bluuebunny/crossref_metadata_2025_split huggingface dataset:
Norwegian Sea Oceanic Basin and Prograded Margins Composite Tectono-Sedimentary Element
Authors: Faleide Jan Inge , Abdelmalak Mohamed Mansour , Zastrozhnov Dmitrii , Lasabuda Amando P. E. , Hjelstuen Berit Oline Blihovde , Laberg Jan Sverre , Planke Sverre 
Published: March 2024

Abstract
The Norwegian Sea oceanic basins and prograded margins have developed since NE Atlantic break-up in the earliest Eocene. Significant amounts of sediments were fed to the regionally subsiding and widening Norwegian Sea during the Cenozoic as a result of several phases of uplift and erosion of the bounding shelves and their hinterland. Despite an overall passive-margin evolution, the area experienced tectonic events and associated processes that interrupted the regional subsidence, causing contraction/inversion and tilting. The post-break-up depositional history of the mid-Norwegian margin comprises two main stages: (1) middle Eocene–Pliocene margin subsidence and relatively modest sedimentation during a period of climatic decline; and (2) latest Pliocene–Pleistocene full-scale northern hemisphere glaciations that resulted in deep erosion of shelves and hinterlands, and very high sedimentation rates and large-scale continental margin progradation. Slope failures within rapidly deposited glacial sediments affected both prograded margins, releasing large slides that travelled downslope into the oceanic Norway and Lofoten basins. Despite a long exploration history for hydrocarbon prospects in deeper waters and large amounts of data acquisition, no significant discovery has been made.
Abstract A001: Silencing of EYA4 regulates stemness in H3K27M-mutant diffuse midline glioma
Authors: Barravecchia Ivana , Sharma Monika , Magnuson Brian , Ferris Sarah F. , Apfelbaum April , Koschmann Carl , Lyssiotis Costas A. , Ljungman Mats , Galban Stefanie 
Published: March 2024

Abstract
Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG biopsies. We hypothesized that ALDH-mediated stemness and resistance may in part be driven by the oncohistone itself. Upon deletion of H3K27M, ALDH1A3 expression decreased dramatically and was accompanied by a gain in astrocytic marker expression and a loss of neurosphere forming potential, indicative of changes in differentiation. Here we show that the oncohistone regulates histone acetylation through ALDH1A3 in a Wnt-dependent manner and that loss of H3K27M expression results in re-sensitization of DMGs to radiotherapy. The observed elevated Wnt signaling in H3K27M-altered DMG likely stems from a dramatic suppression of mRNA and protein expression of the Wnt inhibitor EYA4 driven by the oncohistone. Thus, our findings identify EYA4 as a bona fide tumor suppressor in DMG that upon suppression, results in aberrant Wnt signaling to orchestrate stemness and differentiation. Future studies will therefore explore whether overexpression of EYA4 in DMG can impede growth and invasion. In summary, we have gained mechanistic insight into H3K27M-mediated regulation of cancer stemness and differentiation, which provides rationale for exploring new therapeutic targets for DMG.
Citation Format: Ivana Barravecchia, Monika Sharma, Brian Magnuson, Sarah F. Ferris, April Apfelbaum, Carl Koschmann, Costas A. Lyssiotis, Mats Ljungman, Stefanie Galban. Silencing of EYA4 regulates stemness in H3K27M-mutant diffuse midline glioma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A001.
Abstract A017: Cell-specific photodynamic therapy for high grade gliomas
Authors: Arias Alberto Guillermo 
Published: March 2024

Abstract
High grade gliomas (HGG) are infiltrative tumors. Surgery is the initial treatment, aiming to alleviate intracranial pressure and reduce tumor volume. Additional treatment includes radiotherapy and chemotherapy with Temozolomide. Despite these interventions, the 5-year survival rate for HGG patients remains below 10%, with a median survival of less than 2 years. Thus, there is an urgent need for novel therapeutic approaches In this talk I will present in vitro studies on a novel therapeutic approach using cell-specific Photodynamic Therapy. This therapy uses a drug that is activated by light exposure, called photosensitizer, generating reactive oxygen species capable of inducing cell death. This type of treatment has been used in clinical practice for decades, but its use in cancer treatment is rather new and is currently being evaluated in clinical trials in different cancer types. Here, we used a new cyclic peptide obtained through in vivo panning that can bind selectively to HGG cell lines. This peptide was coupled to the photosensitizer "Verteporfin". In vitro studies showed high toxicity and specificity of this peptide using different conditions, doses and incubation periods. Using immunodeficient mice with intracranial and also subcutaneous tumor induction, we studied the biodistribution of this peptide, showing higher accumulation in the tumor than in the healthy brain. These preliminary results set the ground for upcoming in vivo preclinical studies. Furthermore, we seek to explore the diagnostic and therapeutic potential of our HGG-specific peptide by coupling it to the radionuclide Lutetium 177.
Citation Format: Alberto Guillermo Arias. Cell-specific photodynamic therapy for high grade gliomas [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A017.
Abstract A021: Exosome delivered combinatorial treatment for malignant brain tumors
Authors: Thomas Sydney , Gourishetti Karthik , Rangavajhula Karthik , Bhere Deepak 
Published: March 2024

Abstract
Glioblastoma (GBM), a World Health Organization (WHO) Grade IV astrocytoma, is a highly aggressive brain tumor with poor prognosis. Current therapeutic approaches, which include surgery, chemotherapy, and radiation therapy, are largely ineffective and often result in tumor recurrence. Several characteristics of the tumors make them challenging to treat, including their protection by the blood-brain barrier, which hinders effective treatment delivery. Our research addresses this issue by using exosomes, which are small cell-derived vesicles, as delivery vehicles for microRNA (miR) therapies. Dysregulation of miR expression has been implicated in tumorigenesis, and targeting these dysregulated miRs is emerging as a promising approach to tumor treatment. In particular, miR-7 and miR-124 have been identified as tumor-suppressive miRs that are downregulated in various tumors, including GBM. In this study, stem cell-derived exosomes loaded with miR-7 and miR-124 have been evaluated as a combinatorial approach for treating GBM. In our work, human adipose stem cells (ADSCs) were transduced with the target miR-7 and miR-124 plasmids and cultured in exosome-depleted FBS. The miR-containing exosomes from the ADSCs were then isolated, purified, quantified, and characterized for use in subsequent studies. Murine and human GBM cells as well as primary patient-derived primary GBM cells were treated with miR-7 and miR-124 exosomes, and the efficacy of exosome treatment was determined using cell viability assays and microscopy. The mechanisms of miR modulation of cell proliferation and cell death pathways were analyzed with time-course western blot analysis. Orthotopic animal models of GBM will be used to assess the effectiveness of our methods in vivo. Our results have demonstrated successful delivery of miR-7 and miR-124 to GBM cells via stem cell-derived exosomes. Data show that treatment with these tumor-suppressive miRs halts GBM growth in vitro by modulating multiple pathways involved in tumor growth and progression. While we await results of our in vivo studies, our preliminary data demonstrate that delivery of miR-7 and miR-124 via stem cell-derived exosomes is a promising therapeutic approach for treating GBM.
Citation Format: Sydney Thomas, Karthik Gourishetti, Karthik Rangavajhula, Deepak Bhere. Exosome delivered combinatorial treatment for malignant brain tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A021.
Abstract A035: Radiation-induced senescence as a driver of glioblastoma recurrence
Authors: Jordan Ben R. , Tomimatsu Nozomi , Di Cristofaro Luis Macedo , Kanji Suman , Mukherjee Bipasha , Burma Sandeep 
Published: March 2024

Abstract
Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR), yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. An understanding of mechanisms driving GBM recurrence is critical for improving therapy. During GBM therapy, both the tumor and normal brain tissue surrounding the tumor are treated with up to 60 Gy of IR. IR is a potent inducer of senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting matrix metalloproteinases, chemokines, cytokines, and growth factors that create a senescence-associated secretory phenotype (SASP). We have shown previously that IR-induced senescence of astrocytes in the brain leads to the secretion of SASP factors that promote the growth and invasiveness of tumor cells in mouse models of GBM (Fletcher-Sananikone, et al, Cancer Research, 2021). Following up on this study, we irradiated a panel of GBM cell lines and found that a significant fraction of these senesced rapidly in a p21-dependent manner. Senescent glioma cells upregulated SASP genes in a NF-kB-dependent manner, prominently, the interleukin IL6, which is an activator of the JAK-STAT pathway. Conditioned media from senescent GBM cells activated the JAK-STAT pathway in non-senescent GBM cells as well as promoted tumor cell proliferation and radioresistance. Interestingly, conditioned media from senescent GBM cells could also activate the NF-kB pathway and induce SASP in non-senescent cells. These results indicate that senescent GBM cells can activate pro-tumorigenic pathways in their non-senescent counterparts and SASP can spread from senescent to non-senescent cells. Bioinformatic analyses of the transcriptomic profiles of irradiated GBM cells and publicly available data from the TCGA database revealed that the inhibitor of apoptosis protein cIAP2 is a critical survival factor for senescent glioma cells. We find that targeting cIAP2 using Smac mimetics triggers apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells, like astrocytes. Upregulation of cIAP2 in irradiated tumor cells was also observed in PDX models of GBM. Using these PDX models, we are currently validating novel senolytic-based therapeutic approaches to mitigate tumor recurrence after radiotherapy. In sum, our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence after radiotherapy.
Citation Format: Ben R. Jordan, Nozomi Tomimatsu, Luis Macedo Di Cristofaro, Suman Kanji, Bipasha Mukherjee, Sandeep Burma. Radiation-induced senescence as a driver of glioblastoma recurrence [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A035.
Abstract IA004: Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies
Authors: Singh Sheila K 
Published: March 2024

Abstract
Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for the treatment of GBM. In this talk, we summarize recent clinical and pre-clinical efforts to develop immunotherapeutic and chimeric antigen receptor (CAR) T cell treatment strategies for GBM recurrence, including challenges in the form of fundamental mechanisms of therapy evasion by tumor cells, such as immense intratumoral heterogeneity, suppression of the tumor immune microenvironment, and low mutational burden. Insights from these advances and challenges have shaped our development of a translational research pipeline from initial target discovery, through target validation and exploration of mechanism, to building new biotherapeutics against novel cancer targets, and preclinical testing in our patient-derived animal models of treatment-resistant GBM. We have tracked GBM cell populations that undergo clonal evolution as a result of selective pressures exerted by standard treatments to identify the cellular composition of the recurrence, to allow us to determine the intracellular signaling pathways that drive GBM relapse. Ultimately, we will design rational combinations of therapeutics that can reignite the anti-tumor immune response, effectively and specifically target tumor cells, and reliably decrease tumor burden for GBM patients.
Citation Format: Sheila K Singh. Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA004.
Abstract IA007: Distinct immune landscapes characterize highly and minimally invasive brain metastases
Authors: Siegel Peter 
Published: March 2024

Abstract
Background: Cancer metastasis to the brain is a common complication of advanced disease with limited therapeutic options. Inefficient treatment is influenced, in part, by the unique composition of the brain microenvironment. Brain metastases (BrM) grow in two distinct patterns, either as minimally invasive (MI) masses with well-defined borders, or as tumors with highly invasive (HI) growth into surrounding brain tissue. HI BrM are associated with poor prognoses compared to MI BrM; however, differences in the tumor immune microenvironments (TIME) between these two lesion types remain largely unknown. Here, we investigate how the TIME differs between HI and MI BrM. Methods: We use Nanostring Digital Spatial Profiling coupled with the Cancer Transcriptome Atlas panel on 5 MI and 15 HI BrM patient samples (lung and breast cancer). This technique enables specific isolation of cancer cells at the tumor-brain interface and quantification of 1,825 cancer-specific RNA targets. Additionally, we perform imaging mass cytometry (IMC) on 119 BrM samples (lung cancer, breast cancer, melanoma, other) from 46 patients, encompassing over 350,000 cells. Samples represent BrM from various primary sites, including cancers of the lung, breast, and skin, and include patient-matched samples from the brain-tumor interface (‘margin’) or the centre of the metastatic lesion (‘core’). Results: The Nanostring Digital Spatial Profiling revealed a list of 106 and 73 differentially expressed genes in MI vs HI breast and lung BrM, respectively. Gene set enrichment analyses revealed that an interferon gamma (IFNγ) pathway signature was enriched in MI BrM and lost in HI BrM, which was confirmed by immunohistochemical staining for pSTAT1, consistent with an “immune hot” TIME in MI BrM when compared to HI lesions. Using IMC technology, we identified 20 different cell types, activation states, and spatially-defined cellular neighborhoods across our BrM patient samples. In comparison to MI samples, HI BrM have lower numbers of B cells, CD4+ T cells, and CD4- CD8- T cells in both the core and margin samples, and lower numbers of CD8+ T cells and regulatory T cells in the margin samples only. Conclusion: These data suggest that HI BrM invade into an immunosuppressed microenvironment while MI BrM are characterized by an active anti-tumor immune infiltrate. Together, this work suggests potential immune regulation of BrM invasion, which warrants further investigation.
Citation Format: Peter Siegel. Distinct immune landscapes characterize highly and minimally invasive brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA007.
Abstract PR-004: Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma
Authors: Uccello Taylor P. , Ren Jun , Amoozgar Zohreh , Zhao Yuhui , Lei Pin-Ji , Ho William W. , Roberge Sylvie , Huang Peigen , Duda Dan G. , Xu Lei , Jain Rakesh K. 
Published: March 2024

Abstract
Purpose: Ependymoma (EPN) is a common type of brain tumor in children and is often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of unique EPN subtypes and revealed a critical role of EPHB2. However, the immune system's role in tumor progression and treatment response remains poorly understood. New treatments for EPN are desperately needed and should be developed in a molecular subtype-specific fashion. Experimental Design: We developed a syngeneic mouse model using subtype-specific EPHB2-driven genetically engineered EPN tumor cells. Druggable targets were identified by matching transcriptomic signatures with the target spectrum of FDA-approved drugs. After identifying dasatinib as a potentially effective agent, we measured the changes in the immune microenvironment during EPN growth and after dasatinib treatment. Results: Transcriptomic profiling of EPHB2-driven EPN and analysis of a human EPN dataset revealed multiple protein kinases as potential druggable targets. We found that the multikinase inhibitor dasatinib potently inhibited the growth of EPN both in vitro and in vivo, mainly through blocking EPHB2 and ABL1 signaling. We found an increased frequency of immunosuppressive M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. However, treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing the TAMs toward an anti-tumor M1-like phenotype and increasing CD8 T cell activation. Furthermore, dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 T cells compromised the durability of EPN responses and reduced overall survival. Conclusions: These data indicate that dasatinib may be an effective therapy for EPHB2-driven molecular subgroup of EPNs by activating the anti-tumor immune response and support further investigations of dasatinib in clinical trials.
Citation Format: Taylor P. Uccello, Jun Ren, Zohreh Amoozgar, Yuhui Zhao, Pin-Ji Lei, William W. Ho, Sylvie Roberge, Peigen Huang, Dan G. Duda, Lei Xu, Rakesh K. Jain. Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-004.
Abstract A024: High throughput screen for identifying inducers of Autophagic Cell Death in Ovarian Carcinoma
Authors: Hanjra Pahul , Liu Andrea , Ferrer Marc , Sood Anil K. , Wen Yunfei 
Published: March 2024

Abstract
Ovarian carcinoma continues to have the highest associated mortality among gynecologic malignancies. Despite surgery and chemotherapy, relapse and drug-resistant disease remains common. Thus, new therapeutic targets and improved combination regimens are needed. Autophagy is a conserved process cells use to remove and recycle old or damaged contents and maintain homeostasis, especially in times of cellular stress. Prolonged autophagy can result in cell death independently of apoptosis in a process known as autophagy cell death (ACD). This offers an alternative therapeutic strategy to target cancer cells, which are often resistant to apoptosis. In this study, we performed a high-throughput screen using the Mechanism Interrogation PlatE (MIPE) oncology library in HeyA8 and SKOV3 spheroids to identify drugs with high potential to induce ACD. Screening was performed in two phases: 1) Enrichment for compounds that decreased cell viability; 2) Enrichment for compounds able to induce autophagic flux in SKOV3 spheroids. We used a pft-LC3-RFP-GFP construct which was stably expressed in SKOV3 cells before 3-D culture as an autophagy index, and the accumulation of LC3-RFP in SKOV3 spheroids was measured in response to the treatments from MIPE compounds versus compared to control. An analog of the top hit of the screen results was the SIRT1 inhibitor, EX-527. We next performed a pharmacodynamic study in OVCA432-ip1-luc tumor-bearing mice to identify potential biomarkers of drug activity. We found that expression of the autophagy-related protein, LC3B, increased in tumors in a dose-dependent manner, forming loci indicative of autophagy flux at 20 mg/kg. Work is ongoing to identify rational combinations for use of EX-527 in management of ovarian carcinoma, and to characterize its mechanism of action.
Citation Format: Pahul Hanjra, Andrea Liu, Marc Ferrer, Anil K. Sood, Yunfei Wen. High throughput screen for identifying inducers of Autophagic Cell Death in Ovarian Carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A024.