bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-05. DISSOCIATION OF THE INTRAMOLECULARLY CLEAVED N- AND C-TERMINAL FRAGMENTS OF ADHESION G PROTEIN-COUPLED RECEPTOR GPR133 (ADGRD1) INCREASES ITS CANONICAL SIGNALING IN GLIOBLASTOMA
Authors: Frenster Joshua , Stephan Gabriele , Ravn-Boess Niklas , Bready Devin , Wilcox Jordan , Liebscher Ines , Schöneberg Torsten , Placantonakis Dimitris
Published: November 2021

We previously demonstrated that GPR133 (ADGRD1), an adhesion GPCR that signals via cytosolic cAMP increase, is de novo expressed in glioblastoma (GBM) and enriched in patient-derived glioblastoma stem cells. Knockdown of GPR133 reduces GBM cell proliferation and tumorsphere formation, and abolishes orthotopic xenograft initiation in vivo. GPR133’s requirement for GBM growth and its absence in non-malignant brain suggest its therapeutic potential, yet its mechanisms of action and activation remained unclear. Here, we demonstrate in patient-derived GBM cultures and HEK293T cells that GPR133 gets intramolecularly cleaved into N-terminal and C-terminal fragments (NTF and CTF) right after synthesis in the endoplasmic reticulum. The resulting NTF and CTF remain non-covalently bound to each other, until the mature receptor reaches the plasma membrane, where we observe dissociation of the extracellular NTF from the transmembrane-spanning CTF. While cleavage is not required for correct subcellular trafficking, the cleaved wild-type GPR133 generates significantly higher cytosolic cAMP levels than an uncleavable point mutant GPR133 (H543R), suggesting that cleavage and dissociation are involved in receptor activation. To test this hypothesis in a more controllable proxy system, we generated a fusion of the CTF of GPR133 and the N-terminus of human protease-activated receptor 1 (hPAR1). Indeed, acute thrombin-induced cleavage and shedding of the hPAR1 NTF increases intracellular cAMP levels generated by the GPR133 CTF. These results support a model wherein dissociation of the NTF from the CTF at the plasma membrane promotes GPR133 activation and downstream signaling. To test whether extracellular binding proteins could influence NTF shedding and/or GPR133 signaling activation, we conducted ligand discovery screens and indeed found a new GPR133 binding protein in GBM cells, which is capable of influencing receptor signaling. Together, these findings provide critical insights into GPR133’s mechanism of activation, that will guide future approaches of therapeutic targeting of GPR133 in GBM.
CSIG-06. ELUCIDATING THE ROLE OF CO-OCCURRING MUTATIONS IN FGFR1-DRIVEN PEDIATRIC LOW-GRADE GLIOMA
Authors: Morin Eric , DiGiacomo Jeromy , Malinowski Seth , Alexandrescu Sanda , Jones David , Ligon Keith , Bandopadhayay Pratiti
Published: November 2021

Pediatric low-grade gliomas (pLGGs) have excellent survival, however, with current standard of care, most patients suffer lifelong severe sequalae. pLGGs are almost exclusively driven by single activating mutations in the mitogen-activated protein kinase (MAPK) pathway. As targeted molecular therapy clinical trials focusing on BRAF-altered pLGGs are showing promising results in early clinical trials, similar efforts are underway for FGFR1-altered tumors. In our cohort of FGFR1-4 altered gliomas, we observe frequent occurrence of a second alteration associated with activation of the MAPK or mammalian target of rapamycin (mTOR) pathways in pLGGs. Most commonly in the phosphatase NF1, PIK3CA, PIK3R1 PTPN11 or within the FGFR1 gene itself. However, the impact of second co-occurring mutations on therapeutic response and resistance has not been explored. To address this, we established mouse neural stem cell models over-expressing hot-spot mutated FGFR1 alone or in combination with a second alteration. Immunoblotting revealed that the addition of a second alteration attenuated phosphorylation of ERK, AKT and S6 and influenced cell proliferation both in normal growth conditions and in absence of growth factor. Treatment with an FGFR inhibitor (Infigratinib) showed reduced drug response in double mutant cells compared to hot-spot mutated FGFR1 alone. This was associated with less reduction of phosphorylation of ERK and S6 in the double mutant cells upon treatment. In conclusion, the presence of a second alteration influences proliferation and drug response in models of FGFR1-mutated pLGG, potentially by modulating MAPK and mTOR signaling.
CSIG-15. ALTERATIONS IN THE TRANSSULFURATION PATHWAY ENABLE GLIOBLASTOMA INVASION INTO THE PERITUMORAL WHITE MATTER
Authors: Garcia Joseph , Jain Saket , Akins Erin , Beniwal Angad , Spatz Jordan , Gill Sabraj , Wolf Kayla , Cha Junghwa , Kumar Sanjay , Aghi Manish K
Published: November 2021

Glioblastoma is a primary malignant brain tumor with a median survival under two years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. While numerous factors have been proposed as the primary driving forces behind glioblastoma’s ability to invade adjacent tissues rapidly, little attention has been paid to the alterations in tumor cell metabolism needed for tumor cells to thrive in isolation in the peritumoral white matter. To improve on biased 2D cell culture studies, we defined the links between glioblastoma metabolism in invasion using unbiased CRISPR screens and metabolomics performed in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Through these platforms, we identified targetable metabolic factors which drive cellular invasion in glioblastoma. Metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site-directed biopsies (6-fold change), and 3D organoid models (14-fold change). RNA sequencing revealed 7/30 (23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in glioblastoma invasion, revealing a targetable alteration unique to invading glioblastoma cells.
CSIG-16. PATHWAY-BASED APPROACH REVEALS DIFFERENTIAL SENSITIVITY OF GLIOBLASTOMA TO E2F1 INHIBITION
Authors: Alvarado Alvaro , Tessema Kaleab , Muthukrishnan Sree , Kawaguchi Riki , Swarup Vivek , Goldman Steven , Kornblum Harley
Published: November 2021

The great phenotypic heterogeneity of glioblastoma (GBM) – both inter and intratumorally – has hindered therapeutic efforts. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has not translated to a significant extension of patient survival. We hypothesize that, rather than gene expression as a whole, analysis of targetable pathways could yield important insights into the development of novel classification schemes and, most importantly, to targeted therapeutics. Here, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. The Cancer Genome Atlas samples were clustered using gene set enrichment analysis and the resulting 3 clusters were informative of patient survival and only modestly overlapped with prior molecular classification. We validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity, proliferation and in vivo tumor growth when E2F1, our top target, was silenced. Consistent with our theory, E2F1 knockdown had little or no effect on the growth of the non-enriched lines, despite their ability to proliferate in vitro and in vivo. We similarly analyzed single cell RNAseq datasets and correlated cell cycle and stemness signatures with the gene lists we generated as well as with molecular states and cell specific signatures. Finally, we confirmed a connection between E2F1 and cellular inhibitor of PP2A (CIP2A) in a cluster of samples. Loss of function studies reveals a diminished capacity for DNA damage regulation in E2F1 activated samples. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.
CSIG-20. CANNABIDIOL CONVERTS NFKB INTO A TUMOR SUPPRESSOR IN GLIOBLASTOMA WITH DEFINED ANTIOXIDATIVE PROPERTIES
Authors: Volmar Marie , Cheng Grace , Schick Joel , Kälin Roland , Glass Rainer
Published: November 2021

The transcription factor NFKB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFKB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFKB can be converted into a tumor suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM-datasets. We found that CBD promotes DNA binding of the NFKB subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA binding by RELA lacking phospho-serine 311 was fully sufficient to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC death. Consequently, ROS levels served as predictive biomarker for CBD-sensitive tumors. This evidence demonstrates how a clinically approved drug can convert NFKB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy
CSIG-26. NF2/MERLIN DRIVES MENINGIOMA APOPTOSIS AND SUCEPTIBILITY TO CYTOTOXIC THERAPY
Authors: Eaton Charlotte , Choudhury Abrar , Casey-Clyde Timothy , Swaney Danielle , Krogan Nevan , Raleigh David
Published: November 2021

BACKGROUND

Alterations in NF2 underlie meningioma tumorigenesis, but tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood in meningiomas. Here we integrate proteomic proximity-labelling mass spectrometry with CRISPR interference (CRISPRi), RNA sequencing, and biochemical approaches to discover Merlin drives meningioma apoptosis and susceptibility to cytotoxic therapy.

METHODS

RNA sequencing was performed on triplicate M10G meningioma cells stably expressing CRISPRi machinery and either non-targeting control sgRNAs, sgRNAs suppressing NF2, or sgRNAs suppressing NF2 with Merlin rescue. QPCR in IOMM-Lee and MSC1 meningioma cells expressing non-targeting control shRNAs or shRNAs suppressing NF2 was used for orthogonal validation in vitro. RNA sequencing of euploid meningiomas (n=52) or meningiomas with loss of NF2 as the only copy number variant (n=28) was used for orthogonal validation in vivo. Merlin interactors in meningioma cells were identified using APEX proteomic proximity-labelling mass spectrometry. Mechanistic and functional studies were performed using biochemical, molecular, and cell biology approaches in meningioma cells and CH-157MN meningioma xenografts treated with cytotoxic chemotherapy or ionizing radiation.

RESULTS

Merlin suppression in meningioma cells and xenografts inhibited pro-apoptotic interferon regulatory factor (IRF) target genes and attenuated meningioma apoptosis. Merlin suppression did not alter IRF stability or subcellular localization in meningioma cells, and proteomic proximity-labelling mass spectrometry revealed a novel interaction between wildtype Merlin and ARHGAP35, a DNA binding factor that inhibits glucocorticoid receptor expression (NR3C1). NR3C1 inhibits IRF activity to prevent apoptosis, and Merlin suppression in meningioma cells induced NR3C1expression, which was inhibited by Merlin rescue. Further, NR3C1 suppression rescued meningioma cell apoptosis in the absence of Merlin, and NR3C1 expression was increased in human meningiomas with loss of NF2 compared to euploid meningiomas.

CONCLUSIONS

These data shed light on a novel pro-apoptotic tumor suppressor function of Merlin regulating glucocorticoid signalling and susceptibility to cytotoxic therapy in meningiomas.
CSIG-27. PROTEOMIC ANALYSIS OF GENETICALLY STRATIFIED MENINGIOMA
Authors: Akther Yeasmin , Dunn Jemma , Adams Claire , Sharma Vikram , Banton Matthew , Hanemann Clemens
Published: November 2021

WHO grade II and III as well as some WHO grade I meningioma are clinically aggressive. Approximately 60% sporadic meningiomas harbour mutations in the NF2 gene, others in genes including TRAF7, KLF4, AKT1, SMO and PIK3CA . However, the molecular mechanisms behind meningioma tumourigenesis are still unclear. We aim to identify novel biomarkers and therapeutic targets of meningioma by characterising the proteomic landscape. We performed (phosho)proteomic profiling of grade I, II and III meningiomas and three different mutational groups: AKT1 E17K /TRAF7, KLF4 K409Q /TRAF7 and NF2 -/-. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry. Looking at all grades bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 and upregulation and activation of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins described included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, Hexokinase 2. For the mutation subtypes we have quantified 4162 proteins across all mutational meningioma subgroups with proteomic profiles of mutational subgroups. Comparative analysis showed 10 proteins were commonly significantly upregulated among all mutational subtypes vs. normal meninges, indicating proteomic landscapes of mutational subtypes to be highly variable. 257 proteins were commonly significantly downregulated and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1 E17K /TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. Less proteins were commonly significantly upregulated in KLF4 K409Q /TRAF7 and NF2 -/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 were verified. Analyses of 6600 phospho-sites predicted regulatory kinases. Further validation and functional verification of potential candidates is ongoing.
CSIG-28. REGULATION OF GEMC1 MULTICILIOGENESIS PROGRAM IN CHOROID PLEXUS CARCINOMA
Authors: Zhao Haotian , Page Thomas , Sarowar Tamanna
Published: November 2021

Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.
RADT-03. OUTCOMES OF PATIENTS WITH HER2-POSITIVE BREAST CANCER METASTATIC TO BRAIN TREATED WITH HER2-TARGETED SYSTEMIC THERAPY AND STEREOTACTIC RADIOSURGERY
Authors: Shumway John , Torras Marina , Reeder-Hayes Katherine , Jolly Trevor , Dees Elizabeth , Ray Emily , Muss Hyman , Carey Lisa , Shen Colette
Published: November 2021

OBJECTIVE

For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS). These include monoclonal antibodies such as trastuzumab (H) and pertuzumab (P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen.

METHODS

A single-institution retrospective review collected clinical data on patients with breast cancer metastatic to brain who were treated with SRS from 2009-2020. Statistical analyses were performed using the Kaplan-Meier method and chi-square statistic.

RESULTS

Of 82 patients with breast cancer metastatic to brain treated with SRS, 33 (40%) were HER2-positive, 18 of whom were hormone receptor-positive. At brain metastasis diagnosis, 15 patients (45%) had >1 intracranial metastasis (range 2-7), and the median brain metastasis maximal dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (T-DM1+/-HP, lapatinib+HP, chemotherapy+/-HP) followed by SRS at a median of 18.6 months after starting systemic therapy. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (multi-agent regimens, 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS (T-DM1+/-chemotherapy, lapatinib, HP, hormone therapy, chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups. Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS.

CONCLUSION

In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.
RADT-11. INCREASED USE OF HYPOFRACTIONATED RADIOTHERAPY IN ELDERLY PATIENTS WITH GLIOBLASTOMA IN THE UNITED STATES FROM 2004-2015
Authors: Hall Matthew , Kalman Noah , Odia Yazmin , Tom Martin , Mohler Alexander , Rubens Muni , Walters Rameen , Shah Sunny , Mallory Chase , Gates Kevin , Von Werne Katherine , Mehta Minesh
Published: November 2021

PURPOSE/OBJECTIVES

The prognosis for glioblastoma in elderly patients is poor; randomized trials have demonstrated comparable survival following adjuvant radiotherapy (RT) using conventional or hypofractionation. We used the National Cancer Database (NCDB) to measure trends in the use of hypofractionated RT in glioblastoma patients 70 years of age and older.

MATERIALS AND METHODS

The NCDB was queried for elderly glioblastoma patients treated with a known RT dosing schema from 2004-2015 (n=10,089 patients). Adjusted logistic regression was used to assess the association of treatment year with the annual percentage of patients who received hypofractionated RT (including 40-45 Gy/15 fractions, 34 Gy/10 fractions, or 25 Gy/5 fractions). Average annual percentage change (AAPC) was compared to determine if a significant change occurred in the use of hypofractionated RT during this period. Multivariable regression was used to determine factors associated with the use of hypofractionated RT.

RESULTS

Use of hypofractionated RT was stable between 2.5-3.3% from 2004-2008 and then monotonically increased to 22.2% by 2015 (p< 0.001). The AAPC in the use of hypofractionated RT was +29.6% per year (p< 0.001), with a corresponding decline in conventional fractionation over this period. No significant change was observed in palliative dosing schema or the use of stereotactic radiosurgery. On logistic regression, age, treatment at an academic center, Charlson Deyo score ≥2, and treatment year were significantly associated with utilization of hypofractionated RT. In this dataset, 24.8% of patients who received either conventional or hypofractionated RT died within 3 months of beginning RT.

CONCLUSIONS

During 2008-2015, an increasing number of elderly patients with glioblastoma received hypofractionated RT. Hypofractionated RT should be considered in elderly patients to shorten the time spent receiving medical care during the final months of life. Attention to hospice care is also important, especially in those with brief expected survival who may derive limited benefit from RT.
RADT-13. SPARE TRIAL: SCALP-SPARING RADIATION WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Miller Ryan , Song Andrew , Ali Ayesha S , Bar-Ad Voichita , Martinez Nina, L , Glass Jon , Alnahhas Iyad , Andrews David , Judy Kevin , Evans James , Farrell Christopher , Werner-Wasik Maria , Chervoneva Inna , Ly May , Palmer Joshua , Liu Haisong , Shi Wenyin
Published: November 2021

INTRODUCTION

Current adjuvant treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields.

METHODS

Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment.

RESULTS

Thirty patients were enrolled. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median follow-up was 10.8 months (range 1.6 to 21.3 months). Twenty (66.7%) patients had unmethylated MGMT promotor and ten (33.3%) patients had methylated promoter. Scalp dose constraints were achieved for all patients. Skin adverse events (erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). The median PFS for the entire cohort was 9.1 months (at least 8.5 months, 95% confidence). The median PFS for patients with MGMT promoter methylation status was 11.4 months (at least 9.5 months, 95% confidence). Overall survival was not reached.

CONCLUSIONS

Concurrent TTFields with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.
RADT-15. FIRST EXPERIENCE WITH MAXIMAL SAFE RESECTION AND GAMMATILE BRACHYTHERAPY AS TREATMENT FOR RECURRENT GLIOBLASTOMA
Authors: Gessler Dominic , Neil Elizabeth , Shah Rena , Levine Joseph , Shanks James , Wilke Christopher , Reynolds Margaret , Ferreira Clara , Dusenbery Kathryn , Chen Clark
Published: November 2021

INTRODUCTION

Gammatile (GT) is a recently FDA-cleared brachytherapy platform with 131Cs seeds imbedded into a resorbable collagen carrier for surgically targeted radiation delivery. We report the first experience for recurrent glioblastoma patients who underwent GT treatment following surgical resection.

METHODS

Twenty-two consecutive patients with 23 isocitrate dehydrogenase (IDH) wild-type glioblastomas (14 second; eight third recurrence) who underwent intra-operative MRI/5-ALA guided maximal safe resection followed by GT placement were prospectively followed. There were 6 methylguanine-DNA-methyltransferase promoter methylated (MGMTm) and 17 unmethylated (MGMTu) glioblastomas.

RESULTS

The median hospital stay was one day (range:1-15 days). There was one 30-day readmission (4.5%) for a cerebrospinal fluid leak from the incision site, which resolved with lumbar drainage. There were no other wound complications. One patient (4.5%) suffered new post-operative seizure. Eight patients experienced worsened neurological deficit (8/22 or 36%). While all deficits improved by the 30-day follow-up, 7 of these 8 patients suffered KPS decline due to persistent deficits. There was one 30-day mortality (4.5%) from intracranial hemorrhage secondary to heparinization for an ischemic limb. The median follow-up after GT placement for the remaining 21 patients was 296 days (range:111-931 days). Six months local control (LC) was achieved in ~75% of the patients irrespective of MGMT status. Median overall survival (OS) was 715 days for the MGMTu patients, and not reached (>1000 days) for MGMTm patients. These outcomes compared favorably to the published literature (LC: 3-49%; OS MGMTu: 135-285 days; OS MGMTm: 174-564 days) and an age, KPS, extent of resection matched glioblastoma cohort who underwent maximal safe resection without GT at our institution (LC: 52%; OS MGMTu: 462 days; OS MGMTm: 821 days; p=0.0089 and p=0.0271, respectively when compared to the GT treated patients).

CONCLUSION

This clinical experience supports the safety and efficacy of GT brachytherapy as a treatment option for recurrent glioblastomas.
RADT-18. NEOADJUVANT (PRE RADIOTHERAPY) TEMOZOLOMIDE FOLLOWED BY RADIATION THERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN GLIOBLASTOMA MULTIFORME
Authors: Prajapati Chinmaykumar , Mehta Maitrik , Kunikullaya U Suryanarayan
Published: November 2021

BACKGROUD AND PURPOSE

To evaluate the effect of neoadjuvant [pre-radiotherapy(RT)] temozolomide (TMZ) in glioblastoma multiforme (GBM) patients in terms of overall survival(OS) and progression free survival (PFS).

MATERIAL AND METHODS

Patients with diagnosed GBM are treated with neoadjuvant( pre RT) TMZ followed by concurrent RT-TMZ and adjuvant TMZ. The Kaplan-Meier method is used to estimate OS the differences between groups.

RESULTS

Twenty five patients are match with inclusion criteria. Age group, Recurvsive partitioning analysis (RPA) class and extent of surgery are found to effect on overall survival but statistically not significant. At end of study, 40 percent patients are alive with 9 months PFS and 11 months OS.

CONCLUSION

The neo-adjuvant TMZ with concomitant and adjuvant TMZ is feasible and safe which is associated with an encouraging favorable long-term survival with acceptable toxicity.
RADT-23. RECURRENT OLIGODENDROGLIOMAS AFTER FIRST CHEMO-RADIATION THERAPY RESPONDED REMARKABLY TO RE-RADIATION
Authors: Higuchi Fumi , Uzuka Takeo , Ueki Keisuke
Published: November 2021

Oligodendrogliomas with 1p/19q-codeletion are relatively slow progressive tumors that show good response to chemo-radiation therapy after resection. The median survival is about 15 years regardless of WHO grade, although recurrences are mostly inevitable and there is no standard treatment for recurrence. We experienced 5 oligodendroglioma cases who underwent re-radiation for recurrent tumors after chemo-radiation treatment. We retrospectively investigated those for response to re-radiation, the duration from first radiation to second radiation, and Karnofsky Performance Status (KPS) before and after the re-radiation. Patients were all male; the median radiation dose for primary tumor was 60Gy (54-60Gy), the median age at first radiation was 46 years (35-59), the median duration from the first radiation to re-radiation was 65 months (range 18-116 months), and the median follow-up period after re-radiation was 15 months (1-39 months). In all 5 cases, tumors showed good response to re-radiation. In 3 of the 5 cases, tumor recurred in corpus callosum and/or lateral side of cerebral hemisphere or basal ganglia contiguous with primary tumor sites and were radiated by IMRT (50Gy/25fr) . In 2 cases, tumors recurred around the fourth ventricle and posterior fossa and underwent conventional radiation (54Gy/30fr and 30Gy/10fr). In 2 of the 5 cases, the tumors re-recurred 24 months later after re-radiation, but the KPS were maintained until re-recurrence. For oligodendrogliomas, re-radiation therapy appears to be very effective to recurrent tumors after first chemo-radiation. Although evaluation for longer-term side effects is to be examined, re-radiation appears to be a good option for recurrent oligodendrogliomas after first chemo-radiation therapy.
RADT-28. RECURRENT MENINGIOMA WITH 1p/22q SOMATIC MUTATION OF GNAS: A CASE REPORT
Authors: Hong Weiping , Wen Lei , Shan Changguo , Ye Minting , Yang yanying , Wang hui , Cai Linbo
Published: November 2021

OBJECTIVE

Refractory meningioma faces the problems of low total resection rate, high recurrence rate and high disability rate. Here we report a patient with recurrent refractory meningioma who was benefited from precision treatment plan based on molecular diagnosis.

METHODS

Molecular diagnosis by next generation sequencing (NGS) test was used to test the hybridized captured DNA in the tumor tissue of the patient.

RESULTS

The 53-year-old female diagnosed with meningioma was admitted to our hospital after tumor progression was observed for 3 weeks. She had received 4 operations for the tumor previously. The first three times of postoperative pathology indicated WHO Ⅰ grade meningioma. The fourth postoperative pathology showed excessive meningioma, with active growth of tumor cells in some areas and small focal necrosis, WHO Ⅰ- fair grade. Somatic mutation GNAS p.F309VFS *25 and deletion of the short arm of chromosome 1 / long arm of chromosome 22 were also found (1P / 22Q) by NGS test. The second recurrent foci showed partial amplification of 17q and 19, except for 1p/22q deletions, compared with the first. Meningiomas with 1p/22q deletion are type C meningiomas (more than half are grade WHO Ⅰ). Meningiomas have been shown to be highly vascularized neoplasms, with a 2-fold increase in VEGF expression in atypical meningiomas and a 10-fold increase in malignant meningiomas. According to the molecular diagnosis results, the precise treatment plan was determined: concurrent chemoradiotherapy, followed by anti-VEGF-targeted drugs combined with temozolomide for 2 months. The residual lesions were significantly reduced after treatment.

CONCLUSION

This case is the first to report a meningioma with pituitary tumor driver gene GNAS mutation, which is more prone to recurrence due to the combination of 1P / 22Q chromosome mutation. Molecular diagnosis can guide precise treatment to benefit patients.
RADT-29. CHARACTERISTICS OF PATIENTS WITH MENINGIOMA WHO DEVELOPED SIGNIFICANT EDEMA REQUIRING STEROIDS AFTER GAMMA KNIFE RADIOSURGERY
Authors: Ma Daniel , Schulder Michael , Goenka Anuj
Published: November 2021

Gamma Knife stereotactic radiosurgery (GK-SRS) is an effective treatment of meningioma in the definitive and adjuvant setting. While SRS is generally safe, some patients develop significant post-treatment edema leading to seizures and neurological deficits requiring medical intervention. This study identifies risk factors associated with the development of significant edema after SRS. Between 2014 and 2020, 126 patients with 182 WHO grade I-III meningiomas were treated with GK-SRS at our institution. We retrospectively identified a subset of patients with clinically significant post-treatment edema on MRI and documented steroid use. Clinical and treatment parameters such as treatment intent, dose, tumor location, and tumor volume were collected. The median follow-up was 34 months. A total of 6 patients (4 females and 2 males, median age 60.5) developed symptomatic edema, including 4 of 71 patients treated in the definitive setting, 1 of 16 patient in the postoperative adjuvant setting, and 1 of 39 patient in the salvage setting. 2 patients had convexity meningioma, 3 patients had parasagittal meningioma, and 2 patients had skull base meningioma. The median onset of symptomatic edema after SRS was 5 months (range: 2-5months); the median duration of steroid use was 1.5 months (range: 0.5-3months). Mild headache and vision changes were reported in 2 patients. 4 patients developed seizures and required hospital admission. 1 patient died of cardiac arrest during admission. The remainder of patients were symptom-free following discontinuation of steroids and required no surgical intervention. The median tumor volume was 3.625cc (range: 2.74-12.15cc). All patients received single-fraction SRS with a median dose of 16Gy (range: 16-20Gy). 2 patients had received prior fractionated cranial radiation. A subset of meningioma patients treated with SRS can develop significant post-treatment edema requiring intervention. This small series showed that the risk of symptomatic edema with SRS is low, and most symptoms are transient.
CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Pérez-Larraya Jaime Gállego , Garcia-Moure Marc , Patiño-García Ana , González-Huarriz Marisol , Van der Lugt Jasper , Astigarraga Itziar , García-Ariza Miguel , López-Ibor Blanca , Jones Chris , Mackay Alan , Diez-Valle Ricardo , Fueyo Juan , Gomez-Manzano Candelaria , Dobbs Jessica , Ewald Brett , Alonso Marta , Tejada Sonia
Published: November 2021

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is < 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG.

METHODS

Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later.

RESULTS

Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months).

CONCLUSIONS

DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.
CTIM-13. PHASE 1 CLINICAL TRIAL OF ONCOLYTIC VIRAL IMMUNOTHERAPY WITH CAN-2409 + VALACYCLOVIR IN COMBINATION WITH NIVOLUMAB AND STANDARD OF CARE (SOC) IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA (HGG)
Authors: Wen Patrick , Aguilar Laura , Ye Xiaobu , Reardon David , Bi Wenya Linda , Peruzzi Pierpaolo , Patel Nirav , Strowd Roy , Tatter Stephen , Lee Ian , Walbert Tobias , Snyder James , Brem Steven , Desai Arati , Bagley Stephen , Amankulor Nduka , Lieberman Frank , Mantica Megan , Lopez Lenika , Bell Susan , Manzanera Andrea , Barone Francesca , Guzik Brian , Lawler Sean , Jin Lixian , Timmer William , Danda Neeraja , Desideri Serena , Nabors L Burt , Grossman Stuart , Aguilar-Cordova Estuardo , Tak Paul Peter , Chiocca E Antonio
Published: November 2021

BACKGROUND

CAN-2409 is a replication-deficient adenovirus that delivers HSV thymidine kinase to cancer cells, resulting in local conversion of orally administered valacyclovir into a toxic metabolite. Previously, a phase 1b/2 clinical trial of CAN-2409 combined with standard-of-care (SOC) demonstrated safety and improved survival in HGG patients. Addition of CAN-2409 to nivolumab has the potential to activate locally recruited lymphocytes and teach them to recognize tumor neoantigens, changing the ‘cold’ immunosuppressive tumor microenvironment, and synergizing with the activity mediated by immune checkpoint inhibitors. This notion is supported by preclinical experiments showing that the combination of CAN-2409 with anti-PD1 therapy was more effective than either treatment alone.

METHODS

This ongoing phase 1 clinical trial evaluates safety and initial efficacy of CAN-2409 combined with nivolumab and SOC in newly diagnosed HGG. CAN-2409 is injected during neurosurgery into the tumor bed, followed by 14-days of valacyclovir. Radiation starts within 8 (+/-4) days of surgery. Temozolomide is administered to MGMT-methylation positive patients only. Nivolumab is given every 2 weeks, up to 52-weeks. Deep immune profiling studies are ongoing and initial results will be available shortly.

RESULTS

From February 2019 to March 2021, 41 patients were enrolled and 35 were evaluable for safety from the combination of CAN-2409, nivolumab and SOC: 24 male and 11 female; 34 glioblastoma, 1 diffuse astrocytoma; 33 IDH-wildtype, 2 IDH-mutant; 15 MGMT-methylated, 20 unmethylated. Median age was 62-years (range 28-79), median KPS 90 (range 80-100). With 13 months median follow-up, no unexpected serious adverse events were observed, and 23 patients are still alive. The most frequent possibly related adverse events (>10%) were nausea, fatigue, fever, headache, and increased ALT.

CONCLUSIONS

The combination of CAN-2409 + nivolumab + SOC was well tolerated. Clinical follow-up and extensive biomarker analyses will provide a better understanding of the therapeutic potential of this approach.
CTIM-14. RANDOMIZED PHASE II OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM). NIVOLUMAB BENEFITS OLDER POPULATION
Authors: Ahluwalia Manmeet , Peereboom David , Rauf Yasmeen , Wen Patrick , Reardon David
Published: November 2021

BACKGROUND

Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. VEGF is upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM.

METHODS

90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared between two arms.

RESULTS

90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall Survival was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p=0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P=0.90). Most frequent toxicities ( >20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function.

CONCLUSIONS

Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.
CTIM-18. LUMINOS-101: INITIAL SAFETY AND TOLERABILITY OF PVSRIPO AND PEMBROLIZUMAB COMBINATION THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Sloan Andrew , Buerki Robin , Landi Daniel , Desjardins Annick , Friedman Allan , Ambady Prakash , Becker Kevin , Butowski Nicholas , Cavaliere Robert , Curry William , Ong Shirley , Vega Rafael , Wen Patrick , Bockorny Bruno , Chiocca E Antonio , Elder J Bradley , Bulsara Ketan , Berger Mitchel , Gerstner Elizabeth , Sauvageau Eric , Kelly Andrea , Mixson Lori , Jackson LeAnn , Learn Chris , Dickinson Adam , Nichols W Garrett
Published: November 2021

BACKGROUND

Recurrent glioblastoma (rGBM) is rapidly fatal with current therapies. PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO treatment leads to systemic, tumor antigen-specific, polyfunctional T-cell–mediated anti-tumor response, predominately driven by type I/III interferons. This inflammatory signature generates anti-tumor immunity and upregulates the programmed death (PD)-1 immune checkpoint in the tumor microenvironment. Preclinical models (including GBM) have shown that PVSRIPO+anti-PD-1/L1 therapy was more efficacious than either agent alone, warranting further investigation.

METHODS

Adults with histologically confirmed rGBM (1-2 prior progressions), Karnofsky performance status (KPS) ≥70, and an active, supratentorial, contrast-enhancing lesion (1-5.5 cm), received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery (Day 1), followed by 200 mg pembrolizumab IV at week 2, given every 3 weeks for up to 24 months, to evaluate the safety/efficacy of the combination. A safety lead-in period (n=3-6) with a minimum 21–28-day delay before treatment of subsequent patients was planned, with a data safety monitoring board (DSMB) evaluating safety/tolerability prior to expansion (up to N=30).

RESULTS

The first 3 patients enrolled (ages 55-60, KPS 90-100) all received PVSRIPO followed by pembrolizumab (1-5 cycles), as planned. At cutoff (26-106 days of follow-up), there were no dose-limiting toxicities, treatment-emergent (TE) serious adverse events (SAE), or TEAEs necessitating a delay in initial/subsequent pembrolizumab treatments. All patients experienced a related TEAE, all grade 1 or 2 in severity. One patient experienced an AE of special interest (peritumoral edema, resulting in headache and hemiparesis), successfully managed with low-dose bevacizumab and corticosteroids. The DSMB unanimously recommended the study proceed without modification.

CONCLUSIONS

Intratumoral PVSRIPO+pembrolizumab was reasonably well tolerated, warranting continued investigation of the safety and efficacy of this combination in patients with rGBM.
CTIM-21. AN AGE-SPECIFIC BIOMARKER IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH RADIATION, NIVOLUMAB AND BMS-986205
Authors: Kim Miri , Ladomersky Erik , Zhai Lijie , Bollu Lakshmi , Bell April , Lauing Kristen , Rabin Erik , Horbinski Craig , Lukas Rimas , Wainwright Derek
Published: November 2021

INTRODUCTION

We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that undergo simultaneous treatment with standard radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (a potent IDO enzyme inhibitor) and are newly diagnosed with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated GBM. Our objective was to identify age-dependent immunologic changes before and after treatment with immunotherapy.

METHODS

Patients ≥ 18 years old with newly diagnosed MGMT unmethylated GBM, KPS ≥ 70, and minimal steroid use were eligible for enrollment in this phase 1 trial. PBMCs and serum were drawn at baseline and routine post-treatment time points followed by mass spec analysis of kynurenine (Kyn) and tryptophan (Trp) metabolites, RNAseq, and 18-color flow cytometric analysis.

RESULTS

8 younger adults with a median age of 50 years old and 4 older adults with a median age of 68.5 years old were studied. The median overall survival of younger and older adults was 368 and 108.5 days, respectively (p=0.032, HR 4.8 for age). BMS-986205 treatment decreased the Kyn/Trp ratio of all patients irrespective of age. RNAseq analysis found significant age-related changes using Gene Ontology pathway analysis of T cell related immunity, lymphocyte activation, and NK cell mediated immunity. Flow cytometric analysis is ongoing.

CONCLUSIONS

Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.