bluuebunny/crossref_metadata_2025 huggingface dataset:
COVD-02. ADAPTING RNA-NANOPARTICLE VACCINES FROM GLIOBLASTOMA TO SARS-COV-2
Authors: Mendez-Gomez Hector , Castillo Paul , Jones Noah , Qdaisat Sadeem , Weidert Frances , Mitchell Duane , Sayour Elias
Published: December 2020

BACKGROUND

Glioblastoma (GBM) can be an effective teacher in the war on COVID-19, as an operative vaccine for either must elicit near-immediate protective responses that overcomes disease heterogeneity and immune suppression. Current prophylactic strategies against COVID-19 utilize mRNA vaccines targeting small fragments of the SARS-CoV-2 genome, but these may not induce robust T cell responses or elicit immunity quickly enough.

OBJECTIVE

We sought to adapt an FDA-IND approved mRNA vaccine in GBM against COVID-19 for: 1) activation of near immediate immune responses, 2) targeting of full-length SARS-CoV-2 structural proteins, and 3) induction of bidirectional (B and T cell) adaptive immunity.

METHODS

We utilized a novel engineering design that layers mRNA into a lipid-nanoparticle (NP) shell (much like an onion); this allows greater packaging of mRNA per particle to quickly boost innate/adaptive immune responses against full-length glioblastoma antigens or SARS-CoV-2 structural proteins.

RESULTS

In small and large animal models, RNA-NPs safely mimic viremia activating the quiescent immune system in only a few hours for induction of protective immunity against its mRNA payload. RNA-NPs activate dendritic cells (DCs), upregulate critical innate gene signatures, and induce antigen-specific cellular and humoral immunity. We found that mice receiving SARS-CoV-2 spike RNA-NPs had more effector T cells after vaccination with significant memory recall expansion after in vitro re-stimulation with overlapping SARS-CoV-2 spike peptide mix. We also found increased release of MIP-1-alpha (i.e. CCL3) previously shown by our group (Mitchell et al. Nature 2015) to be responsible for Th1 mediated memory recall to infectious vaccine antigens in GBM patients.

CONCLUSION

SARS-CoV-2 RNA-NPs elicit memory recall response after vaccination. We have obtained FDA-IND approval (BB-19304, Sayour) in GBM with SARS-CoV-2 specific amendment (BB-20871) underway to support first-in-human trials of RNA-NPs targeting both GBM and COVID-19.
COVD-11. THE BRAIN TUMOR AND NOT FOR PROFIT AND CHARITY EXPERIENCE OF COVID 19: REACTING AND ADJUSTING TO AN UNPRECEDENTED GLOBAL PANDEMIC IN THE 21ST CENTURY
Authors: Ellen Maher Mary , Amidei Christina , Arzbaecher Jean , Oliver Kathy , Mungoshi Christine , Cashman Rosemary , Farrimond Stuart , Kruchko Carol , Granero Anita , Tse Chris , Daniels Maureen , Lovely Mary , Payne Sally , Lamb Sharon , Baker Jenifer
Published: December 2020

The COVID-19 pandemic has not only affected individuals, but also disease specific not-for-profits and charities. Brain tumor not-for-profit and charitable organizations around the world exist in all shapes and sizes, and address unmet needs of the patients and caregivers they serve. The International Brain Tumor Alliance(IBTA) carried out an international survey to identify organization changes brought about by the virus and the approaches adopted to address operational challenges created by COVID-19. A 37-question survey was sent across the world. In total, 77 organizations from 22 countries responded. Descriptive statistics and content analysis were used to present RESULTS: Responses fell into three categories: 1) organizational characteristics, 2) the impact of COVID-19 on services, and 3) how COVID-19 has affected the financial and human resources in these organizations. Although organizational characteristics vary widely, common concerns reported across organizations were primarily: a) the disruption of activities which impacted organizations’ abilities to offer their usual services and b) challenges to sustaining funding. Although brain tumor organizations have been impacted by the COVID-19 pandemic, organizations quickly adjusted to this unprecedented global healthcare crisis.
COVD-17. TUMOR TREATING FIELDS FOR GLIOBLASTOMA THERAPY DURING THE COVID-19 PANDEMIC: EXPERT CONSENSUS ON USE AND EXPERIENCE
Authors: Tosha Gatson Na , Barnholtz-Sloan Jill S , Drappatz Jan , Henriksson Roger , Hottinger Andreas , Hinoul Piet , Kruchko Carol , Puduvalli Vinay , Tran David , Wong Eric , Glas Martin
Published: December 2020

BACKGROUND

The COVID-19 pandemic has placed excessive strain on health care systems and this is especially evident in treatment decision-making for cancer patients. Glioblastoma (GBM) patients are among the most vulnerable due to increased incidence in the elderly (median age 64 years, peak between 75–84 years) and the short survival time. A virtual meeting was convened on May 9, 2020 with a panel of international neuro-oncology experts with hands-on experience using Tumor Treating Fields (TTFields). The objective was to assess the risk-to-benefit and to provide guidance for using TTFields in GBM during the COVID-19 pandemic.

PANEL DISCUSSION

Topics discussed included support and delivery of TTFields during the COVID-19 pandemic, concomitant use of TTFields with chemotherapy, and any potential impact of TTFields on the immune system in an intrinsically immunosuppressed GBM population. Special consideration was given to TTFields’ use in elderly patients and in combination with radiotherapy regimens (standard versus hypo-fractionated). Finally, we discussed the need to better capture COVID-19 positive brain tumor patients to analyze longitudinal outcomes and subtle changes in treatment decision-making during the pandemic.

EXPERT CONSENSUS

TTFields is a portable home-use device which can be managed via telemedicine and safely used in GBM patients during the COVID-19 pandemic. TTFields has no known immunosuppressive effects and is a reliable treatment modality with a relatively favorable side-effect profile. This is important during a crisis where other treatment methods might be limited, especially for elderly patients and patients with multiple co-morbidities. It is too early to estimate the full impact of COVID-19 on the global healthcare system and on patient outcomes and strongly recommended the need to collaborate with existing cancer COVID-19 registries (i.e. CCC19, ESMO-CoCARE, etc.) to follow CNS tumor patients. These efforts would have implications in assessing lessons-learned from this crisis and future guideline development.
COVD-18. POTENTIAL TO HARNESS SARS-COV-2 NEUROTROPISM IN THE DELIVERY OF ONCOLYTIC VIROTHERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMA
Authors: Immidisetti Amanda , Munier Sean , Patel Nitesh
Published: December 2020

BACKGROUND

High-grade gliomas (HGG) pose therapeutic challenges stemming from blood brain barrier, infiltrative growth, suppressed immune function, and tumor heterogeneity. Oncolytic viruses (OVs) are gaining traction for addressing these challenges. There is evidence that the SARS-CoV-2 glycoprotein spike binds the ACE-2 receptor in nasal epithelium and reaches the brainstem and thalamus via axonal transport through the olfactory pathway, making it an attractive candidate for OV therapy. Prior studies on chimerization of pathogenic virus-derived glycoprotein spikes with non-pathogenic strains exploit neurotropism of a wild-type virus while improving the safety profile of the resulting OV. We review, 1) the engineering of chimeric OVs used in the treatment of HGG; 2) potential for a novel chimeric virotherapy in which the SARS-CoV-2 glycoprotein spike can be used to deliver OV therapy intranasally; and 3) areas which warrant further investigation to develop this approach for clinical use.

METHODS

We performed an extensive review of chimeric OVs and specific modifications engineered to optimize safety and efficacy. Additionally, we assessed potential to use these principals to engineer the SARS-CoV-2 glycoprotein spike onto a non-pathogenic, replication competent virus to yield a novel chimeric for noninvasive, intranasal delivery.

RESULTS

Viruses with pathogenic properties in wild-type have been successfully used as components of OVs and have demonstrated potential in both preclinical and clinical trials. Outcomes show that despite wild-type virulence, notable toxicities were not observed in clinical trials, highlighting the potential of viral pseudotyping as a safe therapeutic approach.

CONCLUSIONS

The proposed method to utilize the SARS-CoV-2 glycoprotein in a novel chimeric poses advantages including 1) potential for non-invasive delivery, 2) therapy without need for maximal or uniform tumor coverage due to replication competence, 3) ability to reach infiltrative glioma cells, 4) potential to reach the brainstem, and 5) stimulation of host immunity through tumor cell lysis and antigen presentation
COVD-20. COVID-19 INFECTION DURING CHEMOTHERAPY FOR MALIGNANT GLIOMA: OUTCOMES AMONG 3 PATIENTS
Authors: Kim Esther , Koshy Amily , Higgins Shannon , Lassman Andrew , Iwamoto Fabio
Published: December 2020

BACKGROUND

Chemotherapy may increase risk of SARS-COV-2 infection and COVID-19 severity.

METHODS

A patient developed COVID-19 during chemotherapy for glioma. We retrospectively identified others diagnosed with COVID-19 during temozolomide or lomustine for glioma.

RESULTS

(1) A 64 year-old woman (index patient) with anaplastic oligodendroglioma received PCV 22 months previously. Baseline White Blood Cell (WBC) count was 4.2 and Absolute Neutrophil Count (ANC) was 2.7 K/uL. KPS was 90 without comorbidities. For recurrence she initiated temozolomide but developed fever on cycle 1 day 2. SARS-COV-2 PCR was positive. Further temozolomide was held. She is recovering as an outpatient. (2) A 27 year-old man with anaplastic astrocytoma received concurrent RT/temozolomide then 1 cycle of adjuvant temozolomide. Baseline WBC was 8.3, ANC 5.2, and KPS 90. Obesity, asthma, and pre-diabetes were comorbidities. Hyposmia/hypogeusia and low-grade fever began, in retrospect, during concurrent RT/temozolomide. PCR for SARS-COV-2 was negative 2 months after symptom onset; serology detected both IgG and IgM when WBC was 6.6 and ANC 4.0. Cycle 2 of adjuvant temozolomide was held until fever resolved (spontaneously); hyposmia/hypogeusia persist. (3) A 53 year-old man with glioblastoma previously received RT/temozolomide, then lomustine and bevacizumab for progression. WBC was 5.1, ANC 4.0, and KPS 60. He was obese. Fever, chills, and dyspnea developed on lomustine cycle 2 day 38. SARS-COV-2 PCR was positive. He was hospitalized and chemotherapy held; symptoms resolved 12 days after onset, but PCR continued to show detectable virus 32 days later. PCR became negative after 50 days total, and treatment resumed uneventfully.

DISCUSSION

All 3 patients recovered from SARS-COV-2 infection despite active temozolomide or lomustine chemotherapy. Normal ANC, high KPS, and early detection may have contributed to limited symptom severity and duration, despite obesity and other comorbidities in 2 cases. Detection changed management by delaying additional cycles of immunosuppressive chemotherapy until recovery.
COVD-25. THE PARADOXICAL EFFECTS OF COVID-19 ON CANCER CARE IN THE NEURO-ONCOLOGY SETTING
Authors: Cort Nicole , Broom Alex , Kenny Katherine , Page Alexander , Durling Jennifer , Brown Casey , Lipp Eric , Ashley David , Walsh Kyle , Johnson Margaret , Khasraw Mustafa
Published: December 2020

COVID-19 has caused ongoing interruptions to healthcare systems worldwide, shifting care to virtual platforms, and placing significant economic and logistical burdens on clinical practice. The pandemic has created uncertainty in delivering the standard of care, both in areas of cancer diagnosis and treatment, especially within neuro-oncology. Due to the pandemic, care and operational planning goals have shifted to infection prevention, modifying recommendations to decrease viral transmission and increasing telemedicine use, potentially creating a burden on implementing evidence-based medicine. These dynamics have since begun to redefine traditional practice and research regimens, impacting the comprehensive care that cancer patients can and should receive; and the enduring consequences for the delivery of healthcare. The impact of COVID-19 on oncology practice and trials might endure well beyond the short- to mid-term of the active pandemic. Therefore, these shifts must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care. To address these paradoxical effects, we will conduct iterative, qualitative (face-to-face/video conference) interviews with neuro-oncology clinical and research professionals and adult brain tumor patients receiving care during the pandemic. We will capture unique aspects of oncology care: the lived, subjective, situated, and contingent accounts of patients and medical professionals, especially during a pandemic. We will also specifically compare the impact of telehealth during the pandemic on delivery of care to complex neuro-oncology patients. A summary of this in-depth, qualitative approach will result in a sophisticated understanding of neuro-oncology care on the frontline at a time of crisis, as experienced during a pandemic, to articulate best practices for future implementation.
COVD-27. THE COVID-19 PANDEMIC AND NEURO-ONCOLOGICAL PATIENTS
Authors: Norman Sofya , Juthani Rupa
Published: December 2020

INTRODUCTION

The Coronavirus disease 2019 (COVID-19) pandemic has uprooted healthcare systems worldwide, disrupting care and increasing dependence on alternative forms of health care delivery. It is yet to be determined how the pandemic affected neuro-oncology patient outcomes, given that the majority of even “elective” neurosurgical oncology procedures are time-sensitive. This study quantifies changes in neuro-oncological care during the height of the pandemic in New York City and investigates patient outcomes in 2020 compared to a historical control.

METHODS

We performed a retrospective review of patients with brain tumor diagnoses (primary or secondary) who were seen at the Weill Cornell Brain and Spine Center between March 13, 2020 and May 1, 2020. A control cohort from the corresponding time period in 2019 was also reviewed. Alterations in care, including shift from in-person to telehealth, delays in evaluation and intervention, and treatment modifications were evaluated. These variables were analyzed with respect to brain tumor control and mortality.

RESULTS

114 patients from 2020 and 171 patients from 2019 were included, with no significant difference in baseline demographics between the groups. There was no significant difference in outcomes between the cohorts, despite significantly more treatment delays (p= 0.0154) and use of telehealth (p< 0.0001) in 2020. For patients treated during the pandemic in 2020, patients who experienced delays in care did not suffer from worse outcomes compared to those without delays. Patients who utilized telehealth visits had significantly more stable tumor control (P = 0.0027), consistent with appropriate use of in-person visits for patients with progression.

CONCLUSION

Our study showed that use of telehealth and selective alterations in neuro-oncological care during the COVID-19 pandemic did not lead to adverse patient outcomes. This suggests that adaptive physician-led changes during the pandemic were successful and effective. Further studies are needed to evaluate impact on long-term survival.
COVD-28. IMPACT OF COVID-19 IN CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN ARGENTINA. REPORT FROM THE NATIONAL PEDIATRIC CANCER REGISTRY, ROHA NETWORK
Authors: Baroni Lorena , Chaplin Agustina , Alderete Daniel , Fraqueli Lidia , Gallardo Patricia , Moreno Florencia
Published: December 2020

Introduction: The true impact of COVID-19 infection on children undergoing cancer treatment is unknown. At the present time, data on the clinical spectrum and outcome of children with cancer and concurrent COVID-19 are limited, and further data are awaited. Monitor the incidence and survival across this pandemic is critical to understanding the extent to which this occur and to prepare contingency plans. Results: Ninety-seven pediatric patients with cancer and COVID-19 infection have been identified by the Argentinian Oncopediatric Register since April 2020. Sixteen of them had diagnosis of CNS tumor (female=7, male=9); 5 Medulloblastoma, 3 DIPG, 2 GBM, 2 LGG, 2 anaplastic ependymoma, 1 anaplastic ganglioglioma and 1 germinoma. Most frequent aged was between 1–4 years old (6 patients), followed by 15 to 19 (4p), 5–9 (3p) and 10–14 (3p). Most patients were asymptomatic (9p) and the screening was performed regarding a virus exposed (5p), previous to a procedure with anesthesia (2p) and previous a mandatory travel (2p). The most frequent symptom was isolated fever (6p); only 1 patient presented fever with others symptoms. None received specific treatment for COVID infection. No death related to COVID-19 infection was found; 1 patient with metastatic medulloblastoma and COVID-19 infection passed away due to a rapidly tumor progression. Conclusion: Although COVID-19 infection is a new challenging in the management of pediatric brain tumor patients, our experience showed a relative indolent course in this specific population.
COVD-31. THE STATE OF NEURO-ONCOLOGY DURING THE COVID-19 PANDEMIC: A WORLDWIDE ASSESSMENT
Authors: Mrugala Maciej , Ostrom Quinn , Pressley Shelley , Thomas Alissa , Wefel Jeffrey S , Coven Scott , Acquaye Alvina , Haynes Chas , Agnihotri Sameer , Lim Michael , Peters Katherine , Butowski Nicholas , Hervey-Jumper Shawn , Porter Alyx , Oliver Kathy , Dunbar Erin , Taylor Jennie , Schiff David , Nassiri Farshad , Hegi Monika , Armstrong Terri , van den Bent Martin , Chang Susan , Zadeh Gelareh , Chheda Milan
Published: December 2020

To assess the impact of the pandemic on the field, we performed an international web-based survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents from April 24 through May 17. Of 582 respondents, 258 (45%) were in the US, and 314 (55%) were international. 80.4% were affiliated with academic institutions. 94% respondents reported changes in clinical practice; 95% reported conversion to telemedicine for at least some appointments. However, almost 10% practitioners felt the need to see patients in person specifically because of billing concerns and perceived institutional pressure. Over 50% believed neuro-oncology patients were at increased risk of contracting COVID-19. 67% practitioners suspended enrollment for at least one clinical trial: 53% suspended phase II and 62% suspended phase III trial enrollment. 71% clinicians feared for their or their families’ safety, specifically because of their clinical duties. 20% percent said they did not have enough PPE to work safely; about the same percentage were unhappy with their institutions’ response to the pandemic. 43% believed the pandemic would negatively affect their academic career, and 52% fellowship program directors were worried about losing funding for their training programs. While 69% respondents reported increased stress, 44% were offered no psychosocial support. 37% had their salary reduced. 36% researchers had to temporarily close their laboratories. In contrast, the pandemic created positive changes in perceived patient and family satisfaction, quality of communication, and use of technology to deliver care and interactions with other practitioners. CONCLUSIONS: The pandemic has altered standard treatment schedules and limited investigational treatment options for patients. In some cases, clinicians felt institutional pressure to continue conducting billable in-person visits when telemedicine visits would have sufficed. A lack of institutional support created anxiety among clinicians and researchers. We make specific recommendations to guide clinical and scientific infrastructure moving forward.
CSIG-02. R-RAS SUBFAMILY PROTEINS ELICIT DISTINCT PHYSIOLOGIC EFFECTS AND PHOSPHOPROTEOME ALTERATIONS IN NEUROFIBROMIN-NULL MPNST CELLS
Authors: Weber Shannon , Brossier Nicole , Prechtl Amanda , Brosius Stephanie , Barnes Stephen , Wilson Landon , Carroll Steven
Published: December 2020

Loss of the Ras GTPase-activating protein neurofibromin promotes the development of aggressive spindle cell neoplasms known as Malignant Peripheral Nerve Sheath Tumors (MPNSTs) in patients with the genetic disorder neurofibromatosis type 1 (NF1). Currently, the available chemotherapeutic regimens and radiotherapy are ineffective against MPNSTs, so the prognosis for patients with these neoplasms is poor. Neurofibromin loss dysregulates multiple Ras proteins in the classic (H-Ras, N-Ras, K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, R-Ras3/M-Ras) subfamilies. Consequently, it is unclear which Ras proteins or pathways regulated by these Ras proteins should be therapeutically targeted in MPNSTs. We have previously shown that classic Ras proteins drive MPNST cell proliferation and survival. However, the role(s) of the R-Ras subfamily of proteins in MPNSTs have not been elucidated. To determine how R-Ras proteins contribute to the pathogenesis of neurofibromin-null MPNSTs, we introduced dominant negative (DN) R-Ras mutants, which are pan-inhibitors of the R-Ras subfamily, into MPNST cells and assessed the impact of R-Ras subfamily inhibition on mitogenesis, migration and the phosphoproteome. A panel of MPNST cell lines (STS-26T, YST-1, ST88-14, 90–8, NMS2, NMS-PC, S462, T265-2c) was used. Methodologies utilized include immunoblotting, PCR, Transwell migration, 3H-thymidine incorporation, and mass spectrometric analysis of phosphoprotein-enriched specimens. We found that R-Ras and R-Ras2 are widely expressed and can be activated in neurofibromin-null MPNST cells. In contrast to classic Ras proteins, we found that R-Ras proteins drive MPNST both mitogenesis and migration. Using mass spectrometry-based phosphoproteomics, we identified thirteen protein networks that were regulated by DN R-Ras, including networks affecting cellular movement via effects on microtubules. We chose to further study changes in ROCK1 phosphorylation and found that R-Ras subfamily proteins function, at least in some part, through the same pathways as ROCK1. We conclude that R-Ras proteins promote tumorigenesis by regulating distinct signaling pathways that regulate MPNST mitogenesis and migration.
CSIG-03. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH
Authors: Alvarado Alvaro , Tessema Kaleab , Patel Kunal , Kawaguchi Riki , Everson Richard , Ellingson Benjamin , Swarup Vivek , Goldman Steven , Kornblum Harley
Published: December 2020

Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM – both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be compared to other samples by generating sample clusters based on overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported and clusters were informative of patient survival. We also analyzed single cell RNA sequencing datasets and uniformly found two clusters of cells enriched for cell cycle regulation and survival pathways. We have validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity when E2F1, out top target, was silenced and when treated with fulvestrant and calcitriol, which were identified as potential drugs targeting this genelist. Conversely, no changes were observed in samples not enriched for this gene list. Finally, we interrogated spatial heterogeneity and found higher enrichment of the proliferative signature in contrast enhancing compared with non-enhancing regions. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.
CSIG-05. S6K FEEDBACK REGULATION OF THE RECEPTOR TYROSINE KINASE AXL IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Sarma Pranjal , Ennis Kelli N , Wetzel Collin , Plas David R
Published: December 2020

Glioblastoma multiforme (GBM), the most aggressive type of malignant brain cancer in adults, harbors frequent mutations and/or deletions in the tumor suppressor gene PTEN leading to therapeutic resistance. In PTEN-deficient GBM, mTOR complex 1 (mTORC1) and the S6 kinases (S6Ks) mediate increased metabolism and apoptosis resistance. Previously we established that combining the LY-2584702 inhibitor of S6K1 with the BMS-777607 inhibitor of the AXL receptor tyrosine kinase (RTK) was selectively cytotoxic for PTEN-deficient GBM. Here we determined the impact of these inhibitors on S6K1 and S6K2 signal transduction and tumor cell metabolism. While combination of LY-2584702 with BMS-777607 was sufficient to prevent S6K phosphorylation of ribosomal protein S6 (rpS6), treatment with either drug as a single agent was not sufficient to suppress rpS6 phosphorylation. Genetic inactivation of S6Ks revealed that inactivation of S6K2 cooperated with LY-2584702 to prevent S6K substrate phosphorylation. Similarly, persistent S6K signaling in BMS777607-treated GBM cells was significantly reduced when S6K2 was targeted. These results indicate that S6K2 integrates signal transduction inputs from both PTEN-regulated and AXL-regulated pathways. Metabolomic analysis revealed combination effects of S6K and AXL inhibitors in reducing nucleotide precursor metabolic flux. We therefore propose that combination inhibition of S6K and AXL signaling compromises S6K-dependent nucleotide synthesis in PTEN-deficient GBM.
CSIG-07. c-Src PHOSPHORYLATES AND INACTIVATES THE CIC TUMOR SUPPRESSOR PROTEIN IN GLIOBLASTOMA
Authors: Bunda Severa , Heir Pardeep , Li Annie , Yasin Mamatjan , Zadeh Gelareh , Aldape Kenneth
Published: December 2020

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/MEK/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degradation of CIC in glioblastoma (GBM). In this study, we examined whether another important downstream effector of RTK/EGFR, the non-receptor tyrosine kinase c-Src, affects CIC repressor function in GBM. We found that c-Src binds and tyrosine phosphorylates CIC on residue 1455 to promote nuclear export of CIC. On the other hand, CIC mutant allele (CIC-Y1455F), that escapes c-Src-mediated tyrosine phosphorylation, remains localized to the nucleus and retains strong repressor function against CIC targets, the oncogenic ETV transcription factors. Furthermore, we show that the orally available Src family kinase inhibitor, dasatinib, which prevents EGF-mediated tyrosine phosphorylation of CIC and attenuates elevated ETV levels, reduces viability of GBM cells and glioma stem cells (GSC), but not of their control cells with undetectable c-Src activity. In fact, GBM cells and GSC expressing the tyrosine-defective CIC mutant (Y1455F) lose sensitivity to dasatinib, further endorsing the effect of dasatinib on Src-mediated tyrosine phosphorylation of CIC. Importantly we show that combined inhibition of Src and MEK/ERK results in greatest stabilization of CIC and attenuation of proliferation compared to either inhibitor alone. These findings elucidate important mechanisms of CIC regulation and provide the rationale to target c-Src alongside ERK pathway inhibitors as a way to fully restore CIC tumor suppressor function in neoplasms such as GBM.
CSIG-08. TARGETING ION TRANSPORT-REGULATORY KINASES AS A NOVEL TREATMENT FOR GLIOBLASTOMA
Authors: Schiapparelli Paula , Meade Paola Suarez , Miranda-Herrera Pierre , Bechtle Alexandra R , Issacs Farren , Levchenko Andre , Rinehart Jesse , Quinones-Hinojosa Alfredo
Published: December 2020

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Currently, treatment is focused on achieving maximal safe resection, followed by chemo- and radiotherapy. Although surgery remains the most important therapeutic component, complete surgical resection is virtually impossible, as GBM cells readily infiltrate the adjacent brain parenchyma. One fundamental mechanism for GBM cell migration is the ability of these cells to use cell volume regulation as a driving force of cell infiltration and potentially interfering with apoptosis and cell cycle progression. In this work, we targeted the master regulators of cell volume, the kinases STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and Oxidative stress-responsive kinase-1) (OSR1) by using a novel proprietary small molecule inhibitor. In order to study the effects of inhibiting SPAK and OSR1, we analyzed cell proliferation and migration. First, we determined the IC50 using six different patient-derived GBM cell lines; we found IC50 values ranging from 0.2–2μM. Next, cell proliferation was determined by cell cycle analysis through Edu labeling. We found a significant decrease in S phase and cell cycle arrest in G2M (p= 0.001, n=6). In addition, cell migration was determined using boyden chamber assay. We found a dose-dependent reduction in cell migration (p=0.001, n=3). These results correlated with the phenomenon observed in an orthotopic murine model of GBM, in which the inhibitor showed a decrease in tumor growth (p=0.0026, n=4) and greater survival rates in vivo (p=0.0046, n=8). When used in combination with radiation therapy, this small molecule inhibitor was capable of radio-sensitizing GBM cells decreasing clonogenicity (p=0.01, n=3) were observed in vitro. In summary, by targeting the SPAK/OSR1 kinases with a small molecule inhibitor, GBM cells become less aggressive, mainly by interfering with cell migration and proliferation and becoming more sensitive to radiation.
CSIG-09. ATRX DEFICIENCY IN GLIOMA IMPACTS TRANSCRIPTIONAL PROFILES AND THE IMMUNE MICROENVIRONMENT IN VIVO
Authors: Irvin David , Roberts Hannah , Sharin Vladislav , Farooqi Ahsan , Dharmaiah Sharvari , Alvarez Christian , Huse Jason
Published: December 2020

Current treatment for diffuse astrocytoma fails to address its underlying molecular mechanisms leading to inevitable disease progression and eventual patient death. Genomic studies have implicated ATRX alterations as critical to low grade glioma biology. Our lab has previously shown in vitro that ATRX influences glioma motility, cellular differentiation state, and epigenetic programming, however, the influence of ATRX alterations in vivo remains unclear. Here, we leveraged an RCAS/tva mouse tumor model to probe the role of ATRX deficiency in glioma. Atrx deficient murine tumors exhibited lower histopathological grade and were associated with longer survival than Atrx-intact counterparts, and syngeneic allografts of cell lines derived from primary tumors mirrored the differential degrees of aggressiveness seen in primary tumors. Tumor-derived Atrx-deficient cell lines showed increased susceptibility to G-quadruplex stabilizing compounds, pointing to increased replication stress and recapitulating a key phenotype of ATRX-mutant gliomas in humans. Transcriptional profiling revealed enrichments in MYC target genes, E2F targets as well as G2/M checkpoint pathways in Atrx-intact tumors and cells, and enrichment in RAS signaling in Atrx-deficient tumors and cells. Finally, Atrx deficient murine gliomas displayed increased levels of NK cells, a phenotype recapitulated in ATRX-mutant human gliomas, and primary Atrx-deficient glioma lines exhibited increased levels of NK cell-attracting cytokines. These latter findings suggest that ATRX deficiency could influence interactions between glioma cells and their immune microenvironment by way of phenotypically relevant molecular mechanisms.
CSIG-10. GENOTYPE – KINOME GUIDED DEVELOPMENT OF PRECISION EGFR-TARGETED THERAPEUTICS FOR GLIOBLASTOMA
Authors: Smithberger Erin , Shelton Abigail , Butler Madison , Stamper Allie , Bash Ryan , Angus Steven , East Michael , Johnson Gary , Berens Michael , Furnari Frank , Miller C Ryan
Published: December 2020

Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival and limited treatment options. However, it is an attractive candidate for precision therapeutic approaches due to the frequency of amplification and/or activating mutations in the epidermal growth factor receptor (EGFR) gene and the availability of several brain penetrant second- and third-generation EGFR tyrosine kinase inhibitors (TKI). We used comprehensive molecular profiling of a panel of genetically engineered mouse astrocyte models to examine whether mutational profiles, particularly EGFR and PTEN status, could be used to identify kinases upregulated in specific mutational backgrounds. Using RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the kinase transcriptomes and proteomes, respectively, we have identified several potential targets for combination therapy. Overexpression of wild type EGFR in immortalized, Cdkn2a-/- astrocytes resulted in mild rewiring of the GBM kinome. Only 5 kinases aside from EGFR itself were overexpressed on either the transcript or protein levels. One overexpressed kinase, Hck, has been shown to be involved in cell survival, proliferation, adhesion, and migration. In contrast, overexpression of EGFRvIII, a constitutively active, extracellular domain truncation mutant of EGFR, resulted in significant alteration of the GBM kinome – 81 kinases showed differential expression, with 27 upregulated. One potentially attractive target among these was Cdk6, a drug-targetable, prognostically significant cyclin-dependent kinase implicated in proliferation, migration, and invasion. Finally, overexpression of EGFRvIII in cells lacking Pten dysregulated 46 kinases, including 15 upregulated. One particularly interesting target in these cells was Ddr2, a tyrosine kinase involved in migration, invasion, and extracellular matrix remodeling. We conclude that Hck, Cdk6, and Ddr2 represent attractive targets for therapeutic intervention in their relevant genetic contexts. These findings also suggest that molecular diagnostics for EGFR and PTEN status may be useful in guiding development of rational, EGFR TKI-centric drug combinations.
CSIG-12. HDACs-Sp1-BMI1 PATHWAY IS INVOLVED IN THE ATTENUATION OF STRESS- AND THERAPY-INDUCED DEATH IN GLIOMA
Authors: Lo Wei-Lun , Tsai Yu-Ting , Chuang Jian-Ying
Published: December 2020

BMI-1 is a transcriptional repressor and overexpresses in various human cancer tissues, which is also known to involve in the maintenance of “stem cell” features in a cell sub-population within the tumor. Here, we investigate the roles of BMI1 oncogene in brain tumors, notably involving drug-resistant metabolism. Interestingly, microarray datasets in OMCOMINE indicated that BMI1 is not commonly increased in clinical brain tumors, and survival plots in PROGgeneV2 also showed that BMI1 expression is not statistically associated with glioma patients. However, stressful serum starvation and anchorage independence growth conditions enabled to induce upregulation of BMI1. Further investigation, we identified HDAC-Sp1 is a stress-responsive pathway, critically promoting BMI1 expression. HDAC inhibition via vorinostat treatment prevented the binding of Sp1 to BMI1 promoter, leading to decreased BMI1 expression and attenuated tumor growth of TMZ-resistant glioma xenografts. Importantly, increased expression of the HDAC-Sp1-BMI1 axis but not BMI1 alone showed an increased risk of death in both high- and low-grade glioma. Thus, the HDAC-Sp1-BMI1 axis is critical to attenuate stress- and therapy-induced death in glioma cells and the axis inhibition may prevent the recurrence of malignant cells persisting after primary therapy.
CSIG-17. PRMT5 INHIBITION SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT
Authors: Otani Yoshihiro , Namagiri Sriya , Thammegowda Shilpa , Sur Hannah , Chowdhury Ashis , Lewis Cole , Shimizu Toshihiko , Lee Tae Jin , Maric Dragan , Yoo Ji Young , Heiss John , Kaur Balveen , Banasavadi-Siddegowda Yeshavanth Kumar
Published: December 2020

INTRODUCTION

Glioblastoma (GBM) is the most common malignant primary brain tumor. With limited effective therapeutic strategies, prognosis for GBM is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes anti-GBM effect through apoptosis and senescence of mature and immature tumor cells, respectively. In GBM, RAS-RAF- MEK-ERK signaling is aberrantly activated and promotes tumor growth. Therefore, MEK inhibitors, including trametinib are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-tumor efficacy of trametinib in GBM.

METHODS

Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively.

RESULTS

Trametinib treatment upregulated the expression of PRMT5 in GBMNS. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. In concurrence with the trametinib-induced PRMT5 upregulation, trametinib treatment increased the activity of AKT that was blocked with PRMT5 knockdown. In vivo, PRMT5-depletion extended the survival of the tumor bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit.

CONCLUSION

Trametinib treatment induces PRMT5 expression. Depletion of trametinib-induced PRMT5 expression sensitizes GBMNS for trametinib by inhibiting AKT activity.
CTIM-04. UPDATES FOR A PHASE 2 OPEN-LABELED STUDY OF PEMBROLIZUMAB PLUS TTFIELDS PLUS MAINTENANCE TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (2-THE-TOP)
Authors: Ghiaseddin Ashley , Warren Sonisha , Allen Annie , Sampson Deborah , Chen Dongjiang , Sherman Alexandra , Greene Valerie , Rahman Maryam , Tran David
Published: December 2020

INTRODUCTION

Tumor-treating fields (TTFields) are a new standard anti-mitotic treatment for newly diagnosed glioblastoma (ndGBM). Emerging data indicate that TTFields also stimulate innate immunity, leading to adaptive immunity. We hypothesize that immune checkpoint inhibitors synergize with TTFields to promote anti-tumor immunity in ndGBM.

METHODS

24 adult patients with ndGBM will be enrolled following radiotherapy with concurrent temozolomide. To identify TTFields-induced immune effects that are augmented by pembrolizumab, TTFields (200 kHz) is started with cycle 1 of maintenance TMZ while pembrolizumab (200mg Q3W) is added at cycle 2 and continued up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint is PFS vs. historical controls (JAMA, 318:2306–2316). Secondary endpoints include toxicity/tolerability and immune activation by TTFields before and after pembrolizumab as determined by single-cell analysis of peripheral blood mononuclear cells.

RESULTS

As of 06/19/2020, there are 17 evaluable patients. The median follow-up is 12.2 months from cycle 1 of maintenance TMZ. 10 (59%) patients are progression-free, and 13 (76%) are alive. Of 9 patients with follow-up > 12 months, the median PFS is at least 11.2 months vs. historical median PFS of TTFields plus maintenance TMZ of 6.7 months. The most common serious adverse events are pain, weakness, lymphatic swelling, and metabolic disturbances observed in 3 (18%), 2 (12%), 2 (12%), and 1 (6%) patients, respectively. In response to TTFields, we detect a 2.26 (p=0.01) and 5.2-fold (p=0.07) mean increase in the number of classical and plasmacytoid dendritic cells (DC), respectively. Network analysis shows wide-spread pathway upregulation in responders, especially type 1 interferon response genes in DC (FDR=0.02) and cytotoxicity genes in CD8 T cells (FDR=0.03).

CONCLUSIONS

Pembrolizumab in combination with TTFields plus maintenance TMZ is generally well tolerated in patients with ndGBM. Preliminary data demonstrates activation of adaptive immunity and improved efficacy and will be updated.
CTIM-05. COMBINATION OF CONTROLLED INTERLEUKIN-12 GENE THERAPY WITH IMMUNE CHECKPOINT BLOCKADE IN RECURRENT GLIOBLASTOMA: UPDATED RESULTS OF A MULTI-INSTITUTIONAL, OPEN LABEL PHASE 1 TRIAL
Authors: Antonio Chiocca E , Lukas Rimas , Chen Clark , Rao Ganesh , Amidei Christina , Buck Jill , Hadar Nira , Demars Nathan , Miao John , Estupinan Taylor , Loewy John , Wang Yunxia , Gelb Arnold , Cooper Laurence
Published: December 2020

A published clinical trial of veledimex (V)-regulatable interleukin-12 (IL-12) gene therapy (“Controlled IL-12”) under the control of a transcriptional switch (RheoSwitch Therapeutic Systemâ, RTSâ) as monotherapy in recurrent glioblastoma (rGBM) showed sustained infiltration of activated T cells within the tumor months after treatment (Sci Transl Med. 2019;11(505)). These T cells demonstrated up-regulation of immune checkpoint signaling, providing a rationale for combination therapy with the PD-1 inhibitor, nivolumab (nivo). We report interim findings following completion of enrollment (with follow-up ongoing) for a multi-institutional, open label, dose-escalation phase 1 trial (NCT03636477) evaluating safety and tolerability of loco-regional Controlled IL-12 in combination with nivo in adults with rGBM. Replication-incompetent adenovirus coding for RTS-IL-12 (Ad) was administered during surgery by free-hand injection into the tumor and periphery (2 x 1011 viral particles, Day 0) accompanied by V (10 or 20 mg) PO QD x 15 (Days 0 to 14) in combination with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Twenty-one subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n=3; Cohort 2: V 10 mg, nivo 3 mg/kg, n=3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n=3 & 12 in expansion). Safety data were comparable to Ad+V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with nivo labeling. ARs were manageable and generally reversible with no synergistic toxicities. Updated overall survival findings will be presented. Baseline and post-treatment histochemical staining and multiplex immunofluorescence analyses for a subgroup of subjects will be discussed. The safety of this combination immunotherapy has been established, leading to a currently accruing phase 2 clinical trial of loco-regional Controlled IL-12 gene therapy in combination with the PD-1 inhibitor cemiplimab-rwlc (NCT 04006119).
CTIM-09. DOUBLE-BLINDED, PLACEBO CONTROLLED PHASE 2 STUDY OF ERC1671 IN RECURRENT GLIOBLASTOMA: VACCINE OVERALL SURVIVAL IN BEVACIZUMAB NAIVE AND BEVACIZUMAB RESISTANT PATIENTS
Authors: Bota Daniela , Taylor Thomas , Kong Xiao-Tang , Fu Beverly , Hsu Frank , Strik Ankie , Schijns Virgil , Stathopoulos Apostolos
Published: December 2020

ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to determine the safety and effectiveness (overall survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 22 recurrent bevacizumab-naïve rGBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (33–74), 7 patients (32%) are female, and average KPS is 82.3 (70–100). Of the 22, two discontinued before completing one cycle of therapy and two remain on blinded treatment. Currently 18 patients are unblinded due to further progression: 8 were on vaccine and 10 on placebo. Five of those on placebo crossed to vaccine at progression. All but one of the 18 are now deceased. Median overall survival of unblinded patients randomized to ERC1671 + Bevacizumab (n = 8) is 264.5 days from the start of study treatment, compared to 182 days for those randomized to placebo + Bevacizumab who did not cross over (n = 5). Median overall survival of unblinded patients on vaccine at randomization or crossover is 328 days after first study treatment (n = 13). While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. This phase 2 randomized, double-blinded study is ongoing, with the addition of one more site.
CTIM-11. PHASE I/II STUDY TO EVALUATE THE SAFETY AND CLINICAL EFFICACY OF ATEZOLIZUMAB (ATEZO) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Weathers Shiao-Pei , Kamiya-Matsuoka Carlos , Harrison Rebecca , Liu Diane , Sanqui Edmund , Dervin Shannon , Yun Cindy , Loghin Monica , Penas-Prado Marta , Majd Nazanin , Yung W K Alfred , O’Brien Barbara , de Groot John
Published: December 2020

BACKGROUND

Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo (anti-PD-L1) with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status.

METHODS

Eligibility criteria included patients age > 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling tumor immune cell populations, peripheral blood for circulating chemokines/cytokines, and stool for gut microbiome.

RESULTS

60 patients were enrolled. With a median follow-up time of 17.1 months (data cutoff = 15 April 2020), 37 patients have progressed, of which 30 patients have died. Median OS was 19 months (95% CI: 14.9, not reached). Median PFS was 10.6 months (95% CI: 8.2–16.7). Median OS in MGMT methylated patients (n = 18) was 29.9 months (95% CI: 11.4, not reached) and 16.3 months (95% CI: 13.9, not reached) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade > 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 20 of the enrolled 60 patients underwent re-resection post atezo treatment. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending.

CONCLUSIONS

Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated efficacy in line with published trials for newly diagnosed GBM.