bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B018: Epigenetic targeting improves glioblastoma cell sensitivity to chemotherapy
Authors: Tehrani Golnaz Asaadi , Kubick Becca , Datta Meenal 
Published: March 2024

Abstract
Histone deacetylase inhibitors (HDACi) have emerged as a new class of anti-tumor agents for various types of cancers, including glioblastoma (GBM). Recent studies have shown that targeting the GBM epigenome can enhance the effects of standard clinical therapies. Here, we utilized the human U87-GBM cell line to evaluate the cytotoxic properties of three blood-brain-barrier-penetrating HDACi, suberoylanilide hydroxamic acid (SAHA, or Vorinostat), valproic acid (VPA), and CAY10603, both as monotherapies and in combination with the chemotherapeutic agent temozolomide (TMZ). Combination Index (CI) was quantified by MTT assay and human normal astrocytes (HNAs, SV40T) were used as cytotoxic controls. We found that HDACi significantly reduced cell viability and increased cell death of human GBM cells, but not HNAs. Combination therapy of HDACi with TMZ generated increased cytotoxic activity in comparison to TMZ monotherapy, with the combination of VPA and TMZ having the strongest effect (30% viability following VPA/TMZ treatment, compared to 42% SAHA/TMZ, 45% CAY10603/TMZ, and 85% TMZ alone). In contrast, when evaluating epi-drugs as monotherapies, at intermediate concentrations, 1.9 μM CAY10603 was most effective in decreasing U87-GBM cell viability (27%) particularly at micromolar concentrations, compared to 3.7 μM SAHA (36%) and 1.5 mM VPA (51%). In HNAs, CAY10603, SAHA, and VPA decreased cell viability to 80%, 87%, and 90%, respectively.These findings suggest that HDACi synergize with TMZ to enhance its cytotoxicity. The promising anti-tumor effects these HDACi-s warrant preclinical studies.
Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta. Epigenetic targeting improves glioblastoma cell sensitivity to chemotherapy [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 B018.
Abstract B029: A novel lupus-associated antibody that inhibits the growth of aggressive high-grade glioma orthotopic xenografts and enhances radiotherapy via a unique mechanism
Authors: Johns Terrance G. , Kuchibhotla Mani , O'Sullivan Kim , Ng Zi Ying , Palanisamy Ranjith , Campbell James , Dubljevic Valentina , Endersby Raelene 
Published: March 2024

Abstract
A major immune dysregulation in lupus patients is the generation of autoantibodies targeting a range of self-molecules. Some of these lupus antibodies may have anti-tumor activity in high-grade glioma (HGG). An autoantibody, 3E10, was isolated from a mouse model of lupus that has high affinity for DNA. Two different humanized forms of 3E10 were generated, PAT-DX1 (a di-scFV) and PAT-DX3 (a humanized IgG1). Neither DX1 nor DX3 inhibited the in vitro growth of HGG patient-derived cell lines, either alone or in combination with radiotherapy (RT). In contrast, both antibody constructs inhibited the growth of GBM6 orthotopic xenografts in mice as single agents, consistent with our data showing uptake of labelled DX1 in HGG xenografts. Interestingly, despite its larger molecular weight, DX3 displayed greater anti-tumor activity than DX1, possibly due to improved tumor localization. DX1 showed at least additive anti-tumor activity in combination with RT against GBM6 xenografts, significantly extending survival. Neutrophils produce NETs, a proinflammatory form of cell death that generates web-like structures composed of various injurious enzymes and DNA. NET release promotes a favorable tumor environment through induction of cellular proliferation and angiogenesis. NETs cause resistance to therapeutics in a variety of cancers and their inhibition improves response to these therapeutics. Our published data shows that DX1 inhibits the formation of NETs in neutrophils, suggesting this could be its mechanism of action and is consistent with the lack of DX1 in vitro activity. Large scale production of DX1 has been optimized and toxicology and safety studies in rats and non-human primates have not identified any concerns. A first in human Phase 1 clinical trial of DX1 is planned in 2024 and will include HGG patients.
Citation Format: Terrance G. Johns, Mani Kuchibhotla, Kim O'Sullivan, Zi Ying Ng, Ranjith Palanisamy, James Campbell, Valentina Dubljevic, Raelene Endersby. A novel lupus-associated antibody that inhibits the growth of aggressive high-grade glioma orthotopic xenografts and enhances radiotherapy via a unique mechanism [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 B029.
Abstract B031: A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes de novo guanylate synthesis and glioblastoma growth
Authors: Chen Yu-Jung , Iyer Swathi V. , David Hsieh Chun-Cheng , Wang Tao , Li Jing , Lien Michelle C. , Ganbold Mungunsarnai , Xie Xuanhua P. , Jayewickreme Chenura , Brady Sean F , Lim Kyun , Parada Luis F 
Published: March 2024

Abstract
Glioblastoma is a malignant disease with dire prognosis and in urgent need of improved therapeutics. We identify a small compound, Gliocidin, that kills glioblastoma cells while sparing replicative mouse embryonic fibroblasts. Gliocidin activity reveals a de novo purine synthesis pathway metabolic vulnerability in glioblastoma caused by indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). Gliocidin mediated IMPDH2 blockade reduces intracellular guanine nucleotide levels causing nucleotide imbalance, replication stress, and tumor cell death. Gliocidin is a prodrug anabolized into its tumoricidal metabolite by the enzyme nicotinamide nucleotide adenylyltransferase (NMNAT1) of the NAD+ salvage pathway. In vivo, Gliocidin penetrates the blood brain barrier and extends orthotopic murine GBM mouse survival. The DNA alkylating agent, Temozolomide (TMZ), induces Nmnat1 expression causing a synergistic tumor killing effect and additional survival benefit in patient-derived xenograft (PDX) orthotopic mouse models. This study brings Gliocidin to light as a prodrug that can improve the survival of GBM patients.
Citation Format: Yu-Jung Chen, Swathi V. Iyer, Chun-Cheng David Hsieh, Tao Wang, Jing Li, Michelle C. Lien, Mungunsarnai Ganbold, Xuanhua P. Xie, Chenura Jayewickreme, Sean F Brady, Kyun Lim, Luis F Parada. A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes de novo guanylate synthesis and glioblastoma growth [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 B031.
Abstract B038: Accurate quantitative profiling of rna modifications and their associations with glioblastoma
Authors: Morales Shnaider Frank A , Eddings Coston , Simpson Jennifer , Tannous Bakhos A. , Chiu Norman 
Published: March 2024

Abstract
Every chemical group that is added to one of the canonical ribonucleotides, i.e., RNA modification, in a specific transcript can potentially alter the RNA folding as well as the RNA-protein interactions. Hence, RNA modifications are considered as post-transcriptional regulators for RNA splicing, RNA stability, and translation, just to name a few. Today, 170+ different RNA modifications have been identified, but only half a dozen of them are linked to glioblastoma (GBM). On the other hand, other RNA biology studies indicated the interplays between RNA modifications within a specific epitranscriptome could play a regulatory role in cellular activities. Although suitable methods for profiling RNA modifications in a specific epitranscriptome are available, the lack of ribonucleoside standards has prohibited the accurate quantification of each detectable RNA modification. To address this analytical challenge, our group has recently developed a mass spectrometric method that can achieve accurate quantitative profiling of untargeted RNA modifications without using any standards. Using the developed method, all the RNA modifications in patient-derived GBM cell lines could be profiled with high accuracy. In total, 31 different RNA modifications were detected in the GBM epitranscriptomes. By comparing with the profile detected in healthy human brain tissues, a unique set of upregulated RNA modifications is associated with the development of GBM. These findings are supported by the upregulated gene expression data obtained from GBM patients that are available in The Cancer Genome Atlas program.
Citation Format: Frank A Morales Shnaider, Coston Eddings, Jennifer Simpson, Bakhos A. Tannous, Norman Chiu. Accurate quantitative profiling of rna modifications and their associations with glioblastoma [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 B038.
Abstract IA016: Metabolic reprogramming and cancer progression in patients
Authors: DeBerardinis Ralph J. 
Published: March 2024

Abstract
Many human diseases, including cancer, involve alterations of cellular metabolism caused either directly or indirectly by mutations in genes that regulate the metabolic network. In cancer, reprogrammed metabolic activities arising from mutations in tumor suppressors and oncogenes are thought to contribute both to cancer initiation and progression, particularly metastasis. Many factors intrinsic or extrinsic to the cancer cell impact metabolic properties within tumors and influence vulnerabilities that could presumably be exploited to suppress cancer progression. Although many insights about metabolic regulation have been derived from reductionist models of cancer cell growth in culture, these models do not incorporate all of the factors – particularly cancer cell-extrinsic factors – that contribute to cancer progression. I will describe approaches to assess cancer metabolism within intact tumors, including in cancer patients. We use a multidisciplinary approach to infuse 13C-labeled nutrients (13C-glucose, 13C-acetate, 13C-glutamine) during surgical tumor resection in patients with malignancies in the brain, lung, kidney and other organs. Isotope labeling in metabolites extracted from tumors and adjacent, nonmalignant tissue provides information metabolic pathways activated or repressed in the tumors. By following clinical outcomes over time, we have identified labeling features and pathways that correlate with metastasis and early demise. I will discuss how these features reflect the evolution of metabolic properties and liabilities during human cancer progression, and how parallel studies in mice have allowed us to define mechanisms by metabolism supports metastasis.
Citation Format: Ralph J. DeBerardinis. Metabolic reprogramming and cancer progression in patients [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 IA016.
Abstract IA026: Metabolic dependencies of brain metastases
Authors: Pacold Michael E 
Published: March 2024

Abstract
Cells require nutrients to make biomolecules required for growth and proliferation, and restricted availability of these nutrients prevents cell growth. Nutrient limits are imposed by the extracellular environment, such as the brain interstitial fluid, which maintains low levels of amino acids such as serine and glycine. These amino acids serve as neurotransmitters, and are needed to make proteins, nucleotides, and antioxidants. Cells also make some metabolites, such as coenzymes, in limiting quantities. Both acute and chronic nutrient depletion and hypoxia contribute to the pathogenesis of many diseases including autoimmune disease, cardiac disease, and cancer. Cells entering, growing, or proliferating in the brain or other low-nutrient environments must find other sources of serine, glycine, and coenzymes or synthesize their own, and prioritize the efficient use of nutrients and oxygen. We are interested in discovering the metabolic adaptations needed for cells to enter the brain, determining if cells acquire these adaptations before they enter the brain or adapt following entry into the brain, and targeting these adaptations with small molecule inhibitors.
Citation Format: Michael E Pacold. Metabolic dependencies of 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 IA026.
Abstract A014: A valid second line therapy for high grade serous ovarian cancer
Authors: Rizzolio Flavio , Mauceri Matteo , Perina Tiziana , Saorin Gloria , Caligiuri Isabella , Canzonieri Vincenzo , Cemazar Maja , Kamensek Urska , Kranic Simona Brezar 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSOC) requires more effective second-line therapies as current options are limited. Maintenance therapy with PARP inhibitors has improved therapeutic efficacy, but there are no viable options after tumor recurrence. Since 2018, our research group has been investigating the significance of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in OC (Russo Spena et al., 2018). In 2019, we developed a potent and reversible PIN1 inhibitor called VS10 (Russo Spena et al., 2019). To enhance drug delivery efficiency, we produced VS10 nanocrystals using Pluronic F127 and coated them with albumin, resulting in VS10AF nanocrystals. The new nanodrug was characterized using various techniques, including transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements, Fourier-transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD). Subsequent in vitro and in vivo experiments were conducted, including determining the IC50 values through dose-response curves and evaluating synergistic effects. In vivo efficacy and toxicity were assessed using nude mice injected subcutaneously with OVCAR5 cells. The water dispersion of VS10AF demonstrated four times higher solubility compared to VS10 alone, and TEM and XRD analyses confirmed the crystalline nature of the nanoparticles. VS10 release from the drug delivery system exhibited optimal kinetics observed within five days. Both VS10AF and VS10 showed comparable in vitro IC50 values, and synergistic effects were observed when combined with doxorubicin or liposomal doxorubicin. Moreover, in vivo studies demonstrated that the combination of VS10AF and liposomal doxorubicin effectively reduced tumor growth. After first-line chemotherapy, ovarian cancer patients have limited treatment options. PIN1 represents a promising therapeutic target in HGSOC due to its regulation of multiple oncogenes and tumor suppressors. Our findings suggest that VS10AF could serve as an effective PIN1 inhibitor and synergize with second-line chemotherapy drugs such as doxorubicin or liposomal doxorubicin. Furthermore, the excellent safety profile of VS10AF observed in vivo supports its potential for further clinical development.
Citation Format: Flavio Rizzolio, Matteo Mauceri, Tiziana Perina, Gloria Saorin, Isabella Caligiuri, Vincenzo Canzonieri, Maja Cemazar, Urska Kamensek, Simona Brezar Kranic. A valid second line therapy for high grade serous ovarian cancer [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 A014.
Abstract A069: High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants
Authors: Connor Adele E. , Lysaght Joanne , Brennan Donal J. , Simpson Jeremy C. , Perry Antoinette S. 
Published: March 2024

Abstract
Introduction: As high-grade serous ovarian cancer (HGSOC) rarely shows symptoms, most patients present with metastases. Tumor heterogeneity between metastases may impede a patient’s response to therapy and thus impact survival. We aim to decipher the heterobiology of HGSOC lesions using high-resolution imaging of patient-derived explants (PDEs), to determine the differential treatment response between primary and metastatic tumors. Methods: PAX8, CK7, RAD51, γH2AX, Ki67, cPARP, and CD3 were chosen to enumerate tumor and T cells, and their activity. Antibodies were optimized in monolayer and spheroid cultures of HGSOC cell lines, COV318 and OVCAR4. CD3 was optimized in FFPE human tonsillitis tissue. Primary and metastatic HGSOC explants were cultured for 48h followed by 24h fixation. Several immunostaining and optical clearing protocols were tested on PDEs, which were imaged using a fully automated confocal high-content screening system. Results: Immunostaining and automated image analysis facilitated the identification of individual nuclei within PDEs without Refractive Index (RI) matching or optical clearing. However, high background impeded further image analysis, preventing the quantification of certain antibodies. Glycerol-based RI matching and ScaleS tissue clearing were implemented to try and overcome this. However, neither generated sufficiently high-quality images for analysis. A novel Clearing-enhanced 3D (Ce3D) immunostaining system recently developed for high-quality multiplex fluorescence microscopy of large tissue volumes was tested. While individual nuclei were recognized, as well as RAD51 foci and CK7 cytoskeleton staining, image analysis was still impeded due to high background. Conclusions: Protocols without RI matching and optical clearing can stain large, complex structures such as PDEs. However, high background impedes image analysis suggesting the need for optical clearing and RI matching. The inclusion of various RI matching and/or optical clearing steps failed to overcome high background staining. Further work is ongoing to refine immunostaining, RI matching, optical clearing, and mounting of PDEs to allow the quantification of all antibodies.
Citation Format: Adele E. Connor, Joanne Lysaght, Donal J. Brennan, Jeremy C. Simpson, Antoinette S. Perry. High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants [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 A069.
Abstract A079: G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma
Authors: Huang Hsuan Shun , Chu Tang-Yuan 
Published: March 2024

Abstract
The incidence and mortality burden of ovarian high-grade serous carcinoma (HGSC) is increasing rapidly in Taiwan and many urbanized countries. The etiology of HGSC, especially that responsible for the rapid and advanced seeding of the tumor in the peritoneum, which causes late diagnosis and poor prognosis, is elusive. Epidemiological and molecular studies have demonstrated incessant ovulation is the main culprit of ovarian cancer. Our previous studies also elucidated some transforming factors in the ovulatory follicular fluid (FF). We unveiled the oncogenic activities of ovulation on the malignant transformation of fallopian tube fimbria epithelial cells (FTEC), the primary origin of HGSC. We hypothesized that ovulation could also promote the intraperitoneal spreading of tube originated HGSC. First, in both human and mouse specimens, we observed a dramatic influx of neutrophils in the peritoneal fluid during ovulation after LH surge. Ovulatory FF from IVF women, when injected to the mouse peritoneum cavity, readily induced neutrophil influx and activated neutrophil extracellular trap (NET) formation (NETosis). Among the different neutrophil activators in FF, we found G-CSF is responsible for the ROS and PAD4 increases and histone citrullination in NETosis. This FF-GCSF-induced NETosis increases anchoring independent growth (AIG), cell adhesions, and matrigel invasion of STIC-mimicking FTEC and HGSC cells. Interestingly, while the AIG-promoting activity of the ovulation-activated NET showed cell autonomous, the adhesion and invasion activities were non-autonomous conferred by the conditioned medium of the activated neutrophils. Shown by a FF plus tumor cell i.p. coinjection mouse xenograft model, intraperitoneal seeding was increased by the coinjection and was inhibited by the inhibitor (GSK) of NETosis. Taken together, we disclosed an unprecedented intraperitoneal neutrophil influx/activation activity of ovulation. This activity, presumably acting as an antimicrobial to prevent ascending infection during fertilization, is utilized to aid the peritoneal seedings of tubal-origin HGSC.
Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous 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 A079.
Abstract A082: Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and ovarian cancer
Authors: Stack M. Sharon , Liu Yueying , Yang Jing , Hilliard Tyvette S. , Wang Zhikun , Johnson Jeff , Wang Wanrui , Dominique Gena , Harper Elizabeth I. , Stavrou Nicholas M. , Juncker-Jensen Anna 
Published: March 2024

Abstract
Obesity is a recognized non-infectious pandemic that increases ovarian cancer (OvCa) incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity (DIO) mouse model (Liu et al. Can.Res. 2015; 75:5046). DIO also elevated expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of de novo lipogenesis and lipid homeostasis. A follow-up study using DIO models showed a significantly diminished response to standard-of-care (SOC) paclitaxel/carboplatin chemotherapy in high fat diet (HFD) mice relative to low fat diet (LFD) controls (Liu et al., J.Exp.Clin.Can.Res. 2023; 42:165). Both studies showed an effect of DIO on tumor fibrosis and immune landscape and these changes were also observed in the ovarian cancer tumors of women with high body mass index. In the current study, we have evaluated the effect of inhibitors of SREBP1 processing, in combination with SOC chemotherapy, in the context of DIO in pre-clinical models of OvCa. Our results show significantly diminished post-treatment tumor recurrence in HFD mice receiving SOC chemotherapy plus an SREBP1 processing inhibitor, with concomitant alterations in the peritoneal immune landscape. Together these data suggest that the reported negative impact of obesity on OvCa patient survival may be due obesity-induced changes in lipid regulatory factors (SREBP1) and the tumor microenvironment (immune landscape, fibrosis) that alter chemosensitivity. These data demonstrate a contribution of host obesity to ovarian tumor progression and therapeutic response and support future combination strategies targeting SREBP1, immune cells and/or fibrosis in the obese host.
Citation Format: M. Sharon Stack, Yueying Liu, Jing Yang, Tyvette S. Hilliard, Zhikun Wang, Jeff Johnson, Wanrui Wang, Gena Dominique, Elizabeth I. Harper, Nicholas M. Stavrou, Anna Juncker-Jensen. Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and ovarian cancer [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 A082.