg/m(2) i.v. over 3 h) and carboplatin (AUC 6 mg/ml x min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.Conclusions: The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors. [ABSTRACT FROM AUTHOR]