bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-04. BIOMARKER IMMUNE CORRELATES IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) TREATED WITH ATEZOLIZUMAB IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION
Authors: Weathers Shiao-Pei , Knafl Mark , Parra Edwin , Hernandez Sharia , Solis Luisa , Espiridion Beatriz Sanchez , Wistuba Ignacio , Futreal Andrew , Maru Dipen , Kamiya-Matsuoka Carlos , Harrison Rebecca , Joseph Victory , Yun Cindy , Darbonne Walter , Loghin Monica , Penas-Prado Marta , Majd Nazanin , Yung W K Alfred , O'Brien Barbara , Scott Woodman , DeGroot John
Published: November 2021

BACKGROUND

Checkpoint inhibitor therapy has demonstrated overall limited efficacy in the treatment of GBM. Mechanisms of resistance to checkpoint blockade need to be better elucidated. Analysis of the tumor microenvironment is critical to identify correlates of response to immune checkpoint blockade. 60 newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously.

METHODS

Tissue image immunoprofiling was conducted using 2 multiplex immunofluorescence (mIF) panels against; CD3, CD8, PD-1, PD-L1, Granzyme B, FOXP3, CD45RO, CD68, and GFAP antibodies. PDL-1 (Clone SP263) malignant cells expression was assessed by immunohistochemistry. Correlations between mIF biomarkers co-expressions, IHC PD-L1, and clinical outcome including OS, radiographic response, and PFS were evaluated.

RESULTS

Of 60 patients enrolled, image immunoprofiling was performed successfully on pre-treatment tissue in 48 patients. 20 of 60 patients underwent re-resection for suspected recurrent disease of which 10 patients had immunoprofiling performed successfully on pre and post treatment samples. An analysis of CD3CD8+ cytotoxic T lymphocytes was consistent with prior work, showing no or relatively low levels at baseline, and no association with clinical outcome. PDL-1 expression by IHC, at thresholds of >1% or >5%, was not associated with clinical outcome. Tumors with a higher number of GFAP-expressing cancer cells had a significantly lower tumor response (p< 0.05) and median OS (430 vs. 799 days, p< 0.01).

CONCLUSIONS

For newly diagnosed GBM patients treated with standard of care radiation and temozolomide in combination with atezolizumab, T-cell levels and PDL-1 expression were not predictive of outcome. GFAP may represent a novel predictive biomarker of overall survival. Ongoing studies to evaluate the gut microbiome and tumor genomic (WES, CNA) and transcriptomic (RNAseq) features of these and matched tumors are underway.
CTNI-04. RECURRENT GLIOBLASTOMA LONG-TERM SURVIVORS TREATED WITH CUSP9v3
Authors: Halatsch Marc-Eric , Kast Richard , Karpel-Massler Georg , Mayer Benjamin , Zolk Oliver , Schmitz Bernd , Scheuerle Angelika , Maier Ludwig , Bullinger Lars , Mayer-Steinacker Regine , Schmidt Carl , Zeiler Katharina , Elshaer Ziad , Panther Patricia , Schmelzle Birgit , Hallmen Anke , Dwucet Annika , Siegelin Markus D , Westhoff Mike-Andrew , Beckers Kristine , Bouche Gauthier , Heiland Tim
Published: November 2021

CUSP9v3 is a new treatment regimen for glioblastoma. It consists of continuous daily use of 9 drugs repurposed from general medicine. Their primary non-oncology uses are given in parentheses: aprepitant (nausea), auranofin (rheumatoid arthritis), celecoxib (pain), captopril (hypertension), disulfiram (alcohol abuse), itraconazole (fungal infection), minocycline (bacterial infection), ritonavir (viral infection) and sertraline (depression). All drugs have preclinical or clinical data indicating that they can retard glioblastoma growth, as reviewed in the published background papers. In CUSP9v3 all 9 medicines are given daily with added metronomic, low-dose (20 mg/m2 BSA twice daily) temozolomide. After 3 years of daily, uninterrupted use of CUSP9v3, of an initial cohort of 10 recurrent glioblastoma patients, as of May 2021, 3 are alive, functioning well, progression-free at 44, 44, and 57 months after recurrence and CUSP9v3 started. We report now that there were no unexpected toxicities from this combination of 10 daily drugs, although all patients required dose reduction of one or more of the drugs. CUSP9v3 was reasonably well-tolerated. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose reduction or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. There were no treatment-related deaths. In the 3 long-term survivors, the median neutrophil-to-lymphocyte ratio decreased from 2.5 to 1.5 during CUSP9v3 treatment. In the group of the 3 shortest-term survivors that ratio increased from 4.7 to 14.3. CUSP9v3 follows the injunction of Palmer et al. that cancer therapy can be constructed using drug combinations that are independently effective, with non-overlapping mechanisms of action, and non-overlapping resistance pathways. We interpret the data accrued over the last few decades on the ever-shifting spatial and temporal growth drives active at any given moment in glioblastoma as requiring a complex pharmacological approach like CUSP9v3.
CTNI-13. MALIGNANT GLIOMA SUBSET FROM ACTUATE 1801 PHASE 1/2 STUDY OF 9-ING-41, A GLYCOGEN SYNTHASE KINASE 3 BETA (GSK-3β) INHIBITOR, AS A SINGLE AGENT AND COMBINED WITH CHEMOTHERAPY REFRACTORY
Authors: Odia Yazmin , Cavalcante Ludimila , Safran Howard , Powell Steven Francis , Munster Pamela , Ma Wen Wee , Carneiro Benedito , Bastos Bruno , Giles Francis , Sahebjam Solmaz
Published: November 2021

BACKGROUND

GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes tumor progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating checkpoints, e.g. PD-L1 and LAG-3, and increasing NK and T-cell mediated tumor killing. 9-ING-41 is a small-molecule, potent, selective GSK3β inhibitor with preclinical activity. In chemoresistant PDX glioblastoma models, 9-ING-41 enhanced lomustine antitumor effect.

METHODS

Patients with refractory malignancies were treated with 9-ING-41 monotherapy (n=65) or combined with 8 cytotoxic regimens after prior exposure (n=162) in the first-in-human study (NCT03678883). The recurrent gliomas subset was treated with 9-ING-41 monotherapy IV TIW q21day cycles at 3.3, 5, 9.3, 15mg/kg, or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety and tolerability.

RESULTS

An RP2D of 15mg/kg IV TIW was confirmed across all 9 regimens, no accentuation of chemotherapy toxicity noted. Of 18 glioma patients enrolled, 13 were glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, and 1 diffuse astrocytoma; 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received initial radiation and temozolomide (18/18), prior salvage therapies included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), checkpoint inhibitor (4/18). Median recurrences 3 (1-6). NGS alterations included: IDH/wildtype (11), IDH/mutation(3); 1p19q/codeletion(10); MGMT/unmethylated(11), MGMT/methylated(1); EGFR/amplification(6), EGFR/v3mutation(3), TERT/mutation(6), PTEN/loss(3), NF1/rearrangement(2), ATRX/loss (2), TP53/mutation(4), CDKN2A/deletion(2), RB1/loss(1), PALB2/mutation(10). Four patients received 9-ING-41 monotherapy, 14 concurrently treated with lomustine. No SAEs or grade 3/4 AEs attributed to 9-ING-41 noted, only G1/2 vision changes (9/18, 50%), infusion reactions (4/18, 22%). Lomustine-related toxicities included G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Median therapy duration was 55 (4-305); 1 partial response ( >50%) noted with 9-ING-41/lomustine. Median PFS and OS were 1.9 (0.3-11.1) and 6.0 (1.6-16.6) months, respectively.

CONCLUSIONS

9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.
CTNI-26. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING
Authors: O'Brien Barbara , Penas-Prado Marta , Kamiya-Matsuoka Carlos , Weathers Shiao-Pei , Yung W K Alfred , Loghin Monica , Harrison Rebecca , Majd Nazanin , Knight Stephanie , Bacha Jeffrey , Brown Dennis , Johnson Gregory , Langlands John , Schwartz Richard , Kanekal Sarath , Steino Anne , Lopez Lorena , DeGroot John
Published: November 2021

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard-of-care treatment, with a median survival of 3-9 months after recurrence. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independently of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated, bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response is assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of May 2021, Group 1 (Recurrent GBM) is fully enrolled: 35 evaluable patients have received 40 mg/m2/d and 48 evaluable patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 35 evaluable patients have been enrolled (30 mg/m2/day). Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.
CTNI-27. SINGLE AGENT ACTIVITY OF ONC201 IN NON-MIDLINE H3 K27M-MUTANT DIFFUSE GLIOMAS
Authors: Odia Yazmin , Sumrall Ashley , Cloughesy Timothy , Nghiemphu Phioanh , Hall Matthew , Daghistani Doured , Mehta Minesh , Lassman Andrew , Arrillaga-Romany Isabel , Gardner Sharon , Tarapore Rohinton , Lu Guangrong , Allen Joshua , Wen Patrick
Published: November 2021

BACKGROUND

H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti- cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201.

METHODS

We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata).

RESULTS

Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness.

CONCLUSIONS

These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
CTNI-38. PriCoTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Kebir Sied , Pierscianek Daniela , Proescholdt Martin , Hau Peter , Grosu Anca-Ligia , Krex Dietmar , Sure Ulrich , Scheffler Björn , Stuschke Martin , Glas Martin
Published: November 2021

TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). Preclinical studies showed that combination of TTFields and radiotherapy synergistically impaired glioblastoma cell growth. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. Following surgery and wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with. We will present initial practical experiences as well as preliminary safety and tolerance data. There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.
CTNI-51. ADJUVANT TROTABRESIB, A REVERSIBLE POTENT BROMODOMAIN AND EXTRATERMINAL INHIBITOR, PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: INTERIM RESULTS FROM A PHASE 1B DOSE-FINDING STUDY
Authors: Vieito Maria , Simonelli Matteo , de Vos Filip , Moreno Victor , Geurts Marjolein , Lorenzi Elena , Macchini Marina , van den Bent Martin , Del Conte Gianluca , de Jonge Maja , Amoroso Barbara , Sanchez-Perez Tania , Zuraek Marlene , Hanna Bishoy , Aronchik Ida , Filvaroff Ellen , Mendez Cristina , Wei Xin , Nikolova Zariana , Sepulveda Juan Manuel
Published: November 2021

Trotabresib (CC-90010) demonstrated antitumor activity as monotherapy in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270) and enhanced the antiproliferative effects of temozolomide in preclinical studies. CC-90010-GBM-002 (NCT04324840) is a phase 1B dose-finding study investigating standard-of-care temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide or concomitant trotabresib + temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide, post-resection, in patients with newly diagnosed glioblastoma. We present interim results for adjuvant trotabresib + temozolomide. Patients received trotabresib 15, 30, or 45 mg daily (4 days on/24 days off) + temozolomide administered per label for 6 cycles, followed by trotabresib 45 mg monotherapy daily (4 days on/24 days off). Primary objectives are to establish the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trotabresib. Preliminary efficacy, pharmacokinetics, and pharmacodynamics are also being investigated. Of 13 patients enrolled, 5, 6, and 2 received trotabresib 15, 30, and 45 mg, respectively, plus temozolomide. Grade 3/4 treatment-related adverse events were reported in 2, 4, and 1 patients receiving trotabresib 15, 30, and 45 mg, respectively. MTD and RP2D are not yet reached; dose limiting toxicity (grade 4 thrombocytopenia) was reported in 1 patient in the 30-mg group. Of 10 evaluable patients, 1 had complete response and 7 had stable disease per RANO criteria. Trotabresib exposure increased proportionally with dose. Day 4 time to peak trotabresib concentration was 0.5–2.0 hours; mean terminal half life was 60–70 hours. Day 4 blood CCR1 RNA 2–4 hours post-dose was downregulated below baseline in the 15-mg group and ≥ 50% in the 30-mg group. Adjuvant trotabresib + temozolomide appears well tolerated, with promising preliminary efficacy. Treatment was ongoing at data cutoff in 9 patients in the adjuvant cohort; enrollment is continuing in the adjuvant and concomitant therapy dose-escalation cohorts.
DDRE-09. MULTI-INSTITUTION RETROSPECTIVE EXPERIENCE WITH LENVATINIB FOR PROGRESSIVE MALIGNANT GLIOMA
Authors: Carrillo Jose , Wagle Naveed , Carrillo Jose , Juntila Joanna , Nguyen Minhdan , Truong Judy , Landa Eve , Curry Erin , Juarez Tiffany , Kesari Santosh
Published: November 2021

Despite treatment with radiation and temozolomide chemotherapy, malignant gliomas inevitably recur after treatment and have poor prognosis. Clinical trials should be offered when available, but effective treatment options for multiply recurrent tumors is sparse. In our multi-institutional retrospective cohort, we looked at recurrent malignant gliomas treated with Lenvatinib multi-kinase inhibitor. Patients consented to an IRB-approved study protocol that allows for longitudinal history review and analysis at our institution. Lenvatinib is a targeted therapy that is FDA approved for Differentiated Thyroid Cancer, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Endometrial Carcinoma. Lenvatinib binds to tyrosine kinase receptors inhibiting kinase activity by VEGFR1-3, FGFR1-4, PDGFRa, FGF, KIT, and RET. In this cohort, patients received radiation and temozolomide chemotherapy, N=15, median age was 45.5, and 47% were male. At time of surgery 40% underwent biopsy, 40% had STR, and 20% had GTR. Glioblastoma was the most common tumor type at 87%, 6.7% were recurrent anaplastic astrocytoma, and 6.7% were recurrent glioma NOS. IDH mutation was seen in 13% of our cohort, and MGMT methylation was seen in 27%, all patients had available IDH and MGMT data. Patients were heavily treated, median number of recurrences was 3. Patient mean PFS was 2.7 months, and median OS was 24.0 months. Clincal Benefit Rate (PR+SD) to Lenvatinib in recurrent disease was 57%, with 29% Partial Responses and 29% Stable Disease as best radiographic response. This retrospective cohort supports further evaluation of the efficacy of Lenvatinib in recurrent malignant glioma in a clinical trial.
DDRE-20. HIGH-THROUGHPUT SCREENING OF FDA-APPROVED COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS
Authors: Wroblewski Tadeusz , Tatman Philip , Fringuello Anthony , Scherer Sam , Foreman William , Damek Denise , Youssef Samy , Lillehei Kevin , Ormond David , Graner Michael
Published: November 2021

BACKGROUND

Glioma and glioblastoma comprise 28% of all primary central nervous system tumors and cause the majority of primary brain tumor deaths. Despite substantial research into the molecular pathogenesis and genetic landscape of glioma, no currently approved therapies are curative for any glioma or glioblastoma. Patients with glioblastoma have an average survival time of 12-15 months, while patients with grade III gliomas have an average survival time of 3-5 years, and patients with grade II gliomas have an average survival time of 8-15 years. The lack of a curative treatment for these tumors necessitates additional research into novel therapies.

METHODS

In this study, we developed a high-throughput drug screen and culture system to identify existing FDA-approved therapies with the potential to inhibit glioma viability.

RESULTS

In total, we screened 39 tumors: 21 glioblastoma, 10 oligodendroglioma, and 8 astrocytoma. Carfilzomib was the most effective compound across the cohort, decreasing the average tumor viability to 39.0% +/- 16.5%SD. Regardless of tumor grade, MGMT methylation, EGFR amplification, tumor recurrence and etiology, tumor histology, prior treatment, and patient gender, carfilzomib significantly reduced cell viability in every tumor; though was not necessarily the most effective compound in each of these groups. We found HDAC inhibition to be the most effective treatment in grade 1 astrocytomas. However, HDAC inhibition was surpassed by carfilzomib and RNA transcription inhibitors in all higher grades. Interestingly, EGFR inhibition, while significantly effective in 36 tumors, was consistently less effective than carfilzomib across the cohort, though did surpass the effectiveness of HDAC inhibition in grade III gliomas.

CONCLUSIONS

FDA approved compounds can effectively inhibit glioma tumor viability. Specifically, carfilizomib holds great promise. Further in vivo studies are needed to confirm these findings.
DDRE-27. METABOLIC SWITCHING AS A MECHANISM OF DRUG RESISTANCE AGAINST NAMPT INHIBITION IN GLIOMAS
Authors: Sharma Pratibha , Puduvalli Vinay
Published: November 2021

BACKGROUND

Gliomas exhibit significant heterogeneity in treatment response and characteristically deploy resistance mechanisms that render conventional therapies ineffective. Recently, novel agents have been developed that target regulators of differential energy pathways specifically utilized by gliomas. We previously reported on the targeting of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway and its essential role in glioma cell energy metabolism. Here, we determined the mechanisms by which glioma cells bypass blockade of energy metabolism and develop resistance to NAMPT inhibitors.

METHODS

Using isogenic parental and drug-resistant patient-derived glioma stem-like cells (GSCs), we examined adaptive changes after NAMPT inhibition in glycolysis, mitochondrial function (oxidative state, basal respiration rate, spare respiratory capacity, maximum respiration capacity and proton leak) and metabolite levels using Agilent Seahorse assay and targeted metabolomics. Cross reactivity across various NAMPT inhibitors was measured using Cell Titer Glo assay.

RESULTS

GSCs exposed for an extended period to sub-lethal doses of FK866, a potent NAMPT inhibitor, acquired drug resistance to the agent which were also cross-resistant to other NAMPT inhibitors. Drug-resistant GSCs showed a decrease in extracellular acidification rate and oxygen consumption rate compared to isogenic parental lines. Further, metabolomic analysis showed a high accumulation of glutamate, creatine and histidine metabolites in these cells. These results indicate a shift in metabolism of drug-resistant GSCs from carbon metabolism to nitrogen metabolism.

CONCLUSIONS

GSCs resistant to the NAMPT inhibitor, FK866 showed cross resistance to other NAMPT inhibitors indicating specificity of this effect. The resistance mechanism involves a shift of preferential energy generation from glycolysis to amino acid metabolism which allows the cells to use alternative methods to generate NAD. Additional results from ongoing studies to delineate the mechanisms of metabolic switch in the drug resistance lines will be presented that will help develop strategies to combat resistance to NAMPT inhibitors.
DDRE-30. CELL-PENETRATING PEPTIDE ANTAGONIST OF CCAAT/ENHANCER BINDING PROTEIN ß DISPLAYS POTENT ANTI-GLIOBLASTOMA ACTIVITY
Authors: Rotolo Jim , Ghamsari Lila , Ramierez Ricardo , Koester Mark , Leong Siok , Gallagher Erin , Darvishi Emad , Merutka Gene , Kappel Barry
Published: November 2021

CCAAT/Enhancer Binding Protein Beta (C/EBPß) is a transcription factor overexpressed in glioblastoma (GBM). Mechanistically, C/EBPß is a master regulator of mesenchymal transition in GBM, and its increased expression correlates with mesenchymal differentiation and predicts poor clinical outcome. C/EBPß activity requires dimerization with co-factors such as CREB/ATF family members via leucine zipper interactions. ST101 is a novel peptide antagonist of C/EBPß currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPß leucine zipper, thereby preventing dimer formation and inhibiting its transcriptional activity, resulting in selective tumor cell cytotoxicity. Here, we describe ST101 non-clinical anti-tumor activity against GBM. In vitro studies in T98G and U251 cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 2.2 and 1.2 μM, respectively), accompanied by significant impact on C/EBPß-mediated gene expression as determined by qPCR analysis. In contrast, normal human mononuclear and epithelial cells were not sensitive to ST101 (EC50 > 80 μM). In vivo, ST101 displayed significant anti-tumor activity in a U251 GBM subcutaneous xenograft model, resulting in 81.4% tumor growth inhibition (TGI) vs. control and undetectable tumors in 50% of animals. Following ST101 exposure tumors displayed reduced BIRC3 and ID2 gene expression, and significantly increased cleaved caspase 3 immunostaining indicative of cell death induction. In U251 tumors, subtherapeutic ST101 (< 5% TGI) in combination with temozolomide (< 5% TGI) resulted in 52.8% TGI, significantly greater than either single-agent alone. Similarly, in a temozolomide-refractory T98G GBM subcutaneous xenograft model, ST101 (41.6% TGI) in combination with TMZ (< 5% TGI) resulted in significant anti-GBM response (72.4% TGI). These data emphasize the potential of ST101 as a potent peptide therapeutic for GBM.
DDRE-34. RIBONUCLEOTIDE REDUCTASE REGULATORY SUBUNIT M2 AS A DRIVER OF GLIOBLASTOMA TMZ-RESISTANCE THROUGH MODULATION OF dNTP PRODUCTION
Authors: Perrault Ella , Shireman Jack , Lin Peiyu , Ali Eunus , Zolp Andrew , Budhiraja Shreya , Park Cheol , Baisiwala Shivani , James David , Ben-Sahra Issam , Pott Sebastian , Basu Anindita , Ahmed Atique
Published: November 2021

Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies examine pre- and post-tumor recurrence; however, it is incredibly difficult to study tumor evolution during therapy where resistance develops. To investigate this, our lab performed a single-cell RNA-sequencing screen before, during, and after temozolomide-based (TMZ) chemotherapy in a patient-derived xenograft (PDX) model in vivo. Our analysis found 149 genes uniquely expressed during TMZ-therapy compared to pre- and post-therapy (p< 0.0001). Of these, the ribonucleotide reductase (RNR) gene family stood out due to the preferential switch to Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) during therapy. Classically, RRM2, or its isoform RRM2B, forms a complex with RRM1 to create an RNR, mediating deoxynucleoside triphosphate (dNTP) production. Our single-cell data revealed that GBM cells rely on RRM1-RRM2 interaction during therapy, but switch to RRM1-RRM2B in post-therapy recurrent GBM. In vitro, RRM2-knockdown cells increased TMZ susceptibility, whereas RRM1- and RRM2B-knockdowns were more resistant to TMZ (p< 0.001). Immunocytochemistry found elevated yH2AX fluorescence in RRM2-knockdowns after TMZ treatment, signifying reduced DNA repair capacity compared to the control (p< 0.001). To understand the mechanism of RRM2-mediated chemoresistance, targeted metabolomics was applied to quantify dNTP signatures during TMZ-therapy. In response to TMZ, dCTP and dGTP production in GBM cells increased 100-fold and 80-fold respectively (p< 0.001). RRM2-knockdowns produced significantly less dCTP and dGTP (p< 0.0001). By supplementing RRM2-knockdowns with dCTP and dGTP, TMZ-susceptibility was rescued, suggesting that RRM2 drives chemoresistance by promoting production of these two nucleotides. In vivo, following intracranial injection of GBM cells, mice treated with the RRM2 inhibitor Triapine with TMZ survived longer than those treated with TMZ alone, indicating promising clinical opportunities in targeting RRM2 (p< 0.0001). Overall, our data present a novel understanding of how RRM2 activity is altered during therapeutic stress to counteract TMZ-induced DNA damage.
DDRE-37. YB-1 AS A BIOMARKER FOR DRUG RESISTANCE AND TUMOUR PROGRESSION IN MEDULLOBLASTOMA
Authors: Taylor Louisa , Kerr Ian , Coyle Beth
Published: November 2021

Medulloblastoma (MB) relapse is the most significant unmet clinical challenge in childhood cancer. Recently it has become evident that MBs display altered biology at relapse, indicative of the emergence and expansion of a minor, therapy resistant cancer cell population. Thus, the examination of mechanisms underlying therapy resistance is of critical importance. Y-box binding protein 1 (YB-1) is a multi-functional oncoprotein whose elevated expression and nuclear accumulation correlate with drug resistance, metastasis and disease progression in numerous cancers, although little is known about the functional role of YB-1 in MB. Genomic analysis of large-scale publicly available patient datasets revealed YB-1 expression is significantly elevated across MB molecular subgroups and high expression correlates with poor overall survival. Immunohistochemical analysis of YB-1 localisation in patient TMAs revealed significant YB-1 nuclear accumulation, suggestive of elevated YB-1 nuclear activity in these patients. Treatment of Group 3 MB cell lines (D283MED and HDMB-03) with cisplatin and subsequent analysis by nuclear/cytoplasmic fractionation and confocal microscopy revealed significantly increased nuclear and overall YB-1 expression, indicating a role for YB-1 in cellular stress response. In support of this, ChIP analysis in D283MED and HDMB-03 cell lines confirmed YB-1 interaction with multi-drug transporter gene ABCB1, while stable YB-1 knockdown resulted in significantly reduced ABCB1 expression. Likewise, knockdown of YB-1 expression in D283MED cells results in increased susceptibility of cells to vincristine, supporting a role for YB-1 in the acquisition of drug resistance in MB cell lines. Finally, whole transcriptome sequencing of YB-1-knockdown HDMB-03 and D283MED cell lines indicated YB-1 regulation of a variety of cell death, survival and metabolic pathways. We are currently using ChIP-Seq analysis to identify targetable YB-1 downstream “hits” which drive these processes. Ultimately, we aim to identify druggable targets of YB-1 allowing us to establish more effective therapeutic options for the treatment of high-risk MB.
EPID-02. COUNTY MEDIAN FAMILY INCOME AS PROGNOSTIC FACTOR IN NON-SMALL-CELL LUNG CANCER WITH BRAIN METASTASES AT PRESENTATION: A POPULATION-BASED STUDY
Authors: Jusue-Torres Ignacio , Hulbert Alicia , Zakaria Jehad , Albain Kathy S , Hentz Courtney , Melian Edward , Thakkar Jigisha P , Prabhu Vikram C
Published: November 2021

INTRODUCTION

The purpose of this study was to characterize the impact of household income disparities in the survival of patients with non-small cell lung cancer (NSCLC) presenting with brain metastasis on a population-based level.

METHODS

This is a population-based cohort study using the SEER database from 2010-2016 including 15,808 NSCLC patients presenting with brain metastasis. Two-tailed log-rank test was used to compare overall survival between groups and association with survival was quantified using hazard ratios (HR) with 95 % confidence intervals (CI) assessed with univariate and multivariate Cox proportional hazard models.

RESULTS

Patients living in low-income counties had a median survival of 4 months when compared to 5 months for patients living in high-income counties respectively (p< 0.0001). Patients living in first and second bottom quartiles had a median survival of 4 months and 5 months and 6 months for the third and fourth top quartiles, respectively (p< 0.0001). The 1-, 2- and 5-year survival rates for living in the lower household income quartile were 21, 10 and 3% respectively, for the second quartile 24, 10 and 3%; for the third quartile 28, 14 and 4% and for the top fourth quartile 31, 17 and 4% respectively. Multivariate cox proportional hazard analysis adjusted for age, gender, race, hispanic ethnicity, marital status, insurance status, percentage of high school education in the patient’s county, histology, presence of lung metastasis, bone metastasis, liver metastasis, radiation received, surgery performed, and chemotherapy received showed that living in higher quartile household income county is associated with decrease mortality risk (p < 0.0001) HR 0.87 95% CI (0.82-92).

CONCLUSION

This population-based study suggests that living in higher median household income counties is associated with increased survival time and reduced risk of mortality for patients with NSCLC who have brain metastases present at diagnosis, independent of other factors.
EPID-21. EPIDEMIOLOGY AND RISK FACTORS OF PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN AND ADULTS IN THE MIAMI CANCER INSTITUTE (MCI) COHORT
Authors: Ramirez-Menendez Miguel , Israel Shirlinka , Rubens Muni , Fernandez Alejandra , Diaz Zuanel , Hall Matthew , Mohler Alexander , Kotecha Rupesh , Odia Yazmin
Published: November 2021

BACKGROUND

Many epidemiological studies assess risk factors and incidence of primary CNS tumors in the United States; few describe the incidence in specific geographic locations. Environmental or ethnic/racial factors may affect the incidence of primary CNS tumors. Miami-Dade County (MDC) is an ethnically-diverse US county, with 69.4% Hispanic, 12.9% White Non-Hispanic, 15.5% Black Non-Hispanic, Asian 1.6%, 0.3% Native, and 0.3% other. We characterized primary CNS tumors at Miami Cancer Institute (MCI) relative to national reports.

METHODS

We reviewed electronic medical records for all patients (n=1221) diagnosed with CNS tumors at MCI from 2017 to 2021. Descriptive and statistical analyses assessed environmental and clinical variables.

RESULTS

Malignant CNS tumors account for 74% of MCI primary CNS tumors. Diffuse gliomas (41%), meningiomas (26%), and embryonal tumors (5%) were the most common histologies; embryonal tumors most common at younger ages (median: 18 years). The most abundant histological subtypes were glioblastoma (54%), benign meningioma (92%), and medulloblastoma (73%), respectively. Ethnic/racial composition of glioma patients at MCI was 55.9% Hispanic, 24.6% White Non-Hispanic, 6.4% Black Non-Hispanic, 1.8% Other Non-Hispanic, 1.3% Asian, 10% unreported, comparable to MDC. Compared to national averages, the age distribution at MCI was higher among lower grade gliomas (range: 15-96, Median: 61 years), yet lower for malignant gliomas (range: 1-93, median: 47 years). The incidence of malignant CNS tumors did not differ by gender; benign primary CNS tumors were significantly more frequent in females (245/324, 76%; p< 0.001). Smoking history did not associate with incidence of primary CNS tumors; 793/1221 (65%) self-reported as non-smoker.

CONCLUSION

The ethnic/racial composition and incidence of primary CNS tumors by histology at MCI significantly differs from national CBTRUS database (Ostrom et al). This cohort will be further characterized by genetic profiles, race, diet, allergies, family history, substance use, clinical trial enrollment, therapeutic modalities, and overall survival rate.
IMMU-19. EVALUATING EFFECTS OF REVERSING DISTINCT FACETS OF IMMUNOSUPPRESSION IN EXPERIMENTAL GBM
Authors: Ayasoufi Katayoun , Tritz Zachariah , Fain Cori , Khadka Roman , Jin Fang , Hansen Michael , Johnson Aaron
Published: November 2021

Glioblastoma is associated with severe and multifaceted immunosuppression affecting all immune organs. Immunosuppression in GBM is a critical barrier to the success of immunotherapies and patient survival. We demonstrated that immunosuppression in the GL261-model of experimental GBM presents with significant thymic and spleen atrophy, MHCII downregulation, presence of potent immunosuppressive factors in serum, and sequestration of T-cells in the bone marrow. Parabiosis studies determined that soluble factors mediate immunosuppression by inhibiting T-cell proliferation, thymic involution, and loss of peripheral T-cells. In contrast, bone marrow T-cell sequestration was not mediated through soluble factors. While the immunosuppression in GBM is severe, a causative link between each facet of immunosuppression and overall survival is lacking. We used two strategies to block T-cell sequestration into the bone marrow and evaluated the extent survival was impacted in experimental GBM. First, we evaluated the extent a novel and off-the-shelf combination immunotherapy that uses extended 1/2-life IL-2 and anti-PD-1 reverses bone marrow T-cell sequestration. Sham treatment or anti-PD1 monotherapy did not alter T-cell sequestration in the bone marrow and animals had no enhanced survival. Extended 1/2-life IL-2 monotherapy and combination strategy both prevented T-cell sequestration into the bone marrow. However, only combined therapy, which also prevented MHC class II downregulation, improved survival. Second, we determined that glioma-bearing adrenalectomized mice do not present with bone marrow T-cell sequestration. However, sera of glioma-bearing adrenalectomized mice is as immunosuppressive as glioma-bearing controls. Blocking bone marrow T-cell sequestration in the presences of serum immunosuppression led to no survival benefit in glioma-bearing adrenalectomized mice compared to controls. In short, bone marrow T-cell sequestration alone does not correspond with overall survival in experimental glioma. Importantly, a concerted effort to reverse MHC class II downregulation and define inhibitory circulating factors may have the highest impact in immunotherapeutic efficacy and improving patient survival.
IMMU-25. SYNERGY BETWEEN TMZ AND INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY TO IMPROVE OS OF IDH1 WILD TYPE MGMT PROMOTOR UNMETHYLATED GBM PATIENTS
Authors: Van Gool Stefaan , Makalowski Jennifer , Schirrmacher Volker , Stuecker Wilfried
Published: November 2021

The prognosis of IDH1 wild type MGMT promotor unmethylated (MGMT-p-UM) GBM patients remains poor. Addition of TMZ to radiotherapy shifted the median OS from 11.8 to 12.6 months (Stupp, Lancet Oncol 2019). We retrospectively analysed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. Adults with first event of IDH1wt GBM and documented status of MGMT-p-UM, and treated with IMI in the period June 2015 till July 2020, were selected. IMI consisted of 1/ immunogenic cell death (ICD) therapy (NDV injections + modulated electrohyperthermia), 2/ active specific immunotherapy with autologous mature dendritic cells loaded with tumor lysate or ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac® is an approved advanced therapy medicinal product since 27/05/2015), 3/ modulatory immunotherapy adapted to the patient, and 4/ complementary medicines. Twenty-eight patients (11f, 17m) had a median age of 48y (range 18-69) and a KPI of 90 (50-100). Extent of resection was complete (11), < complete (9) or not documented (8). Seven patients were treated with surgery/radio(chemo)therapy and subsequent IMI (Group-1); 21 patients were treated with radiochemotherapy followed by maintenance TMZ + ICD therapy, followed by DC vaccines (Group-2). Both groups received further maintenance ICD therapy. Age, KPI and extent of resection were not different amongst both groups. PFS was not assessed because of challenges about pseudoprogression. The median OS of group-1 patients was 11m (2y OS: 0%). Surprisingly the median OS of group-2 patients was 18m with 2y OS of 17% (CI95%: +31, -15), which was significantly (Log-rank: p = 0.027) different from group-1. The data suggest that addition of IMI after local therapy on its own has no relevant effect on OS in IDH1 wild type MGMT-p-UM GBM patients, similar to maintenance TMZ. However, the combination of both TMZ + IMI significantly improves median OS.
IMMU-31. TUMOR-SPECIFIC ALTERNATIVE SPLICING GENERATES SPATIALLY-CONSERVED HLA-BINDING NEOANTIGEN TARGETS DETECTED THROUGH INTEGRATIVE TRANSCRIPTOMIC AND PROTEOMIC ANALYSES
Authors: Kwok Darwin , Nejo Takahide , Costello Joseph , Okada Hideho
Published: November 2021

BACKGROUND

While immunotherapy is profoundly efficacious in certain cancers, its success is limited in cancers with lower mutational burden, such as gliomas. Therefore, investigating neoantigens beyond those from somatic mutations can expand the repertoire of immunotherapy targets. Recent studies detected alternative-splicing (AS) events in various cancer types that could potentially translate into tumor-specific proteins. Our study investigates AS within glioma to identify novel MHC-I-presented neoantigen targets through an integrative transcriptomic and proteomic computational pipeline, complemented by an extensive spatiotemporal analysis of the AS candidates.

METHODS

Bulk RNA-seq of high tumor purity TCGA-GBM/LGG (n=429) were analyzed through a novel systematic pipeline, and tumor-specific splicing junctions (neojunctions) were identified in silico by cross-referencing with bulk RNA-seq of GTEx normal tissue (n=9,166). Two HLA-binding prediction algorithms were subsequently incorporated to predict peptide sequences with high likelihood for HLA-presentation. Investigation of the tumor-wide clonality and temporal stability of the candidates was performed on extensive RNA-seq data from our spatially mapped intratumoral samples and longitudinally collected tumor tissue RNA-seq. Proteomic validation was conducted through mass-spec analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-GBM repository (n=99).

RESULTS

Our analysis of TCGA-GBM/LGG bulk RNA-seq identified 249 putative neojunctions that translate into 222 cancer-specific peptide sequences which confer 21,489 tumor-specific n-mers (8-11 amino acids in length). Both prediction algorithms concurrently identified 271 n-mers likely to bind and be presented by HLA*A0101, HLA*A0201, HLA*A0301, HLA*A1101, or HLA*A2402. We confirmed the expression of 15 out of 58 HLA*A0201-binding candidates in HLA*A0201+ patient-derived glioma cell line RNA-seq with a subset of candidates conserved spatially. Analysis of CPTAC-GBM mass-spec data detected 23 tumor-specific peptides with 5 containing detected n-mers highly predicted to be HLA-presented.

CONCLUSION

Tumor-specific neojunctions identified in our unique integrative pipeline present novel candidate immunotherapy targets for gliomas and offer a new avenue in neoantigen discovery across cancer types.
INNV-03. DEVELOPMENT OF A NOVEL DUAL-MODALITY BALLOON IMPLANT FOR SIMULTANEOUS HIGH-DOSE-RATE BRACHYTHERAPY AND MAGNETIC NANOPARTICLE HYPERTHERMIA OF BRAIN TUMOR RESECTION CAVITIES
Authors: Wan Shuying , Rodrigues Dario , Stauffer Paul , Kwiatkowski Janet , Khanna Omaditya , Judy Kevin , Yu Yan , Shi Wenyin , Hurwitz Mark
Published: November 2021

PURPOSE

To develop a novel thermobrachytherapy (TBT) balloon implant that delivers hyperthermia and radiation simultaneously, with three specific aims: 1) to fabricate a prototype TBT balloon device; 2) to verify compatibility of all heating and radiation delivery components and evaluate heat and radiation dosimetry in full size skull/brain phantom models; and 3) to characterize in vivo heating patterns in pig brain.

METHODS

Five 3cm diameter TBT balloons were fabricated. Each balloon has two layers: an inner layer to be filled with saline to expand the resection cavity, and an outer layer to be filled with magnetic nanoparticle (MNP) solution to absorb energy from an external magnetic field hence generate heat. The balloon shaft houses 4 ports to fill inner and outer layers, insert a high-dose-rate brachytherapy source into the balloon center, and a fiber optic sensor into the outer layer to monitor and control balloon temperature. A 3D-printed skull phantom was filled with brain tissue-equivalent gel for in-phantom measurements of heating around a TBT balloon. Optically stimulated luminescent dosimeters and Gafchromic film were used to measure radiation dose; while motorized temperature probes placed in catheters were inserted in surrounding gel for thermal mapping. For in vivo experiments, a 1cm balloon was specifically fabricated for pigs 40-50 kg.

RESULTS

The presence of MNP, magnetic field, and 43-55°C heating did not affect radiation dose significantly. Thermal mapping demonstrated spherically symmetric heating in both phantom and in vivo brain tissue, where a higher concentration of MNP and stronger magnetic field of 1.6-4.5 kA/m at 133 kHz was used to achieve temperatures of 55°C in the much smaller balloon.

CONCLUSION

Novel dual-modality balloons have been fabricated and tested successfully in the lab and in vivo, hence providing crucial information to validate thermal modeling for combined heat and radiation treatment of brain tumor resection cavities.
INNV-04. A MULTI-INSTITUTIONAL CLINICAL AND MRI REPOSITORY OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PERIPHERAL NERVE SHEATH TUMORS
Authors: Ly Ina , Hirbe Angela , Jordan Justin , Michaels Olivia , Kwon Daniel , Borcherding Dana , Srihari Divya , Dombi Eva , Widemann Brigitte , Pollard Kai , Pratilas Christine , Boswell Demetrius , de Blank Peter , Melecio-Vázquez Mairim , Chi Ping , Salamon Johannes , Mautner Viktor , Mulder Zachary , Steensma Matthew , Lee Shernine , Korf Bruce , Blakeley Jaishri , Plotkin Scott
Published: November 2021

BACKGROUND

Individuals with neurofibromatosis type 1 (NF1) frequently have peripheral nerve sheath tumors (PNST), including plexiform neurofibromas (PNF), atypical neurofibromas (ANF), and malignant peripheral nerve sheath tumors (MPNST). These tumors reflect a histologic spectrum from benign to malignant. Various clinical and MRI-based features are proposed as risk factors for MPNST development based on small single-institution studies. A major barrier to study these risk factors is collation and annotation of multi-center serial MRIs. To address this, we created a standardized database of clinical data and longitudinal MRIs from NF1-associated PNST from nine international NF1 referral centers.

METHODS

Clinical data from NF1 patients are collected in Research Electronic Data Capture databases housed at Massachusetts General Hospital and Washington University, including demographic information, genotype, disease course, treatment history, and survival. ANF and MPNST require histologic confirmation whereas a diagnosis of PNF can also be made based on clinical/radiographic stability. Longitudinal MRIs predating the histologic diagnosis are uploaded to a HIPAA-compliant cloud-based system.

RESULTS

Data from 200 patients (87 females, 113 males) with 217 tumors (75 PNF, 40 ANF, 102 MPNST) have been collected. 280 regional and 108 whole-body MRIs have been identified. Median age at the time of histologic diagnosis is 30 years (range 5-64). All tumors are histologically confirmed except for 6 PNF which remained stable over time. Median follow-up time is 32 months. Of 147 patients with available survival data, 32 (21.7%) have died from MPNST progression; estimated median overall survival is 20 months.

CONCLUSIONS

In this ongoing work, we have assembled one of the largest systematically annotated clinical and MRI repositories of NF1-associated PNST from pediatric and adult NF1 patients. The data will be accessible to outside researchers which will promote interdisciplinary and multi-center collaborations. Active efforts include the identification of radiomic MRI features to differentiate between PNF and MPNST.