bluuebunny/crossref_metadata_2025 huggingface dataset:
SDPS-01 DEVELOPMENT OF A WEB-BASED CALCULATOR APPLICATION FOR PREDICTING SHORT- AND LONG-TERMSURVIVAL IN PEDIATRIC OPTIC PATHWAY GLIOMA: A POPULATION-BASED DATABASE ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Pennington Zach , Gendreau Julian , Givens Drew , Daniels David
Published: August 2023

Optic pathway gliomas (OPG) are generally low-grade lesions arising from the astrocytes of the visual pathway, most commonly of the optic nerves and chiasm. Uncertainty remains regarding the optimal management of this patient population. We sought to leverage population-level data from the Surveillance, Epidemiology, and End Results program database to develop a predictive calculator for overall survival (OS) amongst pediatric patients with OPG. A total of 1,052 patients who had been diagnosed with OPG were included. Multivariate cox proportional hazard model demonstrated patients of “other” race (hazard ratio [HR]=4.109, 95% confidence interval [CI] 1.076-15.694, p=0.039) exhibited a decreased overall survival, while patients with a median household income ≥$55,000 (HR=0.172, 95% CI 0.065-0.457, <0.001) and those who underwent subtotal resection (HR=3.549, 95% CI 1.092-13.364, p=0.047) had a higher overall survival rate. An online, interactive survival prediction tool (https://spine.shinyapps.io/optic_glioma/) was created to estimate 5-, 10-, and 15-year overall survival probability as well as median survival months. C-index was 0.722 (95% CI 0.642-0.776) for the training set and 0.745 (95% CI 0.661-0.790) for the validation set. Good concordance between the predicted probability and the actual probability of the dataset was also observed. This calculator may serve as a useful clinical tool during patient counseling. Further investigations aimed at developing calculators of visual acuity preservation and progression-free survival are merited; progress toward this end will benefit from continued multicenter collaborations.
SDPS-17 COMPREHENSIVE ANALYSIS OF CELL DIVISION CYCLE ASSOCIATED GENE FAMILY EXPRESSION PATTERN AND PROGNOSIS VALUE REVEALS CDCA2 AS A NOVEL ONCOGENE FOR GLIOMA
Authors: Sun Wei , Han Xuetao , Zhou Huandi , Hou Liubing , Xue Xiaoying
Published: August 2023

Glioma is the most common central nervous system tumors. Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. The cell division cycle associated proteins (CDCA) family gene is involved in a wide range of biological functions in human cancers. Nevertheless, the expression characteristics of CDCAs, and prognostic value landscape of glioma are remain unknown. Based on a wide variety of public databases and integrated several bioinformatics analysis methods, we evaluated expression dysregulations, clinical implications, DNA methylation, copy number alterations, prognostic and therapeutic values of CDCA family gene in glioma. Further, we identified crucial biomarker, CDCA2, that influence the progression of malignant glioma and poor prognosis. Thereafter, we disclosed the effect of CDCA2 knockdown on the biological function of glioma cells through various experiments in vitro. We found that the elevated mRNA expression of CDCAs in glioma. The upregulated expression of CDCAs was found to be associated with the tumor grade in glioma. The overexpression of CDCAs mRNA were correlated with the poor prognosis. Moreover, the expression level of CDCA2 was significantly higher in glioma, and the level is correlated with grade, age, IDH1 mutation and 1p19q codeletion states. Further cell experimental results supported that the ability of cell proliferation, migration, invasion and radioresistance of glioma cells was significantly decreased after downregulated CDCA2 expression, and these changes may be achieved through the RAD51 and p21/CDK2/CyclinE1 signaling pathways. These findings provide new insights into CDCAs from a bioinformatics standpoint and highlight the significance of CDCAs in glioma diagnosis and treatment. And knockdown of CDCA2 inhibits glioma cells' proliferation, migration, invasion and radioresistance. Regulation of CDCA2 on malignant progression of glioma cells may be realized through the RAD51 and p21/CDK2/CyclinE1 signaling pathways.
SDPS-18 RHABDOID TUMOR PREDISPOSITION SYNDROME IN TWO INFANT SIBLINGS WITH ATYPICAL TERATOID RHABDOID TUMORS DUE TO A GERMLINE SMARCB1 MUTATION
Authors: Quintero Ana , Hanson Derek , Pedro Helio , Vogel Timothy
Published: August 2023

Atypical teratoid rhabdoid tumors (ATRT) are aggressive, malignant tumors of the central nervous system (CNS) that develop due to a loss-of-function mutation in the SMARCB1 gene. Rhabdoid tumor predisposition syndrome (RTPS) is characterized by familial cases as a result of pathogenic germline variants of this gene and an increased risk of developing ATRT within the first 2 years of life, which carries a poor prognosis. Genetic penetrance is incomplete with variable expressivity but the patient's age at time of diagnosis remains the most significant indicator of survival. We present a case of RTPS in a sibship born to unaffected parents, one of which was a carrier. The first sibling was diagnosed at 8 months of age after presenting with vomiting, developmental regression, and CN VI palsy for 3 months. Imaging revealed a posterior fossa mass, acquired obstructive hydrocephalus, and spinal metastasis. Four years later, her 3-month-old sister was brought in for evaluation due to vomiting, irritability, and macrocephaly for 2 months, along with a new vertical gaze palsy. Imaging findings also showed a posterior fossa mass and acquired obstructive hydrocephalus but without metastasis. Both siblings underwent craniotomy with subtotal tumor resection and ventriculoperitoneal shunt placement. Chemotherapy was promptly initiated but despite active treatment, they had rapid disease progression and ultimately passed away. Whole exome sequencing of both patients revealed an in-frame deletion involving the SNF5 homology domain of SMARCB1, with consistent findings on whole transcriptome sequencing, and evidence of loss of a single copy of chromosome 22. In this case report, we present a family faced with the devastating outcomes of RTPS and emphasize the importance of genetic testing and counseling for these families after diagnosis in the first child. Families should also be streamlined to a fertility specialist prior to subsequent pregnancies as an opportunity for familial screening.
SDPS-30 ANALYSIS OF THE BRAIN TUMOR MATRISOME REVEALS CANCER ASSOCIATED FIBROBLASTS PREDICT POOR IMMUNOTHERAPY RESPONSE IN GLIOBLASTOMA PATIENTS
Authors: Zarodniuk Maksym , Steele Alexander , Lu Xin , Li Jun , Datta Meenal
Published: August 2023

Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures. We found that glioblastoma can be divided into two ECM-based subtypes that are influenced by the presence of cells resembling cancer associated fibroblasts (CAFs) and are conserved across a number of CNS lesions. In glioblastoma, CAF-like cells are correlated with unfavorable response to immune checkpoint blockade and poor patient survival across a subset of CNS tumors. We show that CAF-like cells reside in the perivascular niche, activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote glioma stem-like cell phenotype. Our analysis provides insights into mechanisms underlying immunotherapy resistance in glioblastoma and suggests that targeting CAF-like cells may provide an effective approach to improve patient survival in a subset of CNS tumors.
SDPS-31 EXTRACELLULAR VESICLES AND THEIR CARGO AS A PHARMACODYNAMIC REPORTER IN GLIOBLASTOMA
Authors: DeLuca Valerie , Tang Nanyun , Hao Yue , Raju Anjali , Shaffer Charles , Riviere-Cazaux Cecile , Burns Terry , Sarkaria Jann , Parney Ian , Pirrotte Patrick , Van Keuren-Jensen Kendall , Berens Michael
Published: August 2023

Glioblastoma (GBM) is a lethal brain tumor with limited treatment options, due in part to the low blood-brain-barrier (BBB) penetrance of many anti-cancer compounds. Development of a non-invasive test that can measure drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase clinical trials of a new compound’s pharmacological suitability and potential efficacy. We present here data supporting that the cargo within extracellular vesicles (EV) can potentially serve as a liquid biopsy that reports on the pharmacodynamics of GBM therapeutics. We treated short-term cell cultures established from four patient-derived xenografts with vehicle, temozolomide, MLN4924, or arsenic trioxide. EVs were isolated from culture supernatants using size exclusion chromatography and then analyzed by RNA sequencing and mass spectrometry (proteomics) to characterize and compare cargo profiles for each condition. We found that depending on treatment, there were shared alterations in EV cargo between models in the expression of long non-coding RNAs, genes that are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis, and circular RNAs. Mass spectrometry of protein cargo further demonstrated both upregulated and downregulated peptide abundances with treatment compared to vehicle. Thus, our preliminary results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To allow for the selective interrogation of patient GBM-derived EVs, we have simultaneously pursued the identification of biomarkers to allow for immunoprecipitation of EVs from patient biofluids. Potential biomarkers, including PTPRZ1, B7H3, and IL13RA2, were screened across isolated EVs from both pre-clinical and clinical patient samples. Future efforts are focused on evaluating immunoprecipitated GBM-EVs from longitudinally collected patient biofluids. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts.
SDPS-34 SCREENING TUMOR INFILTRATING LEUKOCYTES IN GLIOBLASTOMA REVEALS A CORRELATION WITH EGFR POSITIVE TUMOR CELLS WITH PROGNOSTIC IMPLICATIONS
Authors: Goodyke Austin , Arora Sanjana , Orozco Andres Restrepo , Zagorski Joseph , Vitaz Todd
Published: August 2023

Glioblastoma (GBM) is a grade IV brain tumor that is difficult to manage and associated with high rates of relapse and mortality. Treatment failures are attributed to the blood-brain barrier, increased tumor vascularity, tumor heterogeneity, numerous molecular mutations, and an immunosuppressive microenvironment. The immune microenvironment is comprised of tumor-infiltrating leucocytes (TILs), including several immunosuppressive cell types such as myeloid derived suppressor cells (MDSCs) (immature TILs of myeloid lineage). These tumor supporting immune cells augment the microenvironment and create conditions for immune suppression, contributing to tumor progression and negatively impacting patient survival. The aim of this study was to characterize the TILs in individual patients and correlate these findings with treatment course and survival. We hypothesized that a higher prevalence of MDSCs in tumors would be associated with lower survival rates. In order to investigate this, tumor specimens were collected from GBM patients who underwent tumor resection at Corewell Health (IRB# 2020-024). Fresh GBM samples were collected into tumor storage solution and immediately dissociated into single cell suspensions using a GentleMACS dissociator. The subsequent single cell suspension was stained with a panel of antibodies for TILs and tumor surface markers EGFR and PDGFRA. Flow cytometric analysis of these specimen revealed that the TILs comprising the tumor microenvironment were primarily dominated by CD11b+ myeloid cells, with prevalent MDSCs negatively associated with survival in our study group. Interestingly, MDSCs were negatively correlated with EGFR+ tumor cells while CD3+ T cells were positively correlated. In addition, patients previously treated with either temozolomide or bevacizumab had significantly different TIL immunophenotypes. Together, these data suggest that screening approaches utilizing these techniques may elucidate how tumor cells and TILs may be interacting and reacting to treatment and may provide additional diagnostic and prognostic avenues ultimately leading to improved outcomes for these patients.
SDPS-46 CENTRAL NERVOUS SYSTEM (CNS)-RELATED MORTALITY IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER
Authors: Ferraro Emanuela , Nassif Rabih Bou , Reiner Anne , Tosi Umberto , Panageas Katherine , Dang Chau T , Seidman Andrew D , Moss Nelson
Published: August 2023

BACKGROUND

Approximately one third of patients with HER2-positive (+) metastatic breast cancer (MBC) develop brain metastases (BrM). In light of discordant control of extracranial metastases (ECM) versus BrM for standard-of-care antibody-based therapies for these patients, and the frequent use of radiation and surgical therapies particularly for patients with CNS-centric disease, we sought to determine the proportion of HER2+ MBC patients with BrM who suffered neurologic death in the CNS-only and intracranial-plus-extracranial metastasis settings, and the clinical risk factors of such.

METHODS

Clinicopathologic data for HER2+ MBC patients with BrM treated at an NCI-designated Comprehensive Cancer Center between August 2010 and April 2022 were collected, including disease burden at cancer presentation, the timing and pattern of BrM and ECM, and neurologic complications. CNS-related death was defined as any mortality caused by BrM, leptomeningeal progression, or BrM-associated complication.

RESULTS

275 patients were included. 58/275 (21%) presented with CNS as only and first site of metastasis; the remaining (217/275, 79%) developed BrM synchronously with or subsequent to ECM. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS therapies (254/275 [92%] received at least one radiation treatment and 88/275 [32%] underwent BrM resection). After a median follow-up of 2.5 years, 193/275 (70%) patients died, of whom 105 (54%) of CNS-related cause. The median OS was 3 years (95% CI=1.47-5.14) and 2 years (95% CI=1.74-2.34) for patients with CNS-only versus BrM concurrently/subsequent to ECM, respectively (p=0.059). The cumulative incidence of CNS-related death at 5 years was 40% (95%CI=33-46%).

CONCLUSIONS

Almost half of patients with HER2+ BrM suffered neurologic death. Patients with CNS-only disease had better OS than patients with synchronous/preceding ECM, suggesting that overall burden of disease affects mortality. With high rates of durable extracranial control with HER2-directed therapies, new strategies to prevent and eradicate CNS disease are urgent.
SPCR-10 CANCER CO-ROUNDS: A NOVEL INPATIENT MULTIDISCIPLINARY ONCOLOGY ROUNDING MODEL
Authors: Ni Lisa , Viner Jennifer , Phuong Christina , Liu S John , Yee Emily , Petrofsky Mary , Kwon Daniel H , Brondfield Sam , Boreta Lauren C , Daras Mariza
Published: August 2023

BACKGROUND

Although tumor boards are well-established for coordinating care of patients with cancer in the outpatient setting, few studies have evaluated interventions for improving consultative care coordination for hospitalized patients. This study evaluated the hypothesis that implementation of an inpatient co-rounding model of care including medical-, neuro-, and radiation-oncology consult teams would improve the alignment of recommendations from these oncologic services, as perceived by primary teams.

METHODS

A co-rounding model was implemented in September 2021 for hospitalized patients with cancer at a tertiary medical center. The oncologic consulting services met virtually twice weekly to discuss patient care. Providers from the most common primary services for patients with cancer, internal medicine (IM) and neurosurgery, were surveyed via institutional email listservs. The survey included Likert-type questions about the alignment of recommendations across services and open-ended questions for feedback on collaboration among these services. Pre-intervention surveys were distributed, and post-intervention surveys were distributed 9 months later. Wilcoxon rank-sum tests were used to compare responses pre- and post-intervention.

RESULTS

At each session, a median of 6 providers attended (range, 4-8 providers), and a median of 6 patients were discussed (range, 4-8 patients). Of the 331 providers surveyed, there were 119 (36%) respondents pre-intervention and 34 (10%) respondents post-intervention. The 132 unique respondents comprised 68 (52%) IM attending physicians, 48 (36%) IM resident physicians, 6 (5%) neurosurgery advanced practice providers, 6 (5%) neurosurgery attendings, and 4 (3%) neurosurgery residents. Post-intervention, respondents were significantly more likely to perceive alignment in oncologic consultant recommendations (67% strongly agree) compared to pre-intervention (23% strongly agree, p<0.01).

CONCLUSIONS

A novel inpatient co-rounding model was successfully implemented between medical-, neuro-, and radiation-oncology. Primary teams perceived greater alignment in recommendations among these consulting services after implementation. Future directions include evaluation of the impact of this model on patient outcomes.
SPCR-12 A PROCESS IMPROVEMENT FOR INCREASING DEPRESSION AND ANXIETY SCREENING IN PATIENTS WITH BRAIN TUMORS
Authors: O’Sullivan Mary
Published: August 2023

Anxiety and depression are highly prevalent in patients with brain tumors. These conditions significantly affect quality of life and are associated with worsened survival. The Alvord Brain Tumor Center at UW did not have a process to screen patients for anxiety and depression. In response to this, a quality improvement project was developed to identify barriers and facilitators to mood screening and to introduce a new standard process for screening. We formed an interdisciplinary mood screening committee in the clinic to ensure a collaborative process with each profession’s voice accounted. The new process for mood screening consisted of the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) being automatically sent to all return patients’ MyChart accounts 24 hours before their scheduled appointment, repeating up to every six months. Upon completion of the questionnaires, the results would immediately file into the patient’s electronic medical record. The new process was implemented and we collected data from clinic visits over two weeks to determine its impact. Of all patients eligible for screening, 18% completed the screenings as a result of the new screening process, compared to the baseline 15% who had already completed the screenings in the last six months at other clinics within the health system, effectively doubling the number of patients in the clinic with mood screening in the last 6 months. Among those with MyChart accounts, the total response rate to the screenings was 24%. The automaticity of the process will help ensure an ongoing baseline standard for patients to be screened. In the future, an additional process will be developed to ensure that those without access to MyChart have equal opportunity for screening and treatment of mood disorders.
SYST-03 PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD) FROM EPITHELIAL CARCINOMAS: FINAL RESULTS AND MOLECULAR ANALYSES WITH SINGLE CELL RNA SEQUENCING
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Evernden Brittany , Khushalani Nikhil , Czerniecki Brian , Smalley Inna , Vogelbaum Michael , Yu Michael , Smalley Keiran , Forsyth Peter
Published: August 2023

BACKGROUND

LMD has a dismal prognosis with median overall survival (mOS) of 3-4 months (mo). Preclinical studies showed PD-1 axis blocking therapy promotes antigen presentation within the CSF compartment, and increases BBB permeability and ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab with WBRT in LMD (NCT0371768).

METHODS

Patients received Avelumab 800mg IV q2 weeks, up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy, 10 daily fractions. Primary endpoints were safety/DLTs and 3-mo OS. Secondary endpoints i.e., CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6mo were excluded.

RESULTS

15 patients were enrolled i.e., breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). 87% female, median age 59 range 32-82. 1 patient did not complete WBRT. 2 out of 15 patients had gr. 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related <gr. 3 AEs, i.e., hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). Median follow-up was 3.7mo (range, 0.9-36.8mo; 95% CI 1.3-14.7mo). Median follow-up time for survival analyses was 19.8mo. 10 out of 15 patients (66.7%) were alive at 3mo. mOS was 10.5 (95% CI 1.2 - 19.8mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3mo (95% CI, 0.9-15.2mo). 2 patients remain alive and well. ScRNAseq analyses are underway; signatures correlated with outcomes in short vs. long term survivors.

CONCLUSIONS

Combination of Avelumab and WBRT is safe, well tolerated, and shows encouraging activity in LMD with an OS longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short vs. long term survivors should be further explored.
SYST-07 PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA
Authors: Taylor Jessica , Williamson James , Masih Katherine , Bonner Sigourney , Lehner Paul , Gilbertson Richard
Published: August 2023

WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated with major, long-term, debilitating side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. The Gilbertson lab has previously shown that WNT-medulloblastomas are devoid of a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover WNT-medulloblastoma specific antigens for mAb targeting, we have first generated bulk and single-cell RNA sequencing profiles of the wild-type and WNT-medulloblastoma-prone mossy-fibre progenitor lineages in the lower rhombic lip, as well as human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next generated plasma membrane proteome profiles of hindbrain germinal zones and WNT-medulloblastomas. Plasma Membrane Profiling (PMP) deploys an isobaric chemical labelling approach -Tandem Mass Tags (TMT) - that allows multiplexing of up to sixteen variables per mass spectrometry experiment and ex vivo TMT-labelling of primary cells. Using this approach, we have mapped the cell surface proteome of our medulloblastoma models. Interrogation of these developmental and tumour data has unmasked WNT-medulloblastoma associated antigens that are specific for prenatal brain and WNT-medulloblastoma, but that are not expressed on critical postnatal tissues. Our workflow integrates multi-omic data sets to uncover a targetable landscape on the surface of WNT-medulloblastoma cells that we have cross-validated with a large cohort of patient RNA sequencing profiles and histological samples of both mouse and human tumours. To translate this dataset to real patient benefit, we are generating high affinity antibodies of these validated cell-surface proteins for assessment in our pre-clinical mouse models. Through our comparative analyses we have additionally identified non-WNT-specific targets and thus aim to expand this approach to identifying targets in other more agressive CNS tumours and brain metastases.
SYST-13 AAV VECTOR ENCODING FC MODIFIED HER2 ANTIBODIES REDUCES TUMOR BURDEN WITH MINIMIZED PERIPHERAL EXPOSURE IN MODELS OF BREAST CANCER BRAIN METASTASIS
Authors: Laks Dan , Ren Xiaoqin , Shah Ishan , Thompson Jeffrey , Clement Joe , Moyer Tyler , Nonnenmacher Mathieu , Carter Todd
Published: August 2023

We engineered a HER2 Ab that inhibited HER2+ breast cancer cell growth in vitro and led to a profound increase in Ab-dependent CD16A receptor stimulation relative to trastuzumab, the standard of care. Blood-brain barrier penetrant AAV vectors were administered intravenously to mice orthotopically engrafted with HER2+ cancer cells. In both prophylactic AAV administration and a treatment model where AAV was dosed post-engraftment, the vectorized Ab significantly reduced tumor burden and prolonged survival. We employed single-cell RNA-Seq to characterize immune responses to these vectorized Abs. Upon dissociation of brains from tumor engrafted mice that underwent intravenous AAV treatment, we performed transcriptomic profiling of CD45+ immune cells. Our results indicate a pronounced innate immune response to the HER2 Ab that increased tumor-proximal natural killer cells and proliferating microglia. Response to gene therapy also included dendritic cells that are mediators of adaptive immune activation. Therefore, the adaptive immune system could augment the efficacy of the therapy when non-exhausted, tumor-associated T lymphocytes are present. To minimize potential neuronal toxicity, we evaluated the use of a GFAP promoter for astrocyte specific expression. Furthermore, to reduce patient risk of cardiac toxicity induced by antibody exposure, we engineered the Fc domain of the antibody so that it would not bind to FcRN, a receptor which promotes antibody recycling and subsequent increased antibody levels in the periphery. In mouse studies, treatment with a BBB-penetrant capsid with a GFAP driven construct and with binding to FcRN eliminated resulted in a 96% reduction in serum antibody levels, to 84% below an estimated cardiac toxicity threshold. Additionally, there was a 78% reduction in antibody levels in the heart, to 98% below an estimated cardiac toxicity threshold. Remarkably, brain levels were maintained. Our animal data indicate that vectorized HER2 antibody gene transfer may address unmet medical needs of patients.
SYST-14 D2C7 CAR EFFECTIVELY AND SAFELY TREATS EGFRWT AND EGFRVIII-EXPRESSING TUMORS FOLLOWING INTRACRANIAL ADMINISTRATION
Authors: Wilkinson Daniel , Wilson Joseph , Lerner Emily , Ryan Katherine , Chandramohan Vidyalakshmi , Landi Daniel , Bigner Darell , Fecci Peter
Published: August 2023

Glioblastoma (GBM) is the most aggressive primary brain cancer with a median survival of less than 16 months. Therefore, significant treatment advances are of critical need. Immunotherapies, such as chimeric antigen receptor (CAR) T cells, have achieved remarkable success in eliminating hematological cancers. Unfortunately, CARs have overall failed to control solid tumors. One major reason for this failure is tumor heterogeneity, a characteristic especially true of GBM. In GBM, EGFRvIII is a commonly targeted tumor antigen; however, only a subset of tumor cells will express EGFRvIII. Thus, EGFRvIII-negative cells easily escape EGFRvIII-targeting CAR therapies. A better approach would be to target multiple antigens or an antigen that is more homogeneously expressed throughout the tumor. More commonly than EGFRvIII expression, glioma cells overexpress the wildtype isoform of EGFR (EGFRwt). Simultaneously targeting EGFRvIII and EGFRwt, instead of targeting each independently, with a CAR will theoretically expand the amount of tumor that will be eliminated by the CAR. Here, we adapted the D2C7scFv that binds both EGFRwt and EGFRvIII into a third generation CAR. D2C7 CAR potently and specifically killed EGFRwt and EGFRvIII-expressing U87 glioma, but not U87 with EGFR knocked out. In xenograft models, intracranially administered D2C7 CAR significantly prolonged survival of mice bearing orthotopic U87vIII, U87 (EGFRwt), and heterogeneous U87/U87vIII tumors compared tocontrols. Additionally, D2C7 CAR was an effective treatment in an orthotopic EGFR-expressing medulloblastoma model. Furthermore, D2C7 CAR treatment led to a significant survival benefit in mice bearing intrancranial A431, an aggressive, EGFR-expressing carcinoma line, a model of metastasis to the brain. Importantly, D2C7 CAR did not show reactivity towards normal tissue with EGFR expression, suggesting a tumor-specific epitope of EGFR is being targeted. Together, these data provide evidence that D2C7 CAR can treat EGFR/EGFRvIII heterogeneous or homogeneous primary or metastatic brain tumors with potentially little-to-no off-tumor toxicity.
SYST-15 GENERATION AND MULTI-DIMENSIONAL PROFILING OF A CHILDHOOD CANCER CELL LINE ATLAS DEFINES NEW THERAPEUTIC OPPORTUNITIES
Authors: Daniel Paul , Sun Claire Xin , Bradshaw Gabrielle , Shi Hui , Loi Melissa , Chew Nicole , Parackal Sarah , Tsui Vanessa , Liang Yuqing , Koptyra Mateusz , Adjumain Shazia , Sun Christie , Chong Wai Chin , Fernando Dasun , Drinkwater Caroline , Tourchi Motahhareh , Habarakada Dilru , Carvalho Diana , Storm Phillip B , Baubet Valerie , Sayles Leanne C , Fernandez Elisabet , Zhukova Nataliya , Dun Matthew D , Ludlow Louise E , Day Bryan , Stringer Brett W , Neeman Naama , Rubens Jeffrey A , Raabe Eric H , Vinci Maria , Tyrrell Vanessa , Fletcher Jamie I , Ekert Paul G , Dumevska Biljana , Ziegler David S , Tsoli Maria , Sulaiman Nur Farhana Syed , Loh Amos Hong Pheng , Low Sharon Yin Yee , Sweet-Cordero E Alejandro , Monje Michelle , Resnick Adam , Jones Chris , Downie Peter , Williams Bryan , Rosenbluh Joseph , Gough Daniel , Cain Jason E , Firestein Ron
Published: August 2023

Paediatric solid tumours are the leading cause of cancer related death amongst children. Identification of paediatric-specific targeted therapies necessitates the use of paediatric cancer models that faithfully recapitulate the patient’s disease. In adult cancers, comprehensive cell line repositories and data atlases have enabled both hypothesis-driven research and scalable screens for new therapies. The generation and characterisation of paediatric cancer cell lines has significantly lagged behind that of their adult counterparts, underscoring the urgent need to develop a paediatric-focussed cell line resource. Herein, we establish a single-site collection of 261 cell lines, including 224 paediatric cancer cell lines representing 18 distinct extracranial and brain childhood tumour types. We subjected 182 paediatric cancer cell lines to multi-omic analyses across three dimensions (DNA-sequencing, RNA-sequencing, DNA methylation) to classify them based on clinically relevant molecular subtypes. In parallel, pharmacological and genetic CRISPR-Cas9 loss of function screens were performed to identify paediatric-specific drug sensitivities and genetic dependencies. Machine-learning approaches were employed to delineate predictive features of therapeutic vulnerabilities in different subtypes of paediatric cancers. By integrating molecular features with functional genomic and pharmacological profiles, we demonstrate how therapeutic target-biomarkers pairs may be rapidly prioritised and advanced. Lastly, we provide cell line data and resources in an open access portal (vicpcc.org.au/dashboard) to support drug development efforts, clinical trial design, and personalised medicine approaches for paediatric cancers of greatest unmet medical need.
SYST-24 PROPOFOL EXERTS ANTI-TUMOR EFFECTS IN GLIOMA AND THE TUMOR MICROENVIRONMENT VIA NON-CODING RNAS AND SECRETED EXOSOMES
Authors: Penning Donald , Cazacu Simona , Nizar Raphael , Xiang Cunli , Goldstein Hodaya , Krasner Matan , Barbiro-Michaely Efrat , Gerber Doron , Kazimirsky Gila , Rogers Lisa , Brown Stephan , Brodie Chaya
Published: August 2023

BACKGROUND

Glioblastoma (GBM), is the most common primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in tumor recurrence and treatment resistance and therefore represent important therapeutic targets. Recent clinical studies suggest propofol impacts subsequent tumor response to treatments and patient prognosis. The effects of propofol on patient derived GSCs alone and in combination with radiation and temozolomide, (TMZ) have not been reported. Objectives: The molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and its effect on cellular communication with microglia was studied. Using GSC spheroids, differentiated glioma and tumor cells on a microfluid chip, effects of propofol alone and together with radiation and TMZ on the self-renewal and stemness of GSCs, their mesenchymal transit and the proliferation and apoptosis of differentiated glioma cells was analyzed. Using transwell plates, the effects of propofol on the cross-talk of GSCs with human microglia cells was examined.

RESULTS

Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations propofol induced a large degree of cell death as demonstrated using microfluid chip. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM and silencing of this lncRNA partially abrogated propofol’s anti-tumor effects. Propofol also inhibited the pro-tumorigenic GSC-microglia cross talk via extracellular vesicles (EVs) and delivery of BDNF-AS.

CONCLUSIONS

Propofol exerted anti-tumor effects on GSCs and differentiated glioma cells by inhibiting cell renewal, proliferation, and mesenchymal transition and by inducing cell death at higher concentration. Propofol also sensitized GSCs to radiation and TMZ. Propofol, which is widely used in GBM surgeries, should be further explored as a potential repurposed drug during resection and an effective adjunct to radiation and TMZ.
SYST-27 INTERROGATION OF THE TUMOR IMMUNE MICROENVIRONMENT REVEALS DISTINCT IMMUNOSUPPRESSIVE LANDSCAPES IN GLIOBLASTOMA
Authors: Weng Linqian , Guyot Mélanie , Garg Abhishek , Lambrechts Diether , Bergers Gabriele
Published: August 2023

High-resolution sequencing technologies have revealed significant inter-and intra-tumoral molecular heterogeneity in glioblastoma (GBM), leading to an urgent need for novel targeted therapies. Our research using representative murine GBM models and various experimental techniques has shown that classical GBMs (e.g., EGFRvIII+, TIMElow) and mesenchymal GBMs (e.g., NF1ko/PTENko/p53ko, TIMEhigh) are both immunosuppressive but in distinct ways. TIMElow GBMs have a more impaired and less functional tumor vasculature, resulting in low infiltration of T cells with anergic features. TIMEhigh GBMs have a more intact BBB revealing overall more adaptive and innate immune cell infiltrates, but with highly dysfunctional T cells and immunosuppressive TME. Congruently, GSEA analysis of both human and murine GBM scRNA-seq data demonstrated enriched immunosuppressive signatures in the myeloid cell populations of TIMEhigh GBM compared to TIMElow GBM. Our findings have also revealed potential adaptive and intrinsic resistant mechanisms to antiangiogenic immunotherapy in TIMElow and TIMEhigh GBMs, respectively, with TIMElow GBMs exhibiting a transitory response to the treatment, while TIMEhigh GBMs being intrinsically resistant due to their intact tumor vasculature and reliance on dysfunctional T cells. We then tested the efficacy of different immunotherapies, including dendritic cell vaccination, a CD40 agonist, and a myeloid cell PI3K activity inhibitor in TIMElow and TIMEhigh tumors. Surprisingly, our results revealed that the response to these treatments can be either beneficial or detrimental and may depend on factors such as tumor antigenicity and TIME subtype. Overall, our study provides new insights into the intricate immune landscape of GBMs, emphasizes the importance of considering tumor subtypes as they may lead to potential unintended consequences of immunotherapies.
TIPS-09 FIRST-IN-HUMAN PHASE 1 TRIAL OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY ANTI-TUMOR ACTIVITY OF WSD0922-FU (NCT04197934): TRIAL IN PROGRESS
Authors: Kizilbash Sani , Jaeckle Kurt , Mrugala Maciej , Allred Jacob , Reid Joel , Zhong Wei , Burns Terry , Giannini Caterina , Sarkaria Jann , Adjei Alex
Published: August 2023

WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934, sponsored by Wayshine Biopharma and FDA OOPD) is a first-in-human phase 1 dose-escalation trial investigating the safety and tolerability of WSD0922-Fu in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were initially treated with oral WSD0922-FU, with doses escalated in cohorts based on a standard 3 + 3 design to determine the maximum tolerated dose (MTD). After establishing the MTD, this trial has now activated three dose expansion cohorts. Two of these cohorts evaluate different dose/schedule strategies in independent populations. The NSCLC cohort includes patients with EGFR mutant NSCLC and CNS metastases, and examines the safety, tolerability, plasma pharmacokinetics and preliminary efficacy of continuous WSD0922-Fu dosing (twice daily, seven days per week). The HGA cohort includes patients with EGFRvIII mutant HGA at first recurrence after prior radiation/temozolomide and examines the impact of higher doses of WSD0922-Fu administered intermittently (twice daily, five days per week). The HGA cohort also includes a food-effect study which evaluates the effect of the fed and fasted states on plasma PK. The third cohort (Brain tumor penetration cohort) includes patients with HGA (any EGFR mutation and/or EGFR amplification) who need a surgical resection for recurrent disease. Patients enrolled will be treated pre-operatively with WSD0922-Fu for five days, and tumor PK/PD will be examined in samples obtained from image-registered brain tumor biopsies. WSD0922-Fu therapy will be resumed after post-operative recovery. Patient enrollment to all three dose expansion cohorts is ongoing.
TIPS-10 FEASIBILITY OF A MULTI-MODALITY CENTRAL NERVOUS SYSTEM SCREENING EVALUATION IN HER2+ BREASTCANCER PATIENTS
Authors: Malani Rachna , Seidman Andrew , Dang Chau , Panageas Katherine , Young Robert , Boire Adrienne , Wilcox Jessica
Published: August 2023

BACKGROUND

Breast cancer is the most common cancer in the world and the second most common to metastasize to the central nervous system (CNS). CNS-metastases are the most common type of brain tumor and have a rising incidence. They are associated with neurologic morbidity and mortality and remain a major clinical challenge. Survival withCNS-metastases is short with a median survival in the order of months. The incidence of CNS-metastases is 5.1% in breast cancer however true prevalence is not known; at autopsy this incidence ranges between 20-40%. One contributing factor towards the development of CNS-metastases in breast cancer is HER2-positivity. Between 25%-48% of patients with HER2-positive metastatic breast cancer develop CNS-metastases. Currently, routine CNS surveillance imaging is not recommended, however guidelines suggest having a low threshold for evaluation with imaging and/or cerebrospinal fluid (CSF) analysis because of the high rate of CNS-metastases. The clinical relevance of occult CNS-metastases, survival after identification of occult CNS-metastases and the importance of earlier initiation of CNS therapy are unknown. Existing treatment strategies for CNS-metastases rely on a combinatorial approach of chemotherapy, radiotherapy and/or surgery which typically affords limited disease control. This trial seeks to study if surveillance imaging and CSF analysis are feasible as early disease detection mechanisms.

METHODS

This is a two-cohort study to establish feasibility of multi-modality CNS surveillance. Patients with HER2+ metastatic breast cancer patients (with no known CNS-metastases) who are either Stage IV (Cohort A) or Stage II/III are eligible (Cohort B). On study, patients will undergo MRI Brain and CSF analysis at 6 monthly intervals. CSF analysis includes cytology, circulating tumor cells and cell-free DNA analysis. We plan to enroll 20 patients (10 onto each cohort). 1 of 20 patients have enrolled. This is the first multi-modality screening feasibility study for patients HER2-positive breast cancer.
TIPS-13 A PHASE II STUDY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS
Authors: Guo Chengcheng , Yang Qunying , Cao Xi , Liao Yixiang , Zhang Ji , Jiang Xiangbing , Li Deipei , Chen Yinsheng , Chen Zhongping
Published: August 2023

BACKGROUND

A single arm clinical trial (NCT04588987) about combination therapy of programmed cell death protein 1 blockades camrelizumab with antiangiogenic agent apatinib has been initiated to investigate their effectiveness for patients with recurrent high-grade Gliomas (HGG).

METHODS

Patients with recurrent HGG will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib.

RESULTS

Up to date (March 9, 2023), 18 patients are enrolled (13 for recurrent glioblastomas and 5 for anaplastic astrocytoma), with a medial follow-up time is 19 months. The median cycles of postoperative combination therapies were 4.5 cycles (95%CI: 3.87-5.12 ), with median progression-free survival of 4.0 months (95%CI: 2.78-5.28 ). One patient (1/18, 5.5%) discontinue the combination treatment because the patient often underwent the extended periods of hospitalization because of unacceptable liver dysfunction, and the other patient (1/18, 5.5%) withdraw the from the trail after receiving the surgery. All enrolled patients appeared one or more treatment-related adverse effects. The most common adverse effects were constipation(58%), hypertension (52%), leukocytopenia (52%), and nausea (47%).

CONCLUSION

the short-term results indicated that the combination therapy might be beneficial for patients with recurrent HGG and improve the patients’ overall survivals. We will present our detailed progress and results on the conference.
TIPS-20 A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN, A TOPOISOMERASE II POISON THAT APPEARS TO CROSS THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS
Authors: Silberman Sandra , Hsu Sigmund , Muzyczenko Zena , Picker Donald
Published: August 2023

Berubicin is a doxorubicin (Dox) analog that appears to cross the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%. A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and Europe is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS). A pre-planned, non-binding futility analysis will be performed after approximately 30 to 50% of all planned patients have reached the primary endpoint. Currently, 97 patients are enrolled with 65 in the Berubicin arm and 32 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 80% and 69% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 38% (Lomustine arm), although less than or equal to 5% of patients discontinued the study due to these events. The data available shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. The study is continuing to evaluate the efficacy of this novel drug candidate and potentially provide therapeutic options for patients after first-line therapy. An updated profile of the patient population, safety, and initial efficacy will be presented.
Association between fresh fruit consumption and the risk of chronic obstructive pulmonary disease-related hospitalization and death in Chinese adults: a prospective cohort study
Authors: Huang Xin , Li Jiachen , Cao Weihua , Lyu Jun , Guo Yu , Pei Pei , Xia Qingmei , Du Huaidong , Chen Yiping , Ling Yang , Kerosi Rene , Stevens Rebecca , Yang Xujun , Chen Junshi , Yu Canqing , Chen Zhengming , Li Liming
Published: August 2023

Background:

Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China.

Methods:

Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders.

Results:

During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR = 0.78, 95% confidence interval [CI]: 0.71–0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m2 ≤ BMI < 24.0 kg/m2); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68–0.89) and 0.69 (95% CI: 0.59–0.79) compared with their counterparts, respectively.

Conclusions:

High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.