bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-47. PHASE II STUDY OF ABEMACICLIB IN RECURRENT GBM PATIENTS WITH CDKN2A/B LOSS AND INTACT RB
Authors: Lee Eudocia , Muzikansky Alona , Arrillaga-Romany Isabel , Chukwueke Ugonma , Cloughesy Timothy , Colman Howard , Daras Mariza , de Groot John , Mcfaline-Figueroa Jose , Nayak Lakshmi , Prins Robert , Reardon David , Taylor Jennie , Ligon Keith , Wen Patrick 
Published: December 2020

Abstract
Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in glioblastoma (GBM) with more than 80% of patients estimated to be affected. We conducted an open label, multi-center, phase II trial of abemaciclib in participants with recurrent glioblastoma (GBM) at their first relapse and with documented evidence of CDKN2A/B loss and intact RB from archival tissue. A total of 32 patients enrolled on the non-surgical arm of the study with 13 women (40.63%) and median KPS 90 [range 60–100]. The PFS6 rate was 9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days [95% CI, 228, 488]. Out of 31 evaluable patients, best response was PR 1 (3.2%), SD 11 (35.5%), and PD 19 (61.3%). The most common grade 3 or higher toxicities at least possibly related to abemaciclib included leukopenia (21.9%), neutropenia (18.6%), lymphopenia (9.4%), and thrombocytopenia (6.3%). Abemaciclib has minimal activity in this preselected recurrent GBM population. Correlative studies from the surgical arm of this study are pending.
CTNI-48. NOVEL TREATMENT OF END STAGE RECURRENT GLIOBLASTOMA TREATED WITH A NONINVASIVE ONCOMAGNETIC DEVICE USING OSCILLATING MAGNETIC FIELDS – A NEW AND POWERFUL NONINVASIVE THERAPY
Authors: Helekar Santosh , Sharpe Martyn , Pichumani Kumar , Ijare Omkar , Nguyen Lisa , Baskin David 
Published: December 2020

Abstract
Noninvasive treatment with alternating electric fields at 200 kHz (Optune therapy) has been approved for recurrent and newly diagnosed glioblastoma (GBM). We have recently tested and confirmed in vitro, and in patient derived xenografted mouse models, the oncolytic potential of powerful newly developed device generating oscillating magnetic fields (OMF) using rotating magnets. This device is completely different and has different mechanisms of action than Optune therapy. We report the successful treatment of an endstage recurrent GBM in a 53-year-old man. The patient had undergone radical surgical excision and standard of care chemoradiotherapy, as well as experimental gene therapy for a left frontal tumor. 18 months after this treatment, there was recurrence with progressive enlargement and leptomeningeal spread, making the patient’s condition not suitable for further treatment. We conducted a 5-week treatment (followed by a pause of one week) consisting of daily exposure (on weekdays) with intermittent OMF. The patient tolerated the treatment well. At 4 weeks there was a progressive reduction of the contrast-enhanced tumor (CET) volume to less than 60% of the pre-treatment volume on magnetic resonance imaging scans. Caregiver report indicated mild subjective improvement in speech and cognitive function. The daily decrease in volume was correlated with the amount of daily treatment, with longer treatments showing an increase in shrinkage of the CET volume. After the treatment pause in the 6th week, there was an apparent increase in CET volume. However, a marked reduction in the choline peak and an increase in the lipid peak on a proton magnetic resonance spectrogram of the tumor at this timepoint documented that this represented necrotic tissue. We are excited about this new and powerful treatment for glioblastoma and will present the details of treatment and imaging studies during therapy.
CTNI-54. LONG-TERM USE OF EVEROLIMUS PLUS OCTREOTIDE FOR RECURRENT INTRACRANIAL OR SPINAL MENINGIOMA: A SINGLE INSTITUTION EXPERIENCE
Authors: Youssef Michael , Pham Lily , Demirhan Mehmet , Harrison Rebecca , Loghin Monica , Johnson Jennifer , Alfaro-Munoz Kristin , Bhat Krishna , Yeboa Debra , Prabhu Sujit , Raza Shaan , de Groot John , Demonte Franco , Kamiya-Matsuoka Carlos 
Published: December 2020

Abstract

BACKGROUND
Selection of systemic therapy for recurrent meningiomas with progression after resection and/or radiation therapy represents a challenge. The combination of everolimus, an mTOR inhibitor, plus octreotide long-acting repeatable (LAR), a somatostatin agonist, suggests synergistic activity in preclinical studies. Its long-term clinical impact in recurrent meningiomas warrants further study.

METHODS
We reviewed the records of adult patients with recurrent intracranial or spinal meningioma (WHO grade I, II, or III), not candidates for further surgery or radiation therapy, who were treated with everolimus and octreotide, between 1/1/2015 and 06/1/2020 at MD Anderson Cancer Center. Patients received everolimus (10 mg PO daily) each 28-day cycle and octreotide 30 mg SC once monthly. Molecular features were determined by next generation sequencing (T-200–1, Oncomine).

RESULTS
A total of 18 patients were identified, including WHO grade I tumors (n=4), grade II (n=10), and grade III (n=4); furthermore, 8 patients harbored NF2 mutation, followed by mutations in CREBBP (n=2), NOTCH2 (n=1), MHL1 (n=1), PTEN (n=1), SETD2 (n=1), and TP53 genes (n=1). One patient had spinal meningioma. The 6- and 12-month PFS were 77.8% and 61.1%, 6- and 12-month OS were 94.4% and 83.3% respectively. Seven (38.9%) patients had tolerated treatment for more than 12 cycles, 3 (16.7%) remain on treatment for more than 24 cycles and 1 patient is still on treatment for 31 cycles. Only 1 patient required dose reduction to 7.5 mg daily due to pneumonitis, otherwise there is an acceptable toxicity profile. Four patients had resolution of trigeminal neuralgia.

CONCLUSIONS
In our patient population, combination treatment with everolimus and octreotide seems to have antitumor activity and proved to be safe without major side effects from long-term exposure. It also contributed to control of neuralgia. Further tissue analysis of the role of mTOR pathway and SSTR2A expression is ongoing.
CTNI-59. FIRST SAFETY ANALYSIS OF ANAPLASTIC MENINGIOMA PATIENTS TREATED WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Mawrin Christian 
Published: December 2020

Abstract

BACKGROUND
Anaplastic meningioma (AM) is a rare and aggressive intracranial tumor with very limited treatment options. TTFields is an established therapy and indicated for the treatment of newly diagnosed and recurrent glioblastoma (GBM) patients. The phase 3 study METIS tests the application in another intracranial cancer type, more specifically brain metastases of non-small cell lung cancer. First preclinical data show that TTFields can reduce proliferation of patient-derived meningioma cells and one first case report of a GBM patient with an in-field meningioma was published. First clinical trials are underway to investigate the safety and efficacy in meningioma patients (NCT02847559). Here, we describe first surveillance data on anaplastic meningioma patients treated with the TTFields device indicated for GBM treatment.

METHODS
Global post-market surveillance data of patients with anaplastic meningioma were assessed employing the MedDRA body system (System organ class (SOC) and preferred terms) with data cut-off in April 2020.

RESULTS
A total of 29 patients with AM were treated since 2015 to date. The median age is 57y (range 26-74y; based on YOB). Of those 9 (31%) were female and 20 (69%) were male. 15 (52 %) patients with AM reported at least one adverse event (AE). A total of 51 AEs were reported, of those 32 were assessed by the manufacturer as potentially related to TTFields treatment. Most commonly reported were skin reactions beneath the transducer arrays (n=15). No serious adverse events related to TTFields were reported.

CONCLUSION
Here we present the first post-market surveillance data of anaplastic meningioma patients treated with TTFields. Clinical studies are warranted to investigate the safety and efficacy for the use of TTFields in anaplastic meningioma patients.
DDRE-02. THERAPEUTIC TARGETING OF BRAIN METASTASIS WITH ERK INHIBITOR LY3214996 USING A NOVEL IN VIVO MODEL OF LUNG-TO-BRAIN METASTASIS
Authors: Singh Mohini , Nayyar Naema , Brastianos Priscilla 
Published: December 2020

Abstract
Brain metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring ten times more frequently than primary brain tumors. BM develop in 40–50% of advanced lung adenocarcinoma (LUAD), but the lack of durable response to chemotherapy, immunotherapy, or targeted therapy results in death within a year of BM diagnosis. Several advances have been made in identifying genetic drivers of primary cancers. For instance, the ERK pathway is critical in oncogenesis, with aberrations linked to driving the progression and metastasis of LUAD. Unfortunately, BM remain poorly understood due to both the difficulty of obtaining a sizable collection of metastatic tissue samples as well as a lack of clinically relevant models. Typical models of BM utilize inoculation routes that are invasive and cannot fully recapitulate the entirety of the metastatic cascade. Here we present a novel murine model of BM through an intrathoracic inoculation method that recapitulates the development of primary lung tumors and brain metastases as seen in patients. Using this method, we evaluated the efficacy of LY3214996, an ERK inhibitor, in targeting BM. Seven days post-inoculation of a patient-derived NSCLC-BM line, mice received LY3214996 P.O. daily for 21 days, and were monitored weekly for metastases with bioluminescent imaging. Upon endpoint lungs and brains were also removed and imaged. In vitro we demonstrated a reduction in cell growth and invasion across multiple cell lines of varying KRAS status (NSCLC and NSCLC-BM) treated with LY3214996. In vivo, we saw a reduction in both lung tumor weight as well as frequency of BM. Further research is necessary to elucidate the dosing and efficacy of LY3214996 in our models in different genetic contexts. Nonetheless, our technique presents a novel preclinical tool to interrogate the metastatic process, allowing validation of genetic drivers as well as therapeutic screening.
DDRE-16. SYNERGISTIC TUMOR SUPPRESSION FROM COMBINATION OF ONC201 AND EPIGENETIC MODULATORS EZH2 OR HDAC INHIBITOR PROVIDES A NOVEL TREATMENT STRATEGY FOR GBM AND DMG
Authors: Zhang Yiqun , Zhou Lanlan , Howard Safran , Seyhan Attila , El-Deiry Wafik 
Published: December 2020

Abstract
ONC201 is a promising anti-cancer agent that kills tumor cells by triggering an integrated stress response (ISR) dependent on ATF4. ONC201 demonstrated tumor regression and prolonged disease stability in patients with histone H3K27M-mutated midline glioma. The Enhancer of Zeste Homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is a histone methyltransferase that tri-methylates H3K27 (H3K27me3) and silences target genes. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. Based on the fact that the H3K27 mutation reduces H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3), we hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H3K27 methylation with EZH2i as a mimic of H3K27M-mutation and by increasing H3K27 acetylation with histone deacetylase inhibitors (HDACi). We evaluated synergy of EZH2i EPZ-6438 or HDACi vorinostat with ONC201 against GBM cell lines, U251 and T98G-1 and DMG cell line, SF8638. Cell viability was determined with the Cell Titer Glo assay. Apoptosis was evaluated through immunoblotting of cleaved PARP and flow cytometry analysis of cell distribution. ISR activity was evaluated using immunoblotting of ATF4. Our result demonstrate that ONC201 synergistically reduced cell viability with vorinostat in U251, T98G-1 and SF8628 cell lines, induced apoptosis in combination with vorinostat in U251 and SF8628. ONC201 synergistically reduced cell viability and induced apoptosis with EPZ-6438 in U251. The immunoblotting detected no enhancement of ATF4 by addition of EPZ-6438 to ONC201. Immunoblotting analysis showed that EPZ-6438 reduced H3K27me3 in U251. Our results unravel potent synergy between ONC201 and EZH2i or HDACi in GBM and DMG cell lines, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity.
DDRE-19. SPIDER VENOMS AS SOURCES OF MOLECULES FOR NEW CANCER TREATMENTS: THE EFFECTS OF THE SNX-482 PEPTIDE ON MACROPHAGE MODULATION
Authors: de Lima Munhoz Jaqueline , Thome Rodolfo , Ishikawa Larissa , dos Santos Natalia Barreto , da Rocha-e-Silva Thomaz A A , Sutti Rafael , Verinaud Liana , Araujo João Luiz Vitorino , Rostami Abdolmohamad , Raposo Catarina 
Published: December 2020

Abstract
Malignant primary brain tumors remain among the most difficult cancers to treat. In malignant tissues, macrophages are accumulated in a high infiltration being known as tumor-associated macrophages (TAMs). These cells are associated with poor prognostics in many types of cancer. Studies in our group demonstrated that the venom of Phoneutria nigriventer (PnV), a wandering spider from South America, has reduced the development of glioblastoma (GBM) in a murine model, inducing a large infiltrate of TAMs. Subsequently, in vitro results demonstrated that PnV activates macrophages, increasing the ability to kill tumor cells. The aim of this study was to analyze the effects of the peptide SNX-482 presented in the venom of Hysterocrates gigas in macrophages for further correlation with the PnV. Macrophages were differentiated from bone marrow precursors collected from male C57BL6 mice and differentiated for 7 days with M-CSF. These cells were used for polarization and coculture with T cells and analyzed by flow cytometry. PCR Array was also performed (QIAGEN) for the analysis of gene expression. The results showed that SNX-482 could activate macrophages in a not dose-dependent response. There was an increase in the main activation markers (CD40, CD80, CD86, CD68, CD83, and MHCII). The polarization indicated that the peptide potentiated the proinflammatory effect of M1 macrophages (increased MHCII and iNOS). The screening of 86 cancer-related genes showed that the Ccr4, Pdcd1, Gzmb, and IFN-γ genes had an increase in their expression. Furthermore, we developed in C57BL/6 mouse a pre-clinical model of intracranial glioblastoma using the Gl261 cell line. The results showed an applied-easy-safe model that could alter the gene expression of cancer markers. Taken together, all the results contributed to increasing the knowledge about the peptide SNX-482 and the model for further pre-clinical assays of glioblastoma, making a great advance in the development of new treatments.
DDRE-21. PNOC015: PHASE 1 STUDY OF MTX110 DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY
Authors: Mueller Sabine , Kline Cassie , Villanueva-Meyer Javier , Hoffman Carly , Raber Shannon , Bonner Erin R , Nazarian Javad , Lundy Shannon , Molinaro Annette , Prados Michael , Filbin Mariella , Gupta Nalin 
Published: December 2020

Abstract

OBJECTIVE
To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients.

METHODS
DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells.

RESULTS
Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months.

CONCLUSION
Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.
DDRE-25. NOVEL TEMOZOLOMIDE ANALOGS TO IMPROVE ANTI-TUMOR EFFICACY AND OVERCOME RESISTANCE IN GLIOBLASTOMA MULTIFORME
Authors: Waters Ariana , Tomimatsu Nozomi , Babic Ivan , Nurmemmedov Elmar , Allnutt Annamarie , Quan Yueqin , Nomura Natsuko , Burma Sandeep , Kesari Santosh , Yenugonda Venkata 
Published: December 2020

Abstract
Glioblastoma (GBM) is considered one of the most lethal forms of human cancers, and despite considerable advances in multimodality treatments, it remains an incurable disease with an overall survival of 14 to 16 months after diagnosis. Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), an oral alkylating agent, remains the standard-of-care for GBM. However, intrinisic or acquired resistance to TMZ due to over expression of O6-methylguanine-DNA methyltransferase (MGMT) results in initial treatment inefficacy or tumor relapse, highlighting the significant need for improved treatment strategies. Recently, much effort has been directed towards creating novel TMZ analogs to address the clinical barriers associated with TMZ. While some reported TMZ analogs showed improved brain permeability and anticancer effects in preclinical models, none of them have progressed to testing in humans. There is therefore significant room to improve the brain permeability and anticancer effect profiles of TMZ by incorporating yet unexplored functional groups into new analogs. We have designed and synthesized a series of novel C8-substituted TMZ analogs and have evaluated their anticancer potency against a panel of GBM cell lines with variable levels of MGMT expression. Encouragingly, our analogs demonstrated promising anti-cancer effect in both MGMT low and high expressing lines. We then evaluated our analogs in a variety of cell based assays to compare their activity with TMZ, and performed in vivo brain permeability and anti-tumor efficacy assays in mouse flank models. Our results demonstrated that several of our analogs clearly display improved anti-cancer effects and increased brain permeability over TMZ. This work points to a new direction for the development of novel TMZ analogs for improved patient survival.
DDRE-32. ABC TRANSPORTERS RESTRICT THE BRAIN PENETRATION AND INTRACRANIAL EFFICACY OF ANTICANCER AGENTS EVEN WHEN BLOOD-BRAIN BARRIER INTEGRITY IS LOST
Authors: de Gooijer Mark C , Kemper E Marleen , Buil Levi C M , Çitirikkaya Ceren H , Buckle Tessa , Beijnen Jos H , van Tellingen Olaf 
Published: December 2020

Abstract
The impact of the blood-brain barrier (BBB) in brain tumors on the efficacy of anticancer drug therapy is controversial. In primary as well as metastatic brain tumors, the BBB is often disrupted. Yet, many intracranial cancers respond poorly to systemic therapies. We characterized the integrity of the BBB in a series of experimental intracranial tumor models using magnetic resonance imaging (MRI), fluorescent dyes and autoradiography. We also assessed the distribution and efficacy of docetaxel in healthy brain tissue and brain tumors that were grafted into P-glycoprotein (P-gp) proficient wild-type (WT) and deficient Abcb1a/b-/- recipient nude mice. Leakiness of the tumor vasculature varied from extensive to almost absent. Tumor blood vessels expressed P-gp and breast cancer resistance protein (BCRP). The leakiness of the vasculature resulted in higher docetaxel levels in tumors compared to normal brain. However, P-gp expression in tumor vessels reduced the drug distribution in tumors, which also translated into a reduced efficacy. Taken together, these studies demonstrate that leakiness of the BBB does not necessarily imply good accessibility to brain tumors of drugs that are substrates of P-gp and/or BCRP. Although therapeutic responses may be observed, the full potential of such therapeutics can still be attenuated by drug efflux pumps in the tumor vasculature. Therefore, only BBB-penetrable drugs with low to no affinity for efflux transporters should be considered for treatment of intracranial tumors.
EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS
Authors: Mansouri Sheila , Suppiah Suganth , Mamatjan Yasin , Paganini Irene , Liu Jeff , Karimi Shirin , Patil Vikas , Nassiri Farshad , Singh Olivia , Sundaravadanam Yogi , Rath Prisni , Sestini Robert , Gensini Francesca , Agnihotri Sameer , Blakeley Jaishri , Ostrow Kimberly , Largaespada David , Plotkin Scott , Stemmer-Rachamimov Anat , Ferrer Marcela Maria , Pugh Trevor , Aldape Kenneth , Papi Laura , Zadeh Gelareh 
Published: December 2020

Abstract
Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.