tbuckley/cabot-search huggingface dataset:
A Therapeutic Strategy for Preferential Targeting of <i>TET2</i>-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms
Authors: Yihong Guan, Anand D. Tiwari, James G. Phillips, Metis Hasipek, Dale R. Grabowski, Simona Pagliuca, Priyanka Gopal, Cassandra M. Kerr, Vera Adema, Tomas Radivoyevitch, Yvonne Parker, Daniel J. Lindner, Manja Meggendorfer, Mohamed Abazeed, Mikkeal A. Sekeres, Omar Y. Mian, Torsten Haferlach, Jaroslaw P. Maciejewski, Babal K. Jha
Journal: Blood Cancer Discovery (2020)

Abstract TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2-mutant neoplasia. Significance: Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo. See related video: https://aacrjournals.org/webinar-minimal-tet-activity-targetable-vulnerability-tet2-and-neomorphic-idh12-mutant
TAMI-50. CHITINASE-3-LIKE-1 PROTEIN BINDING COMPLEXES REGULATE IMMUNE SUPPRESSION IN GLIOBLASTOMA
Authors: Apeng Chen, Yinan Jiang, Zhengwei Li, Han Zou, Ulises Santiago, Xiangwei Xiao, Carlos Camacho, Ian Pollack, Baoli Hu
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM), the most common and lethal brain tumor, remains incurable despite intensive multimodal treatment. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Here, we found that Chitinase-3-like-1 (CHI3L1) is highly expressed in GBM and associated with a poor clinical outcome. CHI3L1, also known as human homolog YKL-40, plays a role in tissue remodeling, inflammation and cancer. Interestingly, we found that genetic knockdown (KD) of Chi3l1 in syngeneic immunocompetent mouse GBM models resulted in increased tumor-infiltrating lymphocytes, tumor size reduction, and improved animal survival. Surprisingly, the parallel loss-of-function experiment revealed that Chi3l1 KD did not repress tumor progression in the orthotopic immunodeficient mice with deficient T and B cells. These results suggest the predominant role of CHI3L1 in regulating the GBM immune TME, rather than in tumor cells per se. Mechanistically, we discovered that Galectin-3 (Gal-3) and Galectin-3 binding protein (Gal-3BP) interact competitively with the same binding motif on CHI3L1, leading to selective migration of protumor M2-like versus antitumor M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Transcriptomic analysis revealed that pro-inflammatory signature and T cell mediated immunity and cytotoxicity signaling are significantly enriched in tumor associated macrophages/microglia (TAMs) composed of BMDMs and MG, which were isolated from tumors with Chi3l1 KD versus wild type. In vitro validations suggest that CHI3L1-Gal-3, but not CHI3L1-Gal-3BP protein binding complex, activates PI3K/AKT/mTOR signaling to control the TAM switch of immune suppression and immune stimulation. Together, these results shed light on molecular mechanism of GBM immune evasion and potential new immunotherapeutic strategies for GBM treatment.
EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES
Authors: Alison Mercer-Smith, Wulin Jiang, Alain Valdivia, Juli Bago, Scott Floyd, Simon Khagi, Shawn Hingtgen
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for &amp;gt; 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes &amp;gt; 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.
IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE
Authors: Tabitha Cooney, Kenneth J Cohen, Carolina V Guimaraes, Girish Dhall, James Leach, Maura Massimino, Alessandra Erbetta, Luisa Chiapparini, Fatema Malbari, Kim Kramer, Ian F Pollack, Patricia Baxter, Suzanne Laughlin, Zoltan Patay, Tina Young Poussaint, Katherine E Warren
Journal: Neuro-Oncology (2020)

Abstract Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.
TAMI-17. RELATIONSHIP BETWEEN IRON METABOLISM, IMMUNE CELL INFILTRATION AND SEX-BASED SURVIVAL DIFFERENCES IN GLIOMAS
Authors: Darya Nesterova, Sang Lee, Brad Zacharia, Elizabeth Proctor, Justin Lathia, Joshua Rubin, Michael Berens, Jill S Barnholtz-Sloan, James Connor
Journal: Neuro-Oncology (2020)

Abstract Iron plays a central role in cellular metabolism, both in normal cellular functioning and in tumorigenesis. Recent evidence has shown sex-based survival differences in glioblastoma (GBM) may be related to differential expression of metabolism genes. We previously reported the iron regulating gene, HFE, was shown to have a sex-based survival impact in both low-grade gliomas and GBM. We additionally found that females with low HFE expressing tumors have significantly higher survival than males in GBM. To evaluate the relationship between iron gene expression and sex-based survival differences in GBM, we analyzed TCGA GBM gene expression and clinical data. We first analyzed the impact of iron genes on sex-based survival. In addition to HFE, FTL, TFRC, TF, and SLC39A8 (ZIP8), also showed sex-based survival differences. We then compared correlations of HFE and other iron genes to identify whether male and female GBMs differ in iron regulation and metabolism. HFE expression is significantly positively correlated with HMOX1, SLC25A28, SLC11A2, FTH1, HAMP, and TFR2 only in females. Alternatively, HFE expression is negatively correlated with ACO2 (mitochondrial aconitase) in males and ACO1 (cytoplasmic aconitase) in females. We noted that the expression of certain iron genes was highly associated with immune cell infiltration based on sex. TFR2, LRP1, and XIST expression were negatively correlated with low immune cell infiltration in females, but not males. Alternatively, in males, SLC11A2, ACO2, FOXO1, HIF1a, and HAMP genes were negatively correlated with immune infiltration. This suggests that differences in iron regulation between males and females may be contributing to differences in immune function and subsequent survival in GBM. These data suggest that the iron signature of a tumor reflects and possibly drives the metabolic and immune landscape of the tumor microenvironment thereby directly impacting survival differences between male and female GBMs.
IMG-05. INITIAL RADIOGRAPHIC ASSESSMENT OF DWI AND ADC VALUES IN CHILDREN AND YOUNG ADULTS TREATED WITH DAY101 (TAK-580) FOR RECURRENT LOW-GRADE GLIOMAS (LGG) HARBORING MAPK ALTERATIONS
Authors: Emily Krzykwa, Ronald L Korn, Samuel C Blackman, Karen D Wright
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Apparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated from a diffusion-weighted image (DWI), correlating with tumor cellularity. The higher cellularity of high-grade gliomas results in diffusion restriction and reduced ADC values, whereas the lower cellularity of low-grade gliomas (LGGs) gives higher ADC values. Here we examine changes in ADC values in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580). METHODS Historical, baseline, and on-treatment brain MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MAPK pathway alterations were obtained, de-identified and independently evaluated for ADC changes. Time points included baseline, first follow-up, and best response. Data processing of ADC estimates was performed using pmod molecular image software package. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm. RESULTS There was a clear shift to lower ADC values for the solid component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWI reveals reduced ADCs in responding tumors, with the percent change in ADC from baseline correlating with deeper RANO responses. CONCLUSION DWI analysis reveals reductions in ADC values that correlates with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.
QOLP-12. EMBEDDING OUTPATIENT PALLIATIVE CARE INTO NEURO-ONCOLOGY CLINIC – RESULTS FROM A ONE YEAR PILOT
Authors: Jennie Taylor, Michael Rabow, Susan Chang, Nicholas Butowski, Jennifer Clarke, Margaretta Page, Rosemary Rossi, W Patrick Shibley, Brook Calton
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) patients fall within NCCN and ASCO guidelines for early palliative care (PC). However, data suggests they are less likely than systemic cancers to be referred to PC and often later in their illness. This results in potential missed opportunities, both for improving symptom control and earlier completion of important tasks, like advance care planning. Data on how to best incorporate comprehensive PC into routine neuro-oncology (NO) patient care is needed. METHODS We piloted a program embedding a PC physician into UCSF’s NO clinic one half-day per week. NO physicians were encouraged to refer GBM patients within 3 months of diagnosis and other patients with PC needs. PC visits were offered in-person, by telemedicine, or at home. PC physician and NO social worker made joint visits when possible; chaplaincy support was available by telemedicine. Data was collected using Palliative Care Quality Network (PCQN) database and patient satisfaction survey. RESULTS To date, 37 patients have been referred resulting in 103 visits (average 2.8 visits/person): 25% in-person; 68% telemedicine; 6% at home. PC physician and NO social worker met jointly with 46% visits. Median age was 58 years, 41% female, 81% non-Hispanic white, 84% GBM, median 9 months from diagnosis, and 73% receiving first line treatment. Interventions addressed across visits: 94% non-pain symptoms, 76% psychosocial needs; 71% pain; and 70% GOC. Results from satisfaction survey demonstrated 79% would recommend seeing PC embedded in NO to others and highest benefits were attention to practical considerations to staying healthy at home, discussing preferences for future medical care, and help with coping. CONCLUSIONS Embedding PC into NO clinics is a unique model for addressing symptoms and GOC early, is well received by patients and caregivers, and provides opportunities for collaboration and PC physicians to specialize in caring for needs of NO patients.
Phospho-Tau Antibody Delivery Using Virus-Like Nanoparticles as Carriers Enhances Spatial Memory Functions in Tauopathy Model Rats
Authors: Joseph Susheel Kumar, None Vishnuvardhan, Sushmitha C, Natraj Usha, Savithri Handanahal Subbarao, Subramanian Sarada
Journal: Alzheimers Disease & Dementia (2020)

Anti-tau immunotherapies targeting phospho-epitopes have shown promising outcome in pre-clinical studies, although, with certain limitations in terms of mode of antibody delivery and concentration of antibodies required to obtain positive outcome.
GCT-62. DISSECTING INTRATUMORAL HETEROGENEITY OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS BY SINGLE-CELL RNA-SEQUENCING
Authors: Tomoyuki Nakano, Yuko Matsushita, Ritsuko Onuki, Daisuke Shiokawa, Kiyomi Imamura, Terumi Horiuchi, Eita Uchida, Yui Kimura, Satoshi Ihara, Tomonari Suzuki, Takao Tsurubuchi, Eiichi Ishikawa, Taishi Nakamura, Makiko Yoshida, Atsufumi Kawamura, Kohei Fukuoka, Kurihara Jun, Yasuji Miyakita, Yoshitaka Narita, Keiichi Kobayashi, Motoo Nagane, Hirokazu Takami, Ryo Nishikawa, Mamoru Kato, Yutaka Suzuki, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system germ cell tumor (CNSGCT) is a rare pediatric brain tumor. However, they are found at a relatively high incidence in East Asia. Germinoma is sensitive toward radiotherapy and chemotherapy; however, non-germinoma GCTs (NGGCT) often show poor response. Some cases are a mixture of germinoma and NGGCT (mixed GCT), and they sometimes change histological subtypes at recurrence. Previous report demonstrated that a germinoma and NGGCT component within the same mixed GCT tissue shared the same gene mutation, whereas the genome-wide methylation profiles were distinct from each other. The methylation profiles of germinoma was similar to the primordial germ cells (PGC) at the migration phase, supporting a model that PGC is the cell of origin for CNSGCT. However, tumor heterogeneity hinder information of the mixed bulk RNA-sequence data, causing difficulty in elucidating the mechanism of tumor development. The purpose of this study was to investigate the tumor cells subpopulations at the resolution of individual cells by single-cell RNA-seq. RESULTS Fresh surgical tumor tissue was immediately dissociated mechanically and enzymatically. Tumor cells are separated from CD45-labelled lymphocytes by FACS, and libraries were generated by Chromium Single cell 3’ Reagent Kit. Total of 11 tumor samples were collected and sequenced. Unsupervised Clustering showed individual clusters. One of the clusters had high expression of Oct-4, which is a marker of germinoma. The other clusters showed different subtypes of cells representing the heterogeneity of CNSGCT. Further analysis including a pseudo-time course analysis is underway to identify the lineage of tumor cell development.
LGG-51. BRAF ALTERATIONS IN PEDIATRIC LOW-GRADE GLIOMAS: RESULTS FROM A BRAZILIAN COHORT
Authors: Felipe Restine, Luis Henrique Sakamoto, Juliana Monte Real, Gregorio Pereira, Jennifer Marx Fernandes, Simone dos Santos Aguiar, Sidnei Epelman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric low grade gliomas (PLGG) are the most common central nervous system neoplasms in children. These are driven almost exclusively by alterations in the RAS/MAPK pathway. Specifically, alterations in the BRAF gene have emerged as an important target for therapy. This study aimed to identify the frequency of BRAF alterations in a Brazilian cohort of PLGGs. RESULTS Forty-one patients diagnosed between 2001 and 2017 had enough FFPE tissue available for analysis. Real-time PCR test (n=35) was used to assess for BRAFV600E mutations, while BRAF fusions were detected by break-apart fluorescence in situ hybridization (n=30). The histologic distribution was as follows: 73% pilocytic astrocytoma, 12% ganglioglioma, 3% diffuse astrocytoma, 5% pleomorphic xanthoastrocytomas (PXA) and 7% NOS (n = 41). BRAF fusions were present in 21 patients (51%): 17 pilocytic astrocytomas, 2 xanthoastrocytoma, 1 pilomyxoid astrocytoma and 1 diffuse astrocytoma. BRAFV600E was detected in 4 cases (10%): 2 pilocytic astrocytomas, 1 ganglioglioma and 1 PXA. As expected, BRAF translocations were more frequent in pilocytic astrocytomas (p&amp;lt;0.001). From 22 patients treated in our institution, 59% were male with a mean age of 9.7 years, 50% occurred in the posterior fossa and 77% treated by surgery only. One patient relapsed and died from disease (BRAF V600E positive) (follow-up median=44.7 months). These are the first results using a CLIA method showing the frequency of BRAF abnormalities in a Brazilian population. Although preliminary, BRAF alterations are present in 61% of the cases emphasizing the importance of incorporating this analysis in the current work-up guidelines.
CTNI-07. DELIVERY AND ACTIVITY OF SN-38 BY SACITUZUMAB GOVITECAN IN CNS TUMORS
Authors: Andrew Brenner, John Floyd, Renu Pandey, Jennifer Chiou, Prathiba Surapreneni, Virginia Kaklamani, Kate lathrop, Richard Crownover, Jean Louis Caron, Stefano Tiziani
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Sacituzumab Govitecan (SG, TRODELVY™) is an antibody drug conjugate, with payload and linker characteristics preferable for CNS delivery. SG utilizes a pH hydrolysable linker, allowing SN-38 to be released at the tumor site. SN-38 is the active component of Irinotecan and 1000-fold more potent than the parent compound. We observed SG activity in intracranial xenografts and hypothesized that SG would achieve therapeutically relevant concentration of SN-38 within the CNS. METHODS We performed a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SG, SN-38, and SN-38G in patients undergoing craniotomy for breast cancer brain metastases (BCBM, n=10) or recurrent glioblastoma (rGBM, n=10). Patients received a single dose of SG at 10mg/kg IV the day prior to craniotomy and tumor collected. [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). Patients resumed SG 10mg/kg IV days 1 and 8 of 21 day cycle following recovery and were assessed every third cycle by MRI using RANO criteria. RESULTS To date 16 patients have been treated, including 8 BCBM and 8 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For the rGBM patients, total concentration of SN-38 varied from 93nM to 680nM, with a mean concentration of 420nM. For BCBM, total concentration of SN-38 varied from 173nM to 1160nM, with a mean concentration of 626nM. All GBM patients had residual measurable disease and 4 breast patients had measurable disease. With a median follow-up of 12 weeks from the first postoperative cycle in the first 14 patients, 2 partial responses from each group were observed (ORR of 28% and 50% at 12 weeks respectively). CONCLUSIONS SG achieves therapeutically relevant concentrations of SN-38 at 40-fold mean IC50s for GBM, and 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation.