Showing papers by "Michael D. Prados published in 2014"

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Abstract: Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial

Abstract: Background Outcomes for patients with recurrent glioblastoma multiforme (GBM) are poor and may be improved by immunotherapy. We investigated the safety and efficacy of an autologous heat-shock protein peptide complex–96 (HSPPC-96) vaccine for patients with recurrent GBM.

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk

Abstract: Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02

Abstract: High-grade gliomas are the most common type of brain tumor in adults.1 Despite optimal therapy, patients with glioblastoma (GBM) have a median survival of only 14–19 months, while those with anaplastic astrocytoma (AA) have a median survival of 24–36 months.2 For patients with high-grade glioma whose tumors recur, the median time to tumor progression is only 9–13 weeks.3 There is a need for more effective therapies based on novel mechanisms of action. Epidermal growth factor receptor (EGFR) is amplified and overexpressed in 40%–50% of GBM,4 and nearly half of these tumors have a constitutively activated mutation known as EGFR variant (v)III.5,6 Genomic alterations (deletions or mutations) of phosphatase and tensin homolog (PTEN) lead to protein loss or reduction in 30%–40% of GBM.6–10 These molecular abnormalities activate the pathways for mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR), resulting in tumor proliferation, angiogenesis, and inhibition of apoptosis. Several phase II trials evaluated the benefit of EGFR inhibitors in patients with recurrent malignant glioma. Objective response rates ranged from 0% to 26%, but there was no apparent survival benefit.11–13 Glioblastomas with EGFRvIII and wild-type PTEN14 and tumors with low levels of phospho-Akt15 appear to be sensitive to EGFR inhibitors, suggesting that mTOR inhibition may overcome resistance to these drugs.16 Other studies showed no relationship between EGFR or PTEN genotype and response.17–20 Temsirolimus (CCI-779, Torisel, Wyeth) is metabolized to sirolimus (rapamycin), an mTOR inhibitor. Although temsirolimus inhibits growth in malignant glioma cell lines,21 phase II trials of temsirolimus in recurrent GBM have shown minimal antitumor activity.22,23 In preclinical studies, sirolimus and the EGFR inhibitor EKI-785 achieved synergistic antitumor effects in GBM cell lines.24 Sirolimus and erlotinib also demonstrated synergistic activity, regardless of PTEN status.16,25 A phase I study of gefitinib and sirolimus in recurrent malignant glioma demonstrated acceptable toxicity,26 and a pilot study of gefitinib or erlotinib and sirolimus in heavily pretreated recurrent GBM patients found a 19% partial response (PR) rate and 25% 6-month progression-free survival (PFS6).27 Given the potential synergy of EGFR/mTOR therapy, the North American Brain Tumor Consortium conducted a phase I/II study of erlotinib and temsirolimus in recurrent high-grade glioma.

Targeting Wee1 for the treatment of pediatric high-grade gliomas

Abstract: High-grade gliomas (HGGs) are aggressive brain tumors in children, with 5-year survival rates <20%. For diffuse intrinsic pontine gliomas (DIPGs), the most common type of glioma arising in the brainstem, the prognosis is even worse, with virtually no long-term survivors.1 Despite several decades of research efforts, the outcomes for these children have not significantly changed. This lack of progress can be attributed to a lack of understanding of underlying molecular events leading to pediatric HGG and DIPG tumorigenesis and a lack of relevant models for therapeutic drug testing. A number of genetic and molecular alterations have recently been identified in the oncogenesis of pediatric gliomas. Approximately 15% of pediatric gliomas (World Health Organization grades II–IV) have an activating mutation in the Braf gene (BRAFV600E). Inhibitors targeting components of this activated pathway are entering clinical trials for the treatment of children with BRAFV600E-positive gliomas.2 Platelet derived growth factor receptor (PDGFR) amplification has also been reported in subsets of HGGs and DIPGs, with crenolanib, an inhibitor of PDGFR kinase, currently being tested in children and young adults with the latter type of tumor.3 In addition, recent investigations have found a specific histone mutation (K27M-H3.3) that is present in most DIPGs, whose occurrence is associated with worse clinical outcome.4,5 Investigations targeting molecular biology related to this mutation are ongoing. The molecular underpinnings of pediatric HGGs and DIPGs are distinct from those underlying adult gliomas,6 and therefore the common practice of extrapolating adult therapies to pediatric tumors is precarious. The development of effective strategies for pediatric patients requires laboratory investigations and preclinical testing in relevant, pediatric-specific models. A potential specific molecular target is Wee1, which is a critical driver of G2-M cell cycle progression. Activated Wee1 causes inhibitory phosphorylation of Cdc2, preventing G2-M cell cycle progression. Inhibition of Wee1 in combination with radiation has been shown to reduce tumor growth in adult models of glioblastoma multiforme (GBM), by promoting premature mitosis in cells with damaged DNA.7 Wee1 inhibition alone has also been shown to have antitumor activity in sarcoma cells leading to apoptotic death.8 To date, possible links between Wee1 and known aberrations in pediatric HGG and/or DIPGs such as PDGFR amplification or the specific K27M-H3.3 mutation remain poorly understood. MK-1775 is a selective Wee1 kinase inhibitor and currently the only Wee1 inhibitor to enter early phase 1/2 clinical trials in combination with conventional chemotherapy for adults with advanced solid tumors. In this study, we investigated the expression of Wee1 in pediatric gliomas to evaluate its relevance as a therapeutic target and whether combining MK-1775 with radiation is more effective than radiation alone for the treatment of pediatric gliomas. To our knowledge this is the first investigation that reports on the expression of Wee1 in all grades of pediatric gliomas—including DIPG—and uses relevant pediatric glioma models to assess the effect of MK-1775 in combination with radiation.

A single-institution phase II trial of radiation, temozolomide, erlotinib, and bevacizumab for initial treatment of glioblastoma.

Abstract: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor in adults Despite improvements in survival, it remains largely incurable The current standard of care includes radiation therapy (RT) in combination with low-dose daily temozolomide (TMZ), followed by at least 6 cycles of adjuvant TMZ, based on the seminal phase III study by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada1 Alterations in epidermal growth factor receptor (EGFR) are common in GBM and include overexpression, amplification, and mutation Indeed, EGFR is amplified in ∼45% of GBM tumors2 GBM is also among the most highly vascularized human tumors, and a major driver of microvascular proliferation is vascular endothelial growth factor (VEGF)3 We previously reported the results of a phase II study adding erlotinib (an EGFR inhibitor) to standard initial treatment with RT and TMZ, showing a modest improvement in survival over a historical control4 Phase II studies of bevacizumab (an antibody targeting VEGF) plus RT/TMZ have also been reported,5,6 showing improved progression-free survival (PFS) but not overall survival (OS), and phase III studies testing this combination are in the process of being reported as well7,8 Both EGFR and VEGF pathways are known to be upregulated by radiation, so combining inhibitors of either pathway with RT may be highly effective In addition, preclinical data suggest that a multitargeted approach may have more impact on GBM than treatment with a single agent9 As such, the presented study combined standard RT and TMZ with both erlotinib and bevacizumab to evaluate whether this combination would be more effective than standard therapy Because the full combination of RT/TMZ/erlotinib/bevacizumab has not been previously tested, the study was designed with a 15-patient safety lead-in adding bevacizumab and erlotinib to TMZ after standard RT/TMZ, to confirm that there was no unexpected toxicity to the 3-drug combination prior to combining the 3 drugs with radiation

Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials neuroimaging endpoint workshop (January 30, 2014, Bethesda MD)

Abstract: On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons, biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters.

Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma

Abstract: Background A phase II trial was performed to evaluate the efficacy of a dose-dense, 7 days on/7 days off schedule of temozolomide for patients with recurrent high-grade gliomas (HGG). Methods Sixty patients with recurrent HGG received temozolomide at 150 mg/m(2)/day on days 1-7 and days 15-21 during each 4-week cycle. The primary endpoint was 6-month progression-free survival (PFS-6), with a secondary endpoint of overall survival (OS). A further exploratory objective included the investigation of whether methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter within tumor tissue predicted outcomes. Results Among patients with glioblastoma (n = 40), PFS-6 was 10% (95% CI, 3%-24%) with median OS of 21.6 weeks (95% CI, 16.9-30.6 weeks). PFS-6 for grade III glioma patients (n = 20) was 50% (95% CI, 27%-73%), and median OS was 100.6 weeks (95% CI, 67 weeks to not reached). There were trends towards longer PFS and OS with MGMT promoter methylation (log-rank test; P = .06 for PFS; P = .07 for OS). Additionally, bevacizumab-naive glioblastoma patients had significantly longer PFS and OS (median PFS was 8.07 weeks [95% CI, 8 weeks to not reached] vs 7.57 weeks [95% CI, 7.29-8.29 weeks], log-rank test, P Conclusions The dose-dense temozolomide regimen was well tolerated, although it has no significant activity in this population. Clinical trials.gov identified. NCT00619112 (available at http://clinicaltrials.gov/ct2/show/NCT00619112).

A phase 1 study of AZD6244 in children with recurrent or refractory low-grade gliomas: A Pediatric Brain Tumor Consortium report.

Abstract: 10065 Background: Pathway activating genetic aberrations of the Ras-MAP kinase signaling pathway have been observed in pediatric low grade glioma (LGG), most commonly a fusion gene, BRAF-KIAA1549 o...

Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma.

Abstract: 2019 Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. Buparlisib is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic con...

Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway.

Abstract: 2026 Background: The prognosis for GBM, which appears to be driven by glioma initiating cells (GIC), remains poor. Our hypothesis was that interrupting sonic hedgehog signaling (SHh) would inhibit ...

A phase 2 study of orally administered PLX3397 in patients with recurrent glioblastoma.

Abstract: 2023 Background: PLX3397 is an oral, small molecule that potently and selectively inhibits CSF1R, Kit, and Flt3-ITD kinases. CSF1R is expressed on microglia/macrophages and tumor cells within gliob...

Targeting glioma initiating cells in gbm: abtc-0904, a randomized phase 0/ii study targeting the sonic hedgehog-signaling pathway

Abstract: BACKGROUND: New therapeutic approaches are urgently needed for recurrent GBM (rGBM). Recent studies suggest that GBM oncogenesis and recurrence are regulated by glioma initiating cells (GIC), a minority population of quiescent cells driven by embryonic signaling pathways and resistant to radiation and chemotherapy. Our hypothesis was that interrupting the sonic hedgehog signaling pathway (SHh), an integral mediator of GIC proliferation, would slow tumor progression and improve six month progression free survival (PFS6) in correlation with decreased GSC proliferation and self-renewal. METHODS: A two armed, randomized phase 0/II study of Vismodegib, an inhibitor of SMO was performed in 40 patients undergoing resection for rGBM. Arm I was randomized to receive Vismodegib for 7 days pre-operatively; Arm II was not treated with drug pre-operatively. All patients were treated with Vismodegib alone post-operatively until progression or death. Our primary objective was to estimate six month progression-free survival (PFS6), with secondary endpoints of median overall survival (mOS), response and toxicity. Secondary objectives included determination of: intra-tumoral PK and PD; inhibition of SHh signaling by RT-PCR and immunohistochemistry; and inhibition of GIC proliferation and self-renewal by neurospheres proliferation and limited dilution assays. RESULTS: PK/PD data and tumor specimens obtained from 39/40 patients demonstrated plasma and tissue levels for patients in Arm I (treated pre-operatively) were within therapeutic range. SHh signaling intermediates (Gli-1, Gli-2, PTCH-1b) as determined by RT-PCR and IHC were significantly lower in Arm I vs. Arm II (p < 0.0002). Finally, proliferating CD133 + neurospheres in serum free-media were derived from 17 of the 39 cultures assessed. Array CGH was consistent with GIC (rather than NSC) as the cells of origin, and the proportion of tumor-derived CD133+ neurospheres undergoing proliferation and self-renewal was decreased in Arms I vs. II (p <0.0053 & p < 0.003 respectively). Median PFS and OS was 1.8m and 8.3m respectively; toxicity was minimal. CONCLUSIONS: Vismodegib was well tolerated but poorly efficacious as a single agent in rGBM. However, phase PK and PD studies demonstrated that this agent achieved therapeutic intra-tumoral concentration in rGMB and had biological activity on proliferation and self-renewal of GBM derived CD133+ neurospheres. The phase O/II trial design facilitates a more thorough understanding of an agent's biological effects than the standard phase II trial, and has the potential to enable a more rational approach to this complex and deadly disease. Thus this data suggests that novel combinations pairing SHh pathway inhibition with other agents should be pursued despite lack of single agent efficacy. SECONDARY CATEGORY: Clinical Neuro-Oncology.

Phase ii trial of the phosphatidyinositol-3 kinase (pi3k) inhibitor buparlisib (bkm120) in recurrent glioblastoma conducted by the ivy foundation early phase clinical trials consortium

Abstract: BACKGROUND: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. Buparlisib is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations and inhibits the growth of U87 and human glioma tumor sphere models. METHODS: The Ivy Consortium conducted a phase II study of buparlisib in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1st or 2nd relapse, >18 yrs, KPS >60, adequate bone marrow and organ function, no prior bevacizumab or enzyme-inducing antiepileptic drugs. Patients received buparlisib 100mg daily. The study consisted of 2 concurrent cohorts. In Cohort 1 (up to 15 patients) buparlisib was given for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. In Cohort 2, 50 patients with unresectable GBM received buparlisib with a primary endpoint of PFS6. RESULTS: 13 patients were enrolled into cohort 1, 50 into cohort 2. Treatment was fairly well-tolerated with no grade 4 toxicities. Grade 3 toxicities were asymptomatic lipase elevation (6), rash (4), hyperglycemia (3), fatigue (4), elevated ALT/AST (2), and 1 each with depression, anxiety, hypophosphatemia, thrombocytopenia and lymphopenia. Analysis of tumor specimens from Cohort 1 showed reduction of pAKT by IHC in 4/6 (67%) of evaluable patients. The combined cohorts showed minimal efficacy with median PFS of 1.8 months and median OS of 10.9 months. Best response was stable disease. Only 1 patient in each cohort achieved PFS6. Of the first 40 patients who underwent exome sequencing, there were 4 PIK3CA (10%), 2 PIK3R1 (5%) and 13 PTEN (33%) mutations. Patients with PTEN loss and or PI3K mutations paradoxically had a worse outcome. CONCLUSIONS: Buparlisib is well-tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAKTS473. However, single agent efficacy was minimal. Final correlation of tumor genotype with outcome will be presented. SECONDARY CATEGORY: n/a.

"We will know it when we see it;" bevacizumab and glioblastoma.

Abstract: At a recent joint meeting on January 30, 2014 between stakeholders in the Neuro-Oncology community (clinical scientists, imaging experts, representatives from pharmaceutical and biotechnology companies, and philanthropy) and the Food and Drug Administration (FDA), discussing endpoints for clinical trials in recurrent glioblastoma, this phrase (“we will know it when we see it”) was used on several occasions. Either in a sense of hope or perhaps frustration with the lack of new agents in this disease, the comment reflected a sense by some in the meeting that imaging surrogates of tumor burden remain problematic, objective response remains elusive, landmark time to progression endpoints not validated, and neither of these endpoints are proven (yet) to be a true measure of efficacy for new therapies. There was general agreement that a sustained, durable, objective response could serve as a surrogate for preliminary approval of new agents, even in the context of a single arm study. This agreement assumed reliable, consistent and reproducible measures of “response” were standardized and could be used effectively in multi-institutional settings. Bevacizumab was given accelerated approval using an objective response measure, based upon a single, uncontrolled clinical trial (the BRAIN study), supported by results from a second independent study (1, 2). Confirmed and independently reviewed imaging responses, taking into account enhancing and T-2 /FLAIR sequences and steroid use, were seen in both studies at a much higher rate than historical controls. In full disclosure, I advocated for this indication at the FDA Oncology Drug Advisory Committee meeting, based upon the trial evidence, our own experience and that of others, and feeling that I really “knew it when I saw it.” Full approval by the FDA required confirmation in a larger randomized study.

A phase i study of convection-enhanced delivery of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent high grade glioma

Abstract: BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by poor activity of available agents and compromised delivery across the blood brain barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection established as a result of a pressure gradient, obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in rat, dog, and primate models. A recent study in mice with intracranial glioblastoma xenografts compared routes of delivery for liposomal irinotecan by CED or IV and showed superior anti-tumor activity of CED. A major clinical advance in the use of CED over recent trials is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action for technical complexities. METHODS: With support from an R21 we will conduct the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. This is a single center, prospective, 3 + 3 dose escalating, single-arm, phase I trial with a four-level dose escalation, expecting to enroll at least 3 patients in each level and expanding the highest level to 12 patients total. Dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral (IT) location. Concentration of gadoteridol will be 2 mM for all dose groups; both agents will be combined and co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group will have tumor volume 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG. SECONDARY CATEGORY: Imaging.

Plexiform neurofibromas, trial design, and the definitions of "progression" and "treatment failure".

Abstract: The article by Widermann et al is timely. In the context of this study and recently reported trials in newly diagnosed Glioblastoma, the question of appropriate endpoints and outcome measures, along with trial design, has resurfaced as a critical discussion point, particularly as it relates to decisions concerning drug development. In the current trial children and young adults with progressive plexiform neurofibromas were treated with tipifarnib, a farnesyltransferase inhibitor, or placebo, and allowed a cross-over at progression to either treatment in a second stage. There are a number of unique aspects to the study, starting with the understanding that this is a disease with a poorly understood and studied natural history. These tumors grow slowly and variably over time, are difficult to measure, occur in multiple regions of the body, have a complex biology related to RAS signaling, and there is no effective treatment other than surgery done as an attempt to minimize morbidity. Besides the difficult choice of drug selection, the type(s) of endpoint needed to evaluate efficacy becomes problematic without good historical control studies. The authors chose to use progression as the primary endpoint rather than objective response, and added the placebo control arm because of the uncertain natural history of these tumors. When are plexiform neurofibromas “progressive”? As shown by

Phase II trial of vorinostat (VOR) combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (Alliance N0874/ABTC-0902).

Abstract: 2030 Background: VOR is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single agent activity in recurrent disease (Galanis et al 2009) and rad...

Ed-36inherited variants near terc and tert are associated with longer telomeres and increased glioma risk: genome-wide association results from the ucsf adult glioma study and the engage consortium telomere group

Abstract: High-grade glioma, the most common central nervous system cancer in adults, has poor prognosis. We performed a genome-wide association study (GWAS) and replication analysis of high-grade glioma risk (N = 1,644 cases and 7,736 controls). We identify a novel inherited glioma risk locus, rs1920116 (near TERC), that achieved genome-wide statistical significance (Pcombined = 8.3 × 10−9). We also validate a previously identified glioma risk locus, rs2736100, in TERT (Pcombined = 1.4 × 10−15). Because TERC and TERT are subunits of the telomerase enzyme, and variants in both genes have previously been associated with mean leukocyte telomere length (LTL), we examined the relationship between telomere length and glioma risk loci using data from a recent GWAS of LTL (N = 37,684 individuals). The top glioma risk alleles near TERC and TERT were strongly associated with longer telomere length (P = 5.5 × 10−20 and 4.4 × 10−19, respectively). In a ∼100kb haplotype block containing the TERC gene, every SNP which was associated with glioma at P < 0.01 (N = 54 SNPs) was also associated with longer telomeres at P < 1.0x10−5. Associations in TERT were similarly uniform. Glioma risk alleles near RTEL1 were inconsistently associated with telomere length, suggesting the presence of distinct causal alleles at this locus. No other glioma risk loci were associated with telomere length. The identification of alleles that are strongly associated with both increased glioma risk and longer telomeres suggests that heritable variation in telomere length or telomerase activity may underlie glioma susceptibility.

Ni-61volumetric h-1 mr metabolic imaging for definition of lesion burden and prediction of outcome for patients with newly diagnosed gbm

Abstract: Interpretation of the efficacy of novel therapies for patients with GBM with anatomic MR imaging is complicated by pseudo-progression and pseudo-response. The goal of this study was to obtain volumetric H-1 MRSI data with a rapid 3-D PRESS lactate edited EPSI sequence (Tacq = 10 minutes) at pre- and post-RT scans in order to evaluate the biological properties of the lesion and relate them to overall survival (OS). The population comprised 58 patients with newly diagnosed GBM: 35 received radiation (RT), Temozolomide (TMZ) and Enzastaurin (Group 1) and 24 received RT, TMZ, Tarceva and Bevacizumab (Group 2). The T2L and CEL were defined from the anatomic images and the choline to NAA index (CNI) and normalized levels of lactate (nLac) estimated for each voxel from the MRSI data. Age adjusted Cox Proportional Hazards models were applied to assess the association of these parameters OS (P < 0.05 being considered significant). From pre-RT to post-RT, the median volume of the CEL decreased by 49% for Group 1 and by 42% for Group 2. The median volume of the T2L was relatively stable for patients in Group 1 (median 20.9 to 19.5cc) but decreased with follow-up for patients in Group 2 (median 23.8 to 5.5cc). The maximum CNI within the T2L decreased more for Group 1 (median 9.7 to 5.9) than for Group 2 (median 6.4 to 5.2). Levels of nLac within the T2L at pre- and post-RT scans were significantly associated with OS for both Groups. These findings demonstrate the feasibility of obtaining rapid, volumetric H-1 MRSI data that provide distinct measures of lesion burden and that are associated with OS. Integration of these metrics into the evaluation of novel therapies is likely to be important for resolving ambiguities associated with anatomic imaging methods.