Showing papers by "Michael D. Prados published in 2011"

Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.

Abstract: Purpose Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1 R132MUT ) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1 R132MUT differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1 R132 mutation status.

An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway

Abstract: Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1–dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients. Significance: This study reveals that GBM cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and PI3K-dependent activation of SREBP-1. We show that an LXR agonist causes IDOL-mediated LDLR degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting GBM cell death in vivo . These results suggest a role for LXR agonists in the treatment of GBM patients. Cancer Discovery; 1(5) : 442–56. ©2011 AACR . Read the Commentary on this article by Moschetta, [p. 381][1] This article is highlighted in the In This Issue feature, [p. 367][2] [1]: /lookup/volpage/1/381?iss=5 [2]: /lookup/volpage/1/367?iss=5

Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

Abstract: Purpose Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. Patients and Methods Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. Results The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance.

Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide

Abstract: Due to its molecular heterogeneity and infiltrative nature, glioblastoma multiforme (GBM) is notoriously resistant to traditional and experimental therapeutics. To overcome these hurdles, targeted agents have been combined with conventional therapy. We evaluated the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor (XL765) in in vitro and in vivo studies. In vivo serially passaged human GBM xenografts that are more genetically stable than GBM cell lines in culture were used for all experiments. Biochemical downstream changes were evaluated by immunoblot and cytotoxicity by colorimetric ATP-based assay. For in vivo experiments, human xenograft GBM 39 grown intracranially in nude mice was altered to express luciferase to monitor tumor burden by optical imaging. XL765 resulted in concentration-dependent decreases in cell viability in vitro. Cytotoxic doses resulted in specific inhibition of PI3K signaling. Combining XL765 with temozolomide (TMZ) resulted in additive toxicity in 4 of 5 xenografts. In vivo, XL765 administered by oral gavage resulted in greater than 12-fold reduction in median tumor bioluminescence compared with control (Mann–Whitney test p = 0.001) and improvement in median survival (logrank p = 0.05). TMZ alone showed a 30-fold decrease in median bioluminescence, but the combination XL765 + TMZ yielded a 140-fold reduction in median bioluminescence (Mann-Whitney test p = 0.05) with a trend toward improvement in median survival (logrank p = 0.09) compared with TMZ alone. XL765 shows activity as monotherapy and in combination with conventional therapeutics in a range of genetically diverse GBM xenografts.

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab

Abstract: Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.

A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American brain tumor consortium study 03-03

Abstract: Malignant gliomas, the most common primary brain tumors in adults, have an estimated annual incidence of 15, 000 cases in the United States.1 Despite optimal treatment with maximal surgical resection, radiotherapy, and chemotherapy with the alkylating agent temozolomide, gliomas almost invariably recur. Prognosis at time of recurrence is poor, with median duration of survival of only 25 weeks for recurrent glioblastomas (grade IV glioma) and 40 weeks for recurrent anaplastic gliomas (grade III).2 Currently, there is no single accepted standard of care for patients with recurrent malignant gliomas. Re-resection with carmustine wafers,3 systemic nitrosoureas, and, more recently, bevacizumab4,5 are available options; the benefit of these therapies in either disease control or survival, however, is usually measured in a few months. Clearly, better therapeutic approaches are needed. Several malignancies, including gliomas, present abnormal histone acetylation, histone deacetylase (HDAC) overexpression, and, consequently, aberrant DNA transcription.6 HDAC inhibitors, a relatively new class of antineoplastic drugs, promote cell-cycle arrest, cellular differentiation, and apoptosis of malignant cells.7 Inhibition of HDAC increases acetylation of histones, thereby promoting chromatin remodeling and facilitating transcription of genes involved in tumor suppression and apoptosis.6 Additionally, acetylation of nonhistone proteins involved in tumor pathogenesis, such as hypoxia-inducible factor-1, heat shock protein 90, and p53, likely plays a significant role in the antitumoral activity of HDAC inhibitors.8 More recently, HDAC inhibitors were shown to decrease formation of GBM-derived neurospheres, promote tumor stem cell differentiation, and abrogate tumorigenicity of GBM-derived neurospheres.9 Romidepsin (Istodax; Celgene; formerly known as FK228, {"type":"entrez-nucleotide","attrs":{"text":"FR901228","term_id":"525229482","term_text":"FR901228"}}FR901228, or depsipeptide), a peptide isolated from Chromobacterium violaceum, potently inhibits HDAC10 and has efficacy at nanomolar concentrations against several cancer models. In GBM cell lines, romidepsin decreases levels of the antiapoptotic protein Bcl-xL and increases expression of the cyclin-dependent kinase inhibitor p21.11 In addition, romidepsin decreases tumor growth and induces apoptosis in subcutaneous glioma models.11 Romidepsin has been tested clinically in several solid and hematologic malignancies and has recently received US Food and Drug Administration approval for use in cutaneous T-cell lymphomas.12,13 We performed a limited phase I pharmacokinetics (PK)–driven trial of romidepsin in patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs), because romidepsin is metabolized primarily by cytochromes CYP3A4 and CYP3A514 and EIAEDs potently induce CYP3A4. To assess the clinical antitumor activity of romidepsin, we performed a phase II trial of standard dose romidepsin in patients with recurrent malignant gliomas not receiving EIAEDs.

Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?

Abstract: Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.

Impact of bevacizumab chemotherapy on craniotomy wound healing

Abstract: Object. The FDA approval of bevacizumab for recurrent glioblastoma has resulted in its increased use in this patient population. Phase II trials reported 4%–6% impaired wound healing for bevacizumab initiated postoperatively. The effect of preoperative bevacizumab on subsequent craniotomy healing has not been addressed. Methods. The authors retrospectively reviewed the cases of patients who underwent craniotomy for recurrent glioblastoma between 2005 and 2009, evaluating bevacizumab therapy/duration and healing complications (dehiscence, pseudomeningocele, CSF leak, and wound/bone infection). The Wilcoxon rank-sum test and Kruskal-Wallis test were used to compare continuous variables between groups. The Fisher exact test was used to assess for an association between categorical variables, including the comparison of wound-healing complication rates. Logistic regression models were used to estimate odds ratios of wound-healing complications while adjusting for baseline variables. Results. Two hundred nine patients underwent a second craniotomy (161 patients) or third craniotomy (48 patients) for recurrent glioblastoma. Twenty-six individuals (12%) developed wound-healing complications. One hundred sixty-eight patients received no bevacizumab, 23 received preoperative bevacizumab, and 18 received postoperative bevacizumab. Significantly more patients receiving preoperative bevacizumab developed healing compli cations (35%) than non–bevacizumab-treated patients (10.0%, p = 0.004). Postoperative bevacizumab was associated with 6% impaired healing, not significantly different from non–bevacizumab-treated controls (p = 1.0). Preoperative bevacizumab treatment duration (weeks) did not influence healing (OR 0.98, p = 0.55). More healing complications occurred in patients receiving preoperative bevacizumab than in non–bevacizumab-treated controls before the third craniotomy (44% vs 9%, p = 0.03). Conclusions. Although subject to the limitations of a retrospective study, we demonstrate that preoperative bevacizumab treatment resulted in impaired healing after a second and third craniotomy, compared with minimal effect of postoperative bevacizumab. This effect is more striking for the third craniotomy and for a shorter delay between bevacizumab and surgery. These complications should be acknowledged as increased bevacizumab use results in more post–bevacizumab-treated patients in whom surgery for recurrent glioblastoma is considered. Based on these results, the authors recommend performing repeated craniotomy more than 28 days after last administered dose of bevacizumab whenever possible. (DOI: 10.3171/2010.10.JNS101042)

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Abstract: Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

Abstract: This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas

Abstract: We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily (125 mg/m 2 /dose) during RT; after RT, it was taken at 200 mg/m 2 twice daily for 21 days, in 28-day cycles. Initial and follow-up neuroimaging was centrally reviewed. Forty eligible patients (median age, 5.5 years; range, 3.3‐16.5 years) had a median progression-free survival of 6.8 months (range, 0.2-18.6 months) and median overall survival of 8.3 months (range, 0.2-18.6 months). Kaplan‐Meier estimates (+ standard error) of 1-year progression-free and overall survival were 12.9%+4.9% and 34.3%+ +7.4%, respectively. A single patient remained on tipifarnib without progression at the completion of the study, two years after initiation of treatment. Seven patients were without disease progression for at least six months, three of whom remained controlled for more than a year. The most frequent toxicity was grade 3 lymphopenia. We documented a single instance of “pseudoprogression” by neuroimaging review. We found no discordance among 3 approaches to defining disease progression: as interpreted by treating institutions (based on clinical status and/or imaging) and by central review (using bi-dimensional tumor “area” versus volumetric measurements). For children with diffuse BSGs, tipifarnib administered with irradiation offered no clinical advantage over historical controls. Biopsies and molecular analyses of pediatric BSGs are vital for identification of new agents and for rational use of targeted agents.

DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression

Abstract: We explored the associations of aberrant DNA methylation patterns in 12 candidate genes with adult glioma subtype, patient survival, and gene expression of enhancer of zeste human homolog 2 (EZH2) and insulin-like growth factor-binding protein 2 (IGFBP2). We analyzed 154 primary glioma tumors (37 astrocytoma II and III, 52 primary glioblastoma multiforme (GBM), 11 secondary GBM, 54 oligodendroglioma/oligoastrocytoma II and III) and 13 nonmalignant brain tissues for aberrant methylation with quantitative methylation-specific PCR (qMS-PCR) and for EZH2 and IGFBP2 expression with quantitative reverse transcription PCR (qRT-PCR). Global methylation was assessed by measuring long interspersed nuclear element-1 (LINE1) methylation. Unsupervised clustering analyses yielded 3 methylation patterns (classes). Class 1 (MGMT, PTEN, RASSF1A, TMS1, ZNF342, EMP3, SOCS1, RFX1) was highly methylated in 82% (75/91) of lower-grade astrocytic and oligodendroglial tumors, 73% (8/11) of secondary GBMs, and 12% (6/52) of primary GBMs. The primary GBMs in this class were early onset (median age 37 years). Class 2 (HOXA9 and SLIT2) was highly methylated in 37% (19/52) of primary GBMs. None of the 10 genes for class 3 that were differentially methylated in classes 1 and 2 were hypermethylated in 92% (12/13) of nonmalignant brain tissues and 52% (27/52) of primary GBMs. Class 1 tumors had elevated EZH2 expression but not elevated IGFBP2; class 2 tumors had both high IGFBP2 and high EZH2 expressions. The gene-specific hypermethylation class correlated with higher levels of global LINE1 methylation and longer patient survival times. These findings indicate a generalized hypermethylation phenotype in glioma linked to improved survival and low IGFBP2. DNA methylation markers are useful in characterizing distinct glioma subtypes and may hold promise for clinical applications.

Conditional Probability of Survival in Patients With Newly Diagnosed Glioblastoma

Abstract: Purpose The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard. Patients and Methods Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions. Results The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P .25). The Weibull distribution fits the data significantly better than exponential (P .02), suggesting nonconstant hazard. Conclusion Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons. J Clin Oncol 29:4175-4180. © 2011 by American Society of Clinical Oncology

Myeloid Biomarkers Associated with Glioblastoma Response to Anti-VEGF Therapy with Aflibercept

Abstract: Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. Results: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1 + monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. Conclusions: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis. Clin Cancer Res; 17(14); 4872–81. ©2011 AACR .

Identifying the needs of brain tumor patients and their caregivers

Abstract: The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers’ questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were “very important” but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients’ lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers’ highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients’ treatment process.

The A/G Allele of Rs16906252 Predicts for MGMT Methylation and Is Selectively Silenced in Premalignant Lesions from Smokers and in Lung Adenocarcinomas

Abstract: Purpose: To address the association between sequence variants within the MGMT (O 6 -methylguanine-DNA methyltransferase) promoter–enhancer region and methylation of MGMT in premalignant lesions from smokers and lung adenocarcinomas, their biological effects on gene regulation, and targeting MGMT for therapy. Experimental Design: Single nucleotide polymorphisms (SNP) identified through sequencing a 1.9 kb fragment 5′ of MGMT were examined in relation to MGMT methylation in 169 lung adenocarcinomas and 1,731 sputum samples from smokers. The effect of promoter haplotypes on MGMT expression was tested using a luciferase reporter assay and cDNA expression analysis along with allele-specific sequencing for methylation. The response of MGMT methylated lung cancer cell lines to the alkylating agent temozolomide (TMZ) was assessed. Results: The A allele of rs16906252 and the haplotype containing this SNP were strongly associated with increased risk for MGMT methylation in adenocarcinomas (ORs ≥ 94). This association was observed to a lesser extent in sputum samples in both smoker cohorts. The A allele was selectively methylated in primary lung tumors and cell lines heterozygous for rs16906252. With the most common haplotype as the reference, a 20 to 41% reduction in promoter activity was seen for the haplotype carrying the A allele that correlated with lower MGMT expression. The sensitivity of lung cancer cell lines to TMZ was strongly correlated with levels of MGMT methylation and expression. Conclusions: These studies provide strong evidence that the A allele of a MGMT promoter–enhancer SNP is a key determinant for MGMT methylation in lung carcinogenesis. Moreover, TMZ treatment may benefit a subset of lung cancer patients methylated for MGMT . Clin Cancer Res; 17(7); 2014–23. ©2011 AACR .

A Phase I Trial of Tipifarnib With Radiation Therapy, With and Without Temozolomide, for Patients With Newly Diagnosed Glioblastoma

Abstract: Purpose To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. Patients and Methods After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Conclusion Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

Investigation of intravenous delivery of nanoliposomal topotecan for activity against orthotopic glioblastoma xenografts.

Abstract: Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.

It Is Time to Include Patients With Brain Tumors in Phase I Trials in Oncology

Abstract: Traditionally,themajorityofphaseIstudiesofnovelagentsin oncology have excluded patients with primary brain tumors. Although phase I studies are designed to determine optimal dosing, efficacy data are increasingly used to look for a signal in particular tumors. Excluding patients with primary brain tumors from phase I studies results in a significant handicap in the identification of drugs that may be particularly active in these tumor types. In this era of targeted therapies, we suggest that the reasons for excluding these patients are largely obsolete. It is time to reconsider this practice and include patients with brain tumors in phase I trials in oncology. Several reasons are given for the exclusion of patients with brain tumors from phase I trials. First, patients with brain tumors were historically treated with cytochrome P450 enzyme-inducing antiepileptic drugs (EIAEDs), such as phenytoin and carbamazepine, which potentially accelerated hepatic metabolism of the agent under study. Asaresult,aseparatephaseIstudywasoftenrequiredforpatientswith

A phase II and pharmacodynamic trial of RO4929097 for patients with recurrent/progressive glioblastoma.

Abstract: TPS135 Background: Patients with recurrent glioblastoma (rGBM) have a 6-month progression-free survival (PFS6) of only 10-15%. Cancer stem-like cells (CSCs) are a subset of cells that are capable of self renewal and differentiation within a tumor. These properties are felt to be a major cause of resistance to chemotherapy and radiotherapy. Furthermore, CSCs promote tumor angiogenesis. Therefore, CSCs are an attractive target for therapy of GBM. Proliferation of CSCs occurs via several pathways. One of the major signaling pathways is Notch. Elevation of Notch signaling imparts a tumor growth advantage by keeping tumor cells in a stem cell-like proliferative state. Expression of Notch is critical for survival and proliferation of human gliomas. Gamma secretase (GS) cleaves the Notch receptor as part of normal Notch function and is thus a critical enzyme in the Notch pathway. Therefore, disruption of the Notch pathway by inhibition of GS is a logical treatment strategy for patients with GBM. RO4929097 is an ...