bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-22. TIGER PRO-ACTIVE STUDY: INVESTIGATING DAILY ACTIVITY, SLEEP AND NEUROCOGNITIVE FUNCTIONING IN GLIOBLASTOMA PATIENTS APPLYING TTFIELDS THERAPY IN GERMANY IN ROUTINE CLINICAL CARE
Authors: Glas Martin , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Bähr Oliver
Published: November 2022

Based on the EF-14 trial, Tumor Treating Fields (TTFields) therapy is recommended in treatment guidelines for newly diagnosed glioblastoma (GBM). However, real-world data are limited. The non-interventional TIGER study (NCT03258021) will give insight into patients’ therapy decision, TTFields therapy duration and usage, quality of life, overall survival, and adverse events (AEs) in the real-world setting. Subsequently, we have now established the TIGER PROgram, a collaborative national network of neurooncology centers, that will allow us to use previously established administrative structures for new real-world investigations. Also, it will enable a basic data set across different trials and thereby facilitate meta-analyses across different populations. Here we report on the first study that we initiated within this program, the TIGER PRO-Active Study (NCT04717739), a prospective, an ongoing non-interventional, multicenter study in Germany investigating changes in daily activity, sleep, neurocognitive functioning as potential quality of life parameter in GBM patients whilst receiving TTFields therapy. Furthermore, TTFields therapy usage and serious AEs will be evaluated. Based on the planned subgroup analysis (MGMT and age), the experiences with the ongoing TIGER trial, the expected dropout rate and in consideration of the Central Limit Theorem (sufficiently large group size of n ≥ 30) we will recruit approximately 500 adult patients with newly diagnosed GBM over the course of 2 years. Data on physical activity and sleep will be collected via specific smartphone apps. Neurocognitive functioning will be assessed using the MoCA (Montreal Cognitive Assessment) interview test and quality of life with the EORTC QLQ-C30 and -BN20 questionnaires. Data will be collected over a time period of at least 12 months. First results are expected in 2024.
NCOG-27. A SINGLE-INSTITUTION RETROSPECTIVE SERIES OF SARS-COV-2 INFECTION IN ADULT GLIOMA PATIENTS
Authors: Lanman Tyler , Ruiz Amber , Nagpal Seema
Published: November 2022

A subset of cancer patients is particularly vulnerable to SARS-Cov-2 infection; however, real-world outcomes-based data on primary central nervous system tumor patients is sparse. This retrospective case series describes a cohort of adult glioma patients seen at Stanford Cancer Center between 1/20/2020 through 5/24/2022 who contracted SARS-Cov-2. We identified 18 patients with a diagnosis of glioma, with a median age of 54 years, who were infected with Covid-19. One patient contracted Covid-19 twice during this two-year period. Of these patients, four had pathology confirmed low-grade glioma, defined as oligodendroglioma or astrocytoma WHO grade 2, and 14 patients had high-grade glioma, defined as astrocytoma or glioblastoma WHO grade 4. Median KPS at time of infection was 70. Six individuals had notable cardiovascular comorbidities including coronary artery disease, obesity, and/or diabetes. All but one patient was vaccinated against Covid-19, and 6 were taking dexamethasone at the time of infection. Three patients required hospital admission for management of Covid-19 symptoms, although none required ICU-level of care. None died from Covid-related complications; however, two died from complications of their underlying cancer at the end of study. Our data suggest that glioma patients seen at Stanford Cancer Center do not experience an exceptionally high Covid-19 infectivity, hospitalization, or mortality rate, especially when compared to other vulnerable populations such as lung cancer patients. High vaccination rates, fairly low prevalence of cardiovascular comorbidities, and adherence to pandemic precautions among this cohort may have contributed to these results.
NCOG-28. LEEDS LOW GRADE GLIOMA SERVICE 2010-2022: A 12-YEAR EXPERIENCE
Authors: Kalra Neeraj , Livermore James , Spink Suzanne , Boyer Gillian , O'Malley Lianne , Flatley Michael , Maguire Melissa , Fairclough Sam , Wright Elizabeth , Armstrong Caroline , Stephenson Elisa , Ewan Seonaid , Cooper Sara , Guy Danielle , Saunders David , Igra Mark , Macmullen-Price Jeremy , Currie Stuart , Zaman Arshad , Derbyshire Catherine , Chakrabarty Arundhati , Gooden John , Chumas Paul , Mathew Ryan
Published: November 2022

INTRODUCTION

We present our 12-year experience of the surgical management of lower-grade gliomas (LGGs) by a multidisciplinary team in a large tertiary UK brain tumour centre.

METHODS

Retrospective analysis of all adult patients who underwent surgery in the Leeds Low Grade Glioma Service between January 2010 and January 2022. Data collected included demographics, procedure type, extent of resection, histological diagnosis, morbidity, mortality, tumour location, seizure control, adjuvant therapy, cognitive outcomes, progression-free survival (PFS) and overall survival (OS). Results were statistically analysed by Kaplan-Meier and Log Rank (Cox Proportional Regression Hazard) Testing (p< 0.05).

RESULTS

254 patients underwent surgery between 2010-2022. Of these, 77 patients underwent a second resection surgery, 9 a third, and 1 patient had a total of 4 resections. 184 operations were carried out awake, 115 asleep and 42 patients underwent biopsy only. The most common histology at initial surgery was astrocytoma, IDH1m, WHO Grade 2 (41.7%) with oligodendroglioma, IDH1m, WHO Grade 2 being the second most common. The majority of tumors were located in the right frontal lobe (24%) followed by the left frontal lobe (18%). 32% of tumors were on the left side. The median time between diagnosis and first surgery was 36.5 months. 8 patients died during this time frame, 7 who had resection, 1 had biopsy.

CONCLUSION

Our experience of the surgical management of LGG over the last 12 years shows that maximal safe surgical resection remains important as first-line treatment. Greater extent of resection (EOR) can delay transformation, control seizures and improve survival. Awake surgery is well tolerated and can preserve eloquent function. A multidisciplinary team approach achieves the best outcomes, and is appreciated by our patients
NCOG-30. MULTISESSION RADIOSURGERY FOR UNFAVORABLE NONFUNCTIONING PITUITARY MACROADENOMA: 5-YEAR OUTCOMES FROM A SINGLE INSTITUTION PROTOCOL
Authors: Bhatnagar Akrita , Carrasquilla Michael , Nayar Vikram , Collins Brian , Collins Sean , Anaizi Amjad , Watson Joseph , Jean Walter C , Harris Brent , Conroy Dylan , Suy Simeng , Ebadirad Nelya , Aulisi Edward
Published: November 2022

Nonfunctioning macroadenoma is a commonly diagnosed pituitary tumor. Resection is the favored treatment, with radiosurgery often utilized for residual or progressing disease. Long-term outcomes are established for single-session radiosurgery, but mature outcomes are lacking for multisession radiosurgery. We report our institution’s 5-year efficacy and safety results for unfavorable nonfunctioning pituitary macroadenoma patients treated with 5-fraction robotic radiosurgery. Between 2010-2020, patients who completed 5-fraction radiosurgery for the treatment of unfavorable nonfunctioning pituitary macroadenomas were included. A tumor was considered unfavorable if the gross tumor volume (GTV) was larger than 5 cc or if it closely approached a critical structure (optic apparatus, brainstem or pituitary gland). Local control was calculated using the Kaplan-Meier Method.

RESULTS

Twenty predominately female patients (60%), age from 21-77 (median: 53 years) were included in this study. All underwent primary resection. Indications for radiosurgery included unresectable recurrence (85%) and residual disease progression (70%). Median tumor volume was 3.4 cm3 (range: 0.3-20.8 cm3) and 40% of the tumors were suprasellar. A mean dose of 30 Gy (range: 25Gy-30Gy), was delivered to a median isodose line of 80% (range: 75%-89%). Toxicity was minimal with 12 patients (40%) developing acute short-lived headaches and 1 patient (5%) developing a brief ipsilateral 6th nerve palsy. There was no radiation induced optic or pituitary dysfunction identified in this cohort. At a median follow up of 5 years local control at 5 years was 95%. There was 1 in-field failure pathologically confirmed following surgery for pituitary tumor hemorrhage and 2 radiographically confirmed out-of-field failures in patients with large tumors (> 20 cc) treated with lower doses (25 Gy).

CONCLUSIONS

The treatment of unfavorable nonfunctioning pituitary macroadenoma with 5-fraction robotic radiosurgery provides excellent local control to date, with minimal toxicity. Continued follow-up for the long term optic and pituitary function preservation and tumor control is needed.
NCOG-32. PROGNOSTIC SIGNIFICANCE OF PREOPERATIVE NEUTROPHILIA AND LEUKOCYTOSIS IN CNS LYMPHOMA
Authors: Khan Osaama , Ordon Matt , Gibson Will
Published: November 2022

OBJECTIVE

The purpose of this study is to assess the prognostic value of preoperative neutrophilia and leukocytosis in a retrospective analysis of patients presenting with biopsy proven primary CNS lymphoma (PCNSL). This research is an extension of the growing body of evidence that preoperative hematologic values correlate with overall and progression free survival amongst solid tumors, including those involving the central nervous system. Methodology: Retrospective analysis of 50 patients with biopsy proven PCNSL. Preoperative complete blood counts (CBC) were collected alongside other clinical data including imaging characteristics (focal versus multifocal), molecular subtype, and neutrophil-leukocyte ratio (NLR). Survival time starting at time of biopsy was evaluated using Cox proportional hazard models and log-rank tests.

RESULTS

32 patients met eligibility criteria. Based upon the early data, only the NLR showed statistical significance on univariate analysis (HR 1.092 P=.002 CI 1.06-1.15) Multivariate analysis failed to show a statistical relationship when the independent variables age at diagnosis, preoperative leukocytosis, ANC/ALC, and WBC. The NLR approached statistical significance with multivariate analysis (HR 1.17 P= .053 CI .99-1.57). Molecular subtyping and imaging characteristic analysis is ongoing, and is not included in this analysis (including GCB subtype, MYC gene mutation). Future Direction: Studies like ours are necessary to ensure a cheap, repeatable, and universally available test for PCNSL patients. Preliminary analysis showed a trend towards significance when evaluating the NLR on multivariate analysis. More data is required to further elucidate these findings. Analysis is ongoing and will include other prognostic variables, including molecular profile and imaging characteristics.
NCOG-34. METASTATIC PAPILLARY TUMOR OF THE PINEAL REGION: ROLE OF STEREOTACTIC IRRADIATION AND ADJUVANT TEMOZOLOMIDE
Authors: Koshy Amily , Kim Esther , Higgins Shannon , Haggiagi Aya
Published: November 2022

INTRODUCTION

Papillary tumor of the pineal region (PTPR) is a very rare tumor comprising < 1% of all intracranial neoplasms. It was first included as a distinct tumor entity in the 2007 World Health Organization classification. Due to its rarity, only anecdotal data is currently available to guide management. However, with these tumors being recognized more frequently, further molecular observations and therapeutic experiences are necessary. Herein, we report an unusual case of PTPR with a previously treated leptomeningeal metastasis (LM) whom we successfully managed with Gamma Knife Radiosurgery (GKRS) and adjuvant temozolomide at time of distant brain parenchymal tumor progression. CASE REPORT: A 41-year-old man presented with headache and diplopia in 2015, MRI brain revealed a large cystic enhancing lesion in the pineal region protruding into the third ventricle and causing obstructive hydrocephalus. He had a ventriculoperitoneal shunt placed and underwent partial tumor resection. He then transferred care to our institution and a gross total resection was achieved. Pathology confirmed PTPR. A repeat MRI 15 months later showed evidence of radiographic LM in the cerebellum and he underwent craniospinal proton radiation therapy. He remained stable until January 2020 when a new left temporal heterogeneously enhancing multicystic lesion was identified on surveillance MRI. He underwent subtotal resection of this intra-axial lesion. Histological features of the tumor were similar to his initial tumor. Somatic tumor mutation testing using FoundationOne®CDx did not reveal targetable molecular alterations. Following surgery, he received GKRS and six cycles of adjuvant temozolomide. At 21-month follow up, patient continues to do well.

CONCLUSION

To our knowledge, this is the first case to describe a metastatic brain intraparenchymal PTPR. We also describe a first case of successful therapeutic strategy for a distant recurrence of PTPR.
NCOG-40. UTILITY OF THE SEIZURE CONTROL COMPOSITE INDEX (RANO-SCCI) IN EVALUATING SEIZURES IN CNS TUMOR PATIENTS
Authors: Miller Hope , Christ Alexa , Grajkowska Ewa , Acquaye Alvina , Adegbesan Kendra , Boris Lisa , Burton Eric , Chambers Claudia , Choi Anna , Evans Karen , King Amanda , Komlodi-Pasztor Edina , Leeper Heather , Levine Jason , Lindsley Matthew , Lollo Nicole , Mentges Kelly , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Reyes Jennifer , Roche Kayla , Rogers James , Sahebjam Solmaz , Sass Dilorom (Delia) , Shuboni-Mulligan Dorela , Stockdill Macy , Theeler Brett , Wall Kathleen , Wollet Alex , Wu Jing , Diarte Jose , Gilbert Mark , Avila Edward , Armstrong Terri , Vera Elizabeth
Published: November 2022

BACKGROUND

Seizures are a common symptom in patients with CNS tumors. The RANO-Seizure Control Composite Index (RANO-SCCI) was developed to monitor seizures over time by patients and clinicians. We describe the use of the RANO-SCCI as part of the NCI NOB-Natural History Study.

METHODS

Patients completed a RANO-SCCI prior to their clinic appointment with results shared with clinicians who then completed a RANO-SCCI as part of the same appointment. Seizure reports were tallied by respondent type and further by tumor type and grade. Concordance between patient and clinician report was also investigated.

RESULTS

One hundred fifty-seven patients underwent 250 clinical evaluations. Participants were primarily white (82%) males (57%) with median age 47 years (range: 19 – 78). Most had high grade (60%) primary brain (86%) tumors, were in surveillance (76%), with no prior recurrence (57%) and KPS ≥ 90 (76%). Half of patients and 62% of clinicians reported the patient ever having a seizure. The 12% discordance were all where the patient did not report a seizure, but clinicians did. There was good agreement on seizure reporting since last visit (74% patients, 78% clinicians), and anti-seizure medication use (51% patients, 57% clinicians). Seizures were reported more frequently in patients with high-grade tumors (WHO Grade 3 or 4) (60% patients, 76% clinicians) versus low-grade (WHO Grade 1 or 2) (51% patients, 59% clinicians), and among patients with oligodendrogliomas (71% patients, 85% clinicians) versus non-oligodendroglioma tumors (54% patients, 68% clinicians).

CONCLUSIONS

The RANO-SCCI was used for self-report and clinician report of seizure activity. A higher frequency was reported among oligodendroglioma and high-grade tumors. Disparities between patient and clinician responses may reveal a limitation in the patient’s ability to recognize and assess their seizure symptoms. Further work will investigate reporting congruence and associations with clinical and demographic characteristics.
NCOG-43. A RETROSPECTIVE ANALYSIS OF THE IMPACT OF THE COVID-19 INFECTION ON NEURO-ONCOLOGY CARE AND PATIENT OUTCOMES: A TWO-SITE STUDY
Authors: Johnson Margaret , Durling Jennifer , Brown Casey B , Khasraw Mustafa , Petitt Zoey , Cort Nicole , Lipp Eric S , Buckley Evan D , Herndon James E , Kam Waynekid , Gao Karen , Chheda Milan G , Butt Omar H
Published: November 2022

BACKGROUND

COVID-19 radically changed neuro-oncology care. In this retrospective study, we examine the impact of COVID-19 infection on neuro-oncological care and clinical outcomes in two geographically separate populations.

METHODS

Descriptive statistics compared demographic and clinical history extracted from the medical records of COVID-19 positive patients with primary brain tumors treated between 3/1/2020 and 3/31/2021. All subjects were unvaccinated given our cohort pre-dates the ubiquitous availability of vaccines. Patients were treated at Washington University (WashU) in St. Louis, MO and Duke University in Durham, NC. Each site’s respective institutional review board approved the study, with a data transfer agreement in place.

RESULTS

We identified 62 total (WashU=13; Duke=49) subjects with positive COVID-19 infection. Patients were predominantly white (85.5%), male (56.5%), with KPS >=70 (82.3%) and never smoked (69.4%). WashU patients tended to be older with grade 4 tumors, but this was not significant. At the time of COVID infection 35.5% of patients were receiving cancer-directed therapy. Notably, 37.1% experienced delayed care due to a COVID-19 diagnosis, most often for scheduled systemic treatment or radiation treatment. A further 37.1% had an ER visit, hospitalization, or ICU stay attributed to COVID-19. Of the 17 patients who died during the study period, 4 deaths were attributed directly to COVID-19 and not to their underlying brain tumor or other cause. Finally, telehealth use differed between sites (84.6% at WashU vs 14.3% at Duke). However, this difference could not be attributed to patient age, performance status, or distance from treating institution.

CONCLUSION

COVID-19 infection led to treatment delays and death for a subset, but not the majority of neuro-oncology patients. Telehealth use varied between sites and was not associated with commonly held assumptions about patient distance or performance status, suggesting evolving practice norms following telehealth’s introduction. Study limitations include a small sample size
EXTH-01. INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE RE-INOCULATION IN HER2+ AND TRIPLE NEGATIVE BREAST CANCER LMD XENOGRAFT MODELS
Authors: Law Vincent , Kodomudi Krithika , Snyder Colin , Forsyth Peter , Czerniecki Brian
Published: November 2022

BACKGROUND

Leptomeningeal disease (LMD) occurs in approximately 5% of patients with breast cancer and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in breast cancer patients. In pre-clinical and clinical trials, the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ breast cancer patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in breast cancer-associated LMD immunocompetent animal models.

METHODS

Luciferase-labeled HER2+ TUBO breast cancer cells were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir in patients) for the IT administration of DCVs into the CSF. RESULTS AND

DISCUSSION

breast cancer-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p< 0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ breast cancer-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-g and IL18 response upon DCV treatment.

CONCLUSIONS

Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in breast cancer patients with LMD.
EXTH-02. ANTI-TUMOR EFFECTS AND IN VIVO DYNAMICS OF EPCAM-DIRECTED CAR T-CELLS FOR BRAIN METASTASES FROM LUNG CANCER
Authors: Xu Tao , Karschnia Philipp , Cadilha Bruno , Dede Sertac , Lorenz Michael , Seewaldt Niklas , Nikolaishvili Elene , Müller Katharina , Blobner Jens , Teske Nico , Langer Sigrid , Obeck Hannah , Lorenzini Theo , Mulazzani Matthias , Zhang Wenlong , Ishikawa-Ankerhold Hellen , Buchholz Veit R , Subklewe Marion , Thon Niklas , Straube Andreas , Tonn Joerg-Christian , Kobold Sebastian , von Baumgarten Louisa
Published: November 2022

BACKGROUND

Lung cancer patients are at a high risk for brain metastases, and affected patients frequently succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapeutic avenue for brain metastases.

METHODS

A fully immunocompetent, orthotopic cerebral metastasis model was established in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy. This approach enabled the in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of EpCAM-expressing Lewis lung carcinoma cells was performed, and EpCAM-directed CAR T-cells (EpCAMCAR T-cells) were injected into the adjacent brain parenchyma after brain tumor formation.

RESULTS

All mice had visible tumor take with rapidly growing lesions following intracranial tumor cell injection. In mice treated with EpCAMCAR T-cells, we observed substantial CAR T-cell accumulation within the tumor compared to controls treated with undirected T-cells. This was paralleled by lower velocities of EpCAMCAR T-cells, characterizing antitumor cytotoxicity due to ‘immune cell’-‘tumor cell’ contacts. Consequently, treatment with EpCAMCAR T-cells resulted in reduced tumorous growth as determined per in vivo-microscopy (median tumor area on day 10: 1.8 versus 10.8 mm2; p=0.001) and immunohistochemistry of excised brains. However, the number of intratumoral EpCAMCAR T-cells within the tumor markedly decreased during the observation period, pointing towards insufficient persistence. Accordingly, survival was prolonged in mice receiving EpCAMCAR T-cells but long-lasting remission was rare (median survival: 15 versus 13 days; p=0.012). No CNS-specific or systemic toxicities of EpCAMCAR T-cells were encountered.

CONCLUSION

Our findings indicate that EpCAMCAR T-cells injected into the cerebral parenchyma may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the CAR T-cell persistence within brain metastases are warranted to further boost the therapeutic success.
EXTH-07. AN ANTISENSE OLIGONUCLEOTIDE AGAINST TUMOR MICROTUBES IN GLIOBLASTOMA AS A NEW THERAPEUTIC OPTION TO IMPROVE TUMOR SPECIFIC THERAPY
Authors: Weil Sophie , Azorín Daniel Domínguez , Jung Erik , Higgins Josie , Mohammed Hafeez , Reckless Jill , Ramsden Nigel , Keller Peter , Grainger David , Wick Wolfgang , Winkler Frank
Published: November 2022

Glioblastomas are known to be highly therapy resistant tumors. The description of tumor microtubes (TMs) as long cellular protrusions that connect glioblastoma cells to a network resistant against all standard therapies advanced the basic biological understanding of the disease and offers a new therapeutic target. An antisense oligonucleotide (ASO) against the production of a protein involved in formation and function of TMs was developed and tested in a xenograft mouse model of human glioblastoma cells. After the implantation of fluorescent tumor cells under a chronic cranial window and the establishment of the tumor, the ASO treatment was started with a continuous micropump application directly into the central nervous system (CNS) and treatment effects were observed in a two-photon microscope. Furthermore, co-treatment with irradiation was tested and tumor size as well as protein expression evaluated in and ex vivo. This led to the conclusion that the setup of combined continuous pump application and two photon microscopy is technically feasible and tolerable. It offers the possibility of applying compounds directly into the CNS under live and longitudinal readouts. The fluorescently tagged ASO was traced in the brain parenchyma over weeks proving a high stability of the compound. In combination with radiotherapy, animals treated with the active ASO against the protein of formation and function of TMs showed a smaller tumor size than animals treated with radiotherapy and the non-targeting ASO. The targeted protein was expressed less in the treated animals then the animals receiving the control ASO and the extend of protein expression correlated with tumor size. Hence, after successful therapies with ASOs in other neurologic diseases and the need for better therapeutic options for glioblastoma patients, the development of an ASO against a protein involved in the TM formation and function offers a new therapeutic option with high translational potential.
EXTH-08. DEVELOPMENT OF NOVEL HISTONE DEMETHYLASE INHIBITOR AGAINST DIPG
Authors: Suri Amreena , Venkatesan Srinivasan , Sasaki Takahiro , Ishi Yukitomo , Watanabe Jun , Abe Kouki , Ebetino Frank H , Frontier Alison J , Hashizume Rintaro
Published: November 2022

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is one of most the devastating pediatric brain tumors, and virtually all patients die within two years after diagnosis. It has been shown that targeted inhibition of JMJD3 demethylase activity by GSK-J4 results in restored K27 methylation and a significant delay of tumor progression and prolonged animal survival in intracranial DIPG patient-derived xenograft (PDX) models. Because of its promising anti-tumor activities, GSK-J4 has been used to treat many kinds of tumors in preclinical models including leukemia, lymphoma, neuroblastoma, prostate, and gastric cancer, and DIPG; however, GSK-J4 is not yet in clinical development. The major challenge for GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted in vivo to the active drug GSK-J1, which has restricted cellular and brain permeability. Hypothesis: We hypothesize that development of a stable GSK- J1 analog that offers good cellular and brain transport is essential to improving in vivo efficacy and is required for clinical application of this class of compounds.

METHODS

We developed a novel alcohol derivative of GSK-J1, UR-8, as a lead anti-cancer agent through our screening and drug development activities.

RESULTS

UR-8 has demonstrated selective cytotoxic activity against human K27M DIPG cells in vitro and apparently transported the brain to a useful extent based on its in vivo bio-distribution and effectiveness.

CONCLUSION

UR-8 showed greater anti-tumor activity and survival benefit than that obtained by GSK-J4 treatment in intracranial DIPG PDX models.
EXTH-09. HSP90 INHIBITION AS A NOVEL THERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Sbergio Stefanie-Grace , Sheth Javal , Canty Laura , Pajovic Sanja , Vadivel Arun Anguraj , Carette Sheyenne , Siddaway Robert , Hawkins Cynthia
Published: November 2022

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor. The mean age of onset is 7-9 years with a median survival of 9 months following diagnosis. Histone 3 (H3) mutations (H3K27M) have been identified in approximately 80% of patients, representing an intriguing target, but how to do this is unclear. To address this, we performed a synthetic lethality drug screen of over 2400 compounds on isogenic cells expressing H3K27M and empty vector. 37 drugs were synthetically lethal with H3K27M, including HSP90 inhibitors. In cancer, HSP90 has a higher isoelectric point which can be targeted specifically by PU-H71. Using PU-H71, HSP90 complexed with oncogenic clients can be inhibited to reduce tumor cell viability. We tested PU-H71 on primary patient derived DIPG lines demonstrating caspase-3/7 mediated cell death within 24 hours (n=3) and an IC50 of 100-200 nM (n=5) at 72 hours. HSP90 is a molecular chaperone that supports protein activation and localization; thus, its inhibition may allow simultaneous targeting of multiple oncogenic pathways. To determine which pathways are targeted in DIPG we used PU-H71-conjugated beads to pull-down HSP90 complexed with client proteins. LC-MS/MS characterization of the HSP90 interactome from three DIPG cell lines (SU-DIPG XVII, SU-DIPGXXV, SU-DIPG 50) identified 339 overlapping proteins including MAPK3, SMS, SRM, CTSP1, OAT, GMPS, and PYG. Pathway enrichment analysis highlighted roles in cell cycle regulation and metabolic processes. Treating DIPG with PU-H71 successfully reduced tumor cell viability but PU-H71 has poor brain penetration. To overcome this, a molecular isoform of PU-H71 has been developed, PU-HZ151, which will be used to test the in vivo efficacy of HSP90 inhibition for DIPG.
EXTH-10. TARGETING MITOCHONDRIAL ENERGETICS REVERSES THERAPEUTIC RESISTANCE IN PEDIATRIC DMG AND HGG
Authors: Reslink Matthew , Jane Esther , Premkumar Daniel , Gatesman Taylor , Wendell Stacy , Agnihotri Sameer , Pollack Ian
Published: November 2022

Diffuse midline gliomas (DMGs) and other high-grade gliomas (HGG) are the most commonly lethal intrinsic brain tumors of childhood. Accordingly, novel treatment approaches are needed that consider the heterogeneity of these tumors. Using an extensive pharmacological screen, we identified several two-drug combinations that were particularly effective against a range of DMG and HGG cell lines, the most active being the combination of the histone deacetylase inhibitor, panobinostat, and a proteasome inhibitor, marizomib, both in clinical trials, which synergistically induced tumor-specific apoptosis. However, at clinically achievable concentrations, a small population of resistant tumor cells survived and dominated, mimicking the clinical scenario, which prompted our development of drug resistance models as mechanistic tools. Resistance mechanisms were examined using RNA sequencing of drug-resistant versus -naïve cells. NMNAT2, a critical mediator of NAD synthesis, was overexpressed in DIPGs in the context of high baseline QPRT expression, suggesting a critical role of NAD synthesis and utilization pathways in resistance. Gene-set enrichment analysis suggested a key role for glycolytic pathways in the resistance phenotype. In support of this hypothesis, we observed increased levels of mitochondrial mass and NAD and ATP in resistant cells compared to drug-naïve cells, as well as upregulation of glycolytic intermediates by LC/MS. Conversely, inhibition of OXPHOS and glycolysis pathways resensitized resistant glioma cells to apoptosis in vitro. To test this hypothesis in vivo, mice were injected with drug-naïve or resistant DIPG-013 glioma cells and were exposed to an OXPHOS and glycolysis inhibitor, lonidamine. Lonidamine alone extended survival of naïve (18.6 + 1.4 d vs. 25 + 1.6 d, p=0.0003) and resistant (18.7 + 1 d vs. 62 + 1 d, p=0.0002) DIPG13p models (Log-Rank). This supports the application of metabolic therapy as a novel strategy for treating resistant MGs that has activity in a clinically relevant DIPG model. Supported by NIHS10OD023402, the DIPG/DMG Collaborative, the CNI, and Connor’s Cure.
EXTH-12. PRECLINICAL AND CASE STUDY EXAMINATION OF THE COMBINATION OF THE CLPP AGONIST ONC201 WITH THE PI3K/AKT INHIBITOR PAXALISIB FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA
Authors: Jackson Evangeline , Duchatel Ryan , Persson Mika , Mannan Abdul , Yadavilli Sridevi , Parackal Sarah , Game Shaye , Chong Wai Chin , Jayasekara Samantha , Le Grand Marion , Kearney Padraic , Douglas Alicia , Findlay Izac , Staudt Dilana , Germon Zacary , Skerrett-Byrne David , Nixon Brett , Smith Nathan , Hulleman Esther , Day Bryan , McCowage Geoffrey , Alvaro Frank , Waszak Sebastian , Larsen Martin , Colino-Sanguino Yolanda , Valdes-Mora Fatima , Rakotomalala Andria , Meignan Samuel , Pasquier Eddy , Vitanza Nicholas , Nazarian Javad , Koschmann Carl , Cain Jason , Mueller Sabine , Dun Matthew
Published: November 2022

Diffuse midline gliomas (DMGs), including those of the pons (diffuse intrinsic pontine glioma - DIPG), are pediatric CNS tumors recognized as the most lethal of all children’s cancers. Palliative radiotherapy remains the only approved treatment, with survival just 9-11 months post-diagnosis. The brain-penetrant small molecule therapy, ONC201, shows preclinical and emerging efficacy in early-stage clinical trials. However, patients invariably develop resistance, with some patients and models completely refractory to treatment. Using a powerful combination of pharmacology, proteomics, genomics, epigenetics, in vitro and in vivo modeling, across ten international laboratories, we have uncovered mechanisms underpinning resistance to ONC201. We find ONC201 elicits antagonism of the Dopamine receptor D2 (DRD2), whilst also causing mitochondrial degradation through potent agonism of the mitochondrial protease CLPP. This drives proteolysis of the electron transport chain (ETC) proteins including Succinate dehydrogenase A (SDHA) and the critical mitochondrial tricarboxylic acid (TCA) cycle regulator, Isocitrate dehydrogenase 3B (IDH3B). Loss of TCA activity reduces α-ketoglutarate and inhibits lysine demethylation, increasing methylation of H3K4me3 and H3K27me3, thus, altering the epigenome of DIPG. Mitochondrial disruption elicited redox-activated RAS-PI3K/AKT signaling, counteracted using the PI3K/AKT inhibitor paxalisib. The combination of ONC201 and paxalisib synergistically extended survival of two aggressive DIPG PDX models (SU-DIPG-VI vehicle=73 vs. combination=100-days, p=0.0027; SF8626 vehicle=36 vs. combination=43-days, p=0.0002). Compassionate access to this combination (n=2 patients; immediately post-RT and following re-RT) resulted in dramatic reductions in tumor volume, extending overall survival for the patient at diagnosis and the patient at progression (e.g., MR axial diagnosis scan = 1554 mm2, following twelve months on the combination, current tumor volume = 464 mm2 (~70% reduction), patient remains in progression free survival, 15 months since diagnosis). The clinical utility of our preclinical data is currently under investigation in the PNOC022 clinical trial (NCT05009992).
EXTH-20. IDENTIFICATION OF EX VIVO THERAPEUTIC VULNERABILITIES IN DIFFUSE GLIOMAS USING A FUNCTIONAL GENOMICS APPROACH
Authors: Lin Wan-Hsin , Smadbeck James , Barrett Michael , Feathers Ryan , Dorsay Sadeghian , Johnson Sarah , Karagouga Giannoula , Harris Faye , Murphy Stephen , Quiñones-Hinojosa Alfredo , Kizilbash Sani , Burns Terry , Jaeckle Kurt , Mrugala Maciej , Bendok Bernard , Moniz-Garcia Diogo , Fortin-Ensign Shannon , Rosenfeld Steven , Ida Cristiane , Jentoft Mark , Salomao Marcela , Yang Lin , Emanuel Angela , Schaefer-Klein Janet , Mansfield Aaron , Borad Mitesh , Cheville John , Vasmatzis George , Anastasiadis Panos
Published: November 2022

Diffuse gliomas are aggressive brain tumors that lack effective therapies. Despite advances in the molecular characterization of gliomas, targeted treatments have failed to improve patient outcomes to date. Here, we employed a functional genomics approach to rapidly identify therapeutic vulnerabilities and provide a strategy to individualize patient treatment. Our process combined comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensional ex vivo models (mcancers) for drug screening to assess response to therapeutic agents targeting specific molecular alterations. A total of 32 cases, including 5 oligodendrogliomas (1 primary and 4 recurrent), 5 astrocytomas (1 primary and 4 recurrent), and 22 glioblastomas (5 primary and 17 recurrent), were included in the study. Immunohistochemistry and integrated genomics confirmed that mcancers maintain key molecular alterations, including mutations, chromosomal rearrangements and focal amplifications, cellularity, and heterogeneity, faithfully recapitulating the original tumor. A total of 119 single drugs and 183 combinations were tested, including a panel of 26-brain penetrant targeted agents (18 single drugs and 8 combinations) that was curated to target common glioma oncogenic pathways and was tested across all cases. A strong correlation was observed between therapeutic vulnerabilities of glioma mcancers to targeted agents (EGFR, MET, PDGFR, HDAC inhibitors, etc.) and clinical experience. Single agent activity of panel compounds in the ex vivo setting was generally poor, with only 35% mCancers exhibiting > 70% growth inhibition at Cmax. In contrast, combination strategies, especially ones including epigenetic drugs, were significantly more effective (affecting 22 out of 32 mCancers), underscoring the molecular complexity of gliomas and the need for clinical trials testing combination treatments. Our data identified a number of novel combination treatments with significant efficacy across glioma subtypes and molecular profiles, suggesting that our functional genomics pipeline can guide treatment selection and inform clinical trial enrollment for gliomas.
EXTH-22. TARGETING A NEWLY DISCOVERED IMMUNE CHECKPOINT, SIGLEC-15, INCREASES ONCOLYTIC EFFICACY OF ZIKA VIRUS (ZIKV) IN GLIOBLASTOMA (GBM)
Authors: Kesarwani Ashwani , Bais Sachendra Singh , Nair Sharmila , De Costa Amanda Andrade , Hu Tong , Shi Pei-Yong , Diamond Michael S , Chheda Milan G
Published: November 2022

We are developing ZIKV as a therapy for GBM. We previously demonstrated ZIKV specifically kills GBM stem cells. Using GL261 and CT2A mouse models, ZIKV induces a CD8+ T-cell mediated anti-tumor response and leads to 65% and 40% long term survivors, respectively (0%-untreated controls). ZIKV treatment significantly increases the number of myeloid cells in the tumor microenvironment (with about 10,000 infiltrating macrophages per ZIKV-treated brain, 1,000 cells per untreated brain). We hypothesized that by targeting a myeloid immune checkpoint, we would further enhance efficacy. Siglec-15 is a newly described myeloid checkpoint, and anti-siglec-15 antibody is currently in clinical trial for patients with advanced or metastatic solid tumors (NCT03665285). While there was no effect of anti-siglec-15 treatment alone, we observed increased efficacy when combined with ZIKV (cure rate: GL261-70%, CT2A-60% with ZIKV+anti-siglec-15 antibody; GL261-20%, CT2A-0% with anti-siglec-15 antibody alone; GL261-30%, CT2A-25% ZIKV alone; GL261-0%, CT2A-0% without treatment). Since recurrence is a major problem, we performed re-challenge experiments in cured mice at 6 months. Mice previously treated with anti-siglec-15 antibody and ZIKV had 70% long-term survival, compared to 30% of age matched untreated controls. This supports our earlier findings that an immunological response after ZIKV engenders long-term, tumor-specific, immune surveillance. Lastly, we used Siglec-15 knockout mice to confirm our observations. After treating Siglec-15 knockout mice bearing CT2A tumors with ZIKV, 70% animals were cured. There was no significant difference in survival between CT2A-bearing Siglec-15 knockout mice without ZIKV treatment compared to CT2A-bearing wild type hosts. Taken together, our work suggests targeting putative myeloid suppressor cells, combined with oncolytic ZIKV and its ensuing anti-cancer stem cell and activated CD8+ T-cell effects, may be an effective tool in neuro-oncology. Targeting Siglec-15 may also enhance other oncolytic or cytotoxic therapies.
EXTH-23. BICISTRONIC CAR-T CELLS TARGETING EGFR AND IL13RΑ2 MITIGATE ANTIGENIC HETEROGENEITY IN GLIOMA
Authors: Li Nannan , Yin Yibo , Rodriguez Jesse , Logun Meghan , Zhan Logan , Zhang Jiasi , Binder Zev A , Lin Zhiguo
Published: November 2022

Chimeric antigen receptor (CAR)-T cells have had a significant effect in hematological diseases, with a recent study confirming that the cells can last for ten years in vivo. Unfortunately, to date, CAR-T cells have had little effect in solid tumors. One cause of the treatment difficulty is antigenic heterogeneity. Our experience with CAR-T cells in glioblastoma suggests that addressing antigenic heterogeneity may improve the clinical efficacy. Targeting the epidermal growth factor receptor (EGFR) and interleukin 13 receptor subunit alpha 2 (IL13Rα2) individually could lead to tumor control in the short term, but it will be marked by tumor recurrence through antigen loss or downregulation in the long term. This resistance mechanism can be inhibited by combinatorial targeting. To this end, we have designed a bicistronic construct that targets both EGFR and IL13Rα2 simultaneously, to decrease the potential of antigen escape and tumor recurrence. The bicistronic CAR-T cells employ an “OR” logic gate to modify the T cells and kill the tumor cells in vitro and in vivo, in order to retain effectiveness when one target antigen is lost but the second is still present. Our experimental results demonstrate that and validate the safety and possibility of clinical translation. In addition, the efficiency of transfecting T cells with the single bicistronic vector was higher than two single vectors on monovalent CARs. In summary, the bicistronic CAR-T structure is a promising strategy to address the clinical problem of targeting antigenic heterogeneity in solid tumors and potentially level the barriers for targeted T-cell therapy. Educational Objectives: After completion, participants will be able to explain the importance of antigenic heterogeneity in solid tumors in the context of tumor escape. Participants will also be able to identify a strategy to reducing the problem of antigen escape and tumor recurrence through the implementation of bicistronic CARs.
EXTH-24. FILAMENTOUS PHAGE AS A NANOTHERANOSTIC FOR THE DETECTION, IMAGING, AND TREATMENT OF GLIOMAS
Authors: Lam Fred , Tsedev Uyanga , Belcher Angela
Published: November 2022

Current standard of care treatment for gliomas includes maximal safe surgical resection followed by concurrent chemoradiation, however, the diffuse infiltrative nature of gliomas present certain challenges for neurosurgeons to clearly visualize tumor tissue under conventional white light during microsurgical resection. Fluorescence-guided surgical techniques have been recently introduced to help surgeons better visualize tumor tissue under the operating microscope. Fluorescent dyes conjugated to nanoscale materials that are functionalized with glioma-targeting peptide sequences, such as the 39 amino acid chlorotoxin (CTX) peptide sequence, have demonstrated clinical efficacy in recognizing microscopic tumor cells during surgeries. M13 bacteriophage (phage) are versatile, genetically tunable nanocarriers that have been recently adapted for use as theranostic platforms. Applying p3 capsid CTX fusion with a unique “inho” circular single-stranded DNA (cssDNA) gene packaging system, we produced miniature CTX inho (CTX-inho phage particles with a minimum length of 50 nm that can target intracranial orthotopic patient-derived glioblastoma tumors in the brains of mice. Systemically-administered indocyanine green-conjugated CTX-inho phage accumulated in brain tumors, facilitating short-wave infrared detection. Furthermore, we show that our inho phage can carry cssDNA that are transcriptionally active when delivered to GBM22 glioma cells in vitro. The ability to modulate the capsid display, surface loading, phage length, and cssDNA gene content makes the recombinant M13 phage particle an ideal nanotheranostic platform for neuro-oncological applications.
EXTH-25. EXPLOITING EPIGENETIC DYSREGULATION IN ISOCITRATE DEHYDROGENASE MUTANT GLIOMA VIA THE USE OF HISTONE DEACETYLASE INHIBITORS
Authors: Sears Thomas , Drumm Michael , Piunti Andrea , Horbinski Craig
Published: November 2022

Isocitrate dehydrogenase 1/2 mutations (IDHmut) define a unique subtype of glioma that exhibits profound epigenetic dysregulation through DNA and histone hypermethylation. Though IDHmutgliomas are less aggressive than their IDH wildtype (IDHwt) counterparts, these tumors are still incurable and are invariably fatal. New treatments are therefore needed. Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets already used in the clinic to treat other malignancies, but their potential against gliomas, specifically IDHmutgliomas, have not been extensively studied. We previously showed that IDHwt gliomas are more sensitive than IDHwt gliomas to the cytotoxic and antiproliferative effects mediated by the FDA-approved HDAC inhibitor panobinostat, and that this sensitivity was associated with a greater increase in histone acetylation in IDHmut glioma cultures. Follow-up RNA-Seq showed that panobinostat more greatly affected gene expression in IDHmut glioma cells, with 1999 significant differentially expressed genes showing a 10% or greater change in gene expression in IDHmut cells compared to 388 genes for IDHwt counterparts. This included the known HDAC target and cell-cycle inhibitor CDKN1A, with panobinostat causing a 1.9-fold greater upregulation of CDKN1A in IDHmut cells than IDHwt cells (p= 0.045). In immunocompromised mice intracranially engrafted with IDHmut or IDHwt glioma, 15 mg/kg intraperitoneally-administered panobinostat was detectable after 6 hours within the intracerebral tumors via mass spectrometry at a concentration of 52.4 ng/g (150.1 nM), and extended the survival of IDHmut glioma-engrafted mice (Median: 4 days; Mean: 9.4 days), but not IDHwt glioma-engrafted mice (IDHmut: logrank p= 0.044; IDHwt: logrank p= 0.18). These results suggest that HDAC inhibition via panobinostat may be an effective therapy to treat IDHmutglioma patients. Ongoing studies, including ChIP-Seq, will determine specific sites of histone acetylation and HDACs that are responsible for the greater sensitivity of IDHmut gliomas to HDAC inhibition.
EXTH-28. INTRATUMORAL HETEROGENEITY OF THERAPEUTIC VULNERABILITIES ACROSS ENHANCING AND NON-ENHANCING TUMOR COMPONENTS OF GLIOBLASTOMA: A PARADIGM-SHIFTING PERSONALIZED MEDICINE APPROACH
Authors: Lin Wan-Hsin , Moniz-Garcia Diogo , Feathers Ryan , Brooks Mieu , Middlebrooks Erik , Kinsella Lindsey , Chaichana Kaisorn , Quiñones-Hinojosa Alfredo , Anastasiadis Panos
Published: November 2022

Glioblastoma (GBM) is the most aggressive adult brain tumor with no effective therapy. Despite advances on its molecular characterization, targeted therapeutics remain out of reach. This lack-of-progress is largely attributed to molecular and spatial heterogeneity and absence of clinically applicable models to guide patient care. Moreover, as standard surgical resection is aimed at contrast-enhancing (CE) tumor, the molecular landscape and treatment response of the remaining non-contrast enhancing (nCE) component is largely unknown despite its active role in tumor progression and local recurrence. Here, we aimed to identify the functional impact of tumor heterogeneity and to explore therapeutic vulnerabilities of both CE and nCE components. Four tumor regions (two CE and two nCE) from each of five GBM patients were collected under neuronavigation. The resulting tissue was subjected to generation of 3D tumor models (a brain tumor initiating-enriched cell line and a spheroid-based mcancer model) with comparable success in both CE and nCE samples. A panel of 25 brain penetrant drugs (alone and in combination) targeting GBM drivers (i.e. RTK/Ras/PI3K, RB/cell cycle, p53/apoptosis, DNA damage repair, transcription addiction) was developed and used to test for therapeutic vulnerabilities. From each tumor region, 4.5 ± 3.7 (average ± SD) different targeting strategies were identified exhibiting at least 70% growth inhibition at Cmax. Drug response heterogeneity was relatively rare, varied among cases, and was independent of tumor enhancement status. To our knowledge, this is the first study to systemically assess treatment response from both CE and nCE patient-derived GBM models. Ongoing studies include comprehensive genome and transcriptome profiling and pathway analysis from these different tumor regions. We postulate that interrogation of molecular landscapes and vulnerability profiles of both CE and nCE tumor regions, will enable us to personalize and prioritize effective targeted interventions for GBM treatment.