tbuckley/cabot-search huggingface dataset:
Abstract IA026: Metabolic dependencies of brain metastases
Authors: Michael E Pacold
Journal: Cancer Research (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.
Efficacy and safety of topical <i>Streptococcus</i> postbiotic emollient in adolescents and adults with mild‐to‐moderate atopic dermatitis: A randomized, double‐blind, vehicle‐controlled trial
Authors: Min Seo Kim, Hyeon Jin Kim, So Min Kang, Young Mok Heo, Jiseung Kang, Tae Kyeong Ryu, Hyun Jeong Kim, Young‐Bong Choi, Sol Kim, Youn Hwa Nho, Seunghyun Kang, Lee Smith, Ai Koyanagi, Nikolaos G. Papadopoulos, Hyungwoo Jo, Dong‐Geol Lee, Jung U Shin, Dong Keon Yon
Journal: Allergy (2024)

A complete de-identified patient-level data set will be made available to researchers for the purpose of meta-analysis or a newly proposed study. Data will be made available following submission of a maximum 5-page proposal by the requestor. The study steering committee will review and, if acceptable, provide approval of the request. A signed data sharing access agreement will be required. The data will be provided as SAS or Excel datasets. Any other format requests may incur costs to the requestor. Data requests should be sent to [email protected]. Data will become available one year after publication of the initial study results. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial
Authors: Feng Wang, Ying Jin, Min Wang, Hui-Yan Luo, Wei-Jia Fang, Ying-Nan Wang, Yan-Xing Chen, Run-Jie Huang, Wen-Long Guan, Ji-Bin Li, Yu-Hong Li, Feng-Hua Wang, Xiao-Hua Hu, Yan-Qiao Zhang, Miao-Zhen Qiu, Lu-Lu Liu, Zi-Xian Wang, Chao Ren, De-Shen Wang, Dong-Sheng Zhang, Zhi-Qiang Wang, Wen-Ting Liao, Lin Tian, Qi Zhao, Rui-Hua Xu
Journal: Nature Medicine (2024)
Abstract A033: The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in ovarian cancer
Authors: Tise Suzuki, Wanqiu Chen, Charles Wang, Juli Unternaehrer
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian cancer (HGSOC) remains the deadliest cancer of the female reproductive system. Among the many treatment alternatives, platinum-based therapies have been ubiquitous. However, even though initial response is favorable, most patients experience relapse and chemoresistance. Many studies have highlighted the role of epithelial-mesenchymal transition (EMT) in contributing to chemoresistance. In fact, the EMT transcription factor SNAI1 (Snail) has been associated with the development of aggressive disease. Nevertheless, further studies are necessary to understand the underlying mechanisms by which Snail contributes to recurrence and resistance. Thus, our goal is to develop a clinically relevant model of chemoresistance in which to study the transcriptional landscape and gene signatures related to EMT, platinum resistance, and recurrence in HGSOC. After acquisition and characterization of a HGSOC patient sample, cells were continuously exposed to increasing concentrations of cisplatin in vitro, until approximately a tenfold increase in IC-50 relative to parental cells was achieved. RNA-seq analysis comparing the patient-derived sensitive and resistant cell line pair identified over 4,000 genes that were differentially expressed. Furthermore, gene expression was evaluated against a database of genes associated with platinum resistance, revealing 273 genes linked with mechanisms of apoptosis, extracellular matrix signaling, immune response, cancer stemness, EMT, among others. Additionally, we analyzed previously published chromatin immunoprecipitation-sequencing (ChIP-seq) studies for Snail to determine the potential mechanism of EMT-induced therapy resistance. Our results indicate that most of the genes associated with platinum resistance mechanisms were identified by more than two Snail ChIP-seq studies, indicating their potential for being regulated. Furthermore, to establish whether such genes could also be regulated in HGSOC, we compared our findings to ATAC-seq studies done in ovarian cancer cell lines. Data obtained from these analyses will be used in the future assessment of Snail’s direct regulation of these pathways and functions. Citation Format: Tise Suzuki, Wanqiu Chen, Charles Wang, Juli Unternaehrer. The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in 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 A033.
Abstract PR-008: Modeling epigenetic lesions that cause gliomas
Authors: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein
Journal: Cancer Research (2024)

Abstract Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as potential drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase (IDH) mutant lower-grade gliomas, which exhibit profound DNA hypermethylation as a direct consequence of mutant IDH. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes or, alternatively, by activating proto-oncogenes through disruption of CCCTC-binding factor (CTCF) insulators. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associated domains (TADs). Enhancers and promoters can interact when located in the same TAD but are restricted from interacting across different TADs. In IDH mutant gliomas, CpG sites around CTCF binding sites are frequently methylated, effectively compromising CTCF binding and thus TAD organization, allowing for cross-TAD interactions and aberrant activation of genes. We discovered a CTCF insulator downstream of the PDGFRA proto-oncogene that is recurrently disrupted in IDH mutant gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. In contrast, insulator disruption did not affect Pdgfra expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDH mutant gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of Cdkn2a/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and cooperates with Pdgfra insulator loss. Finally, we use lentiviruses to coordinately inactivate the Pdgfra insulator and Cdkn2a in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo with histological features reminiscent of human IDH mutant gliomas. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that the combination of Pdgfra activation and Cdkn2a silencing can transform OPCs in vitro and drive gliomagenesis in vivo. Citation Format: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein. Modeling epigenetic lesions that cause 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 PR-008.
Abstract PR-004: Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma
Authors: 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
Journal: Cancer Research (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.
LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression
Authors: Noah Lubben, Julia K. Brynildsen, Connor M. Webb, Howard L. Li, Cheryl E. G. Leyns, Lakshmi Changolkar, Bin Zhang, Emily S. Meymand, Mia O’Reilly, Zach Madaj, Daniella DeWeerd, Matthew J. Fell, Virginia M. Y. Lee, Dani S. Bassett, Michael X. Henderson
Journal: Translational Neurodegeneration (2024)

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.
Abstract B046: Irradiation of patient-derived high-grade gliomas reduces 5-ALA-induced fluorescence utility during re-resection
Authors: Paras S. Minhas, Aarooran Durairaj, Melanie McReynolds, Katrin I. Andreasson, YooJin Jung, Joshua Rabinowitz
Journal: Cancer Research (2024)

Abstract High grade gliomas HGGs are among the most aggressive primary brain tumors, yielding a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat HGG’s poor prognosis. Recent studies have established that HGG cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived cell lines. Acute dosages of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), which is known to be converted into the fluorescent metabolite protoporphyrin IX (PpIX) in the porphyrin synthesis pathway. PpIX has been utilized by surgeons in fluorescence-guided tumor resection for clearer visualization of tumor boundaries in recent years. Fractionation of radiation therapy also resulted in dose-dependent changes in the pathway concerning heme synthesis within these cells, especially presenting decreased levels of ALA dehydratase (ALAD) and increased levels of ferrochelatase. As ALAD promotes PpIX accumulation and ferrochelatase catalyzes its conversion to heme, this indicates a decreased favorability for the accumulation of PpIX in the reprogrammed metabolism of HGG cells following radiation. Consequently, we propose that PpIX fluorescence is not a reliable visual aide in surgical re-resection of HGGs post-radiation therapy. Citation Format: Paras S. Minhas, Aarooran Durairaj, Melanie McReynolds, Katrin I. Andreasson, YooJin Jung, Joshua Rabinowitz. Irradiation of patient-derived high-grade gliomas reduces 5-ALA-induced fluorescence utility during re-resection [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 B046.
Abstract B052: Hyaluronic acid influences amino acid metabolism in glioblastoma's U87-MG cell line in a 2D culture via LAT1 transporter expression
Authors: Ashwin A. Bale, Rohit Bhargava, Brendan Harley
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is one of the deadliest forms of brain cancer with high inter and intra tumor heterogeneity and altered metabolism pathways. GBM’s microenvironment is highly complex and plays a key role in determining overall tumor growth and patient survival. Hyaluronic acid (HA) is one of the key components of this tumor microenvironment and is often associated with poor prognosis. HA is present in the form of polymeric chain units, and it is highly likely that the resulting molecular weight (MW) distribution influences how a tumor cell behaves. Through this study, we highlight this differential influence of HA MWs on GBM’s energy metabolism. GBM’s U87-MG cell lines were grown in an adherent culture with media supplemented with different MWs of HA (10, 60 and 500 kDa) and glucose concentrations (0 mM: glucose starved, 5.5 mM: normoglycemic and 25 mM: hyperglycemic). LC-MS analysis on supernatant media coupled with numerical analysis highlighted an interesting influence of HA on GBM’s amino acid metabolism via reduction in LAT1 transporter protein expression. The results also indicated a differential influence on mitochondrial respiration levels with changing ATP demands and a difference in the accumulation of some key products of cell fermentation (lactic acid, glutamic acid, and succinic acid). Overall, these results highlight the differential influence of HA MWs on the metabolic state of GBM. Citation Format: Ashwin A. Bale, Rohit Bhargava, Brendan Harley. Hyaluronic acid influences amino acid metabolism in glioblastoma's U87-MG cell line in a 2D culture via LAT1 transporter expression [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 B052.
Abstract A014: A valid second line therapy for high grade serous ovarian cancer
Authors: Flavio Rizzolio, Matteo Mauceri, Tiziana Perina, Gloria Saorin, Isabella Caligiuri, Vincenzo Canzonieri, Maja Cemazar, Urska Kamensek, Simona Brezar Kranic
Journal: Cancer Research (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.