bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA
Authors: Yang Fan , Shay Chloe , Qin Zhaohui , Saba Nabil , Teng Yong 
Published: April 2023

Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs.
Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.
Abstract 4672: In-vivo tumor implantation site exhibits differential immune response in solid tumors
Authors: Shrimali Rajeev , Borroel Jasmine , Sunico Carmen , Corcoran Bridget , Carapia Bianca , Prendergast Rowan , Sperry Jantzen , Nakashima Jonathan 
Published: April 2023

Abstract
Successful discovery and development of cancer targeted therapeutics depends on testing these agents in the clinically most relevant translational models. Emerging evidence highlights the importance of the local tumor microenvironment in evaluating the efficacy of new therapeutics, especially for immunotherapies. Historically, patient-derived xenograft (PDX) modeling involves subcutaneous implantation which minimally represents the actual human tumor site. Here, we use PBMC humanized PDX models to demonstrate differences in the tumor microenvironment, overall immune response, and the pharmacological outcome, between subcutaneous and orthotopic PDX models. These findings highlight the importance of testing cancer therapeutics in the most physiologically relevant setting for greater translation into clinical success.
Citation Format: Rajeev Shrimali, Jasmine Borroel, Carmen Sunico, Bridget Corcoran, Bianca Carapia, Rowan Prendergast, Jantzen Sperry, Jonathan Nakashima. In-vivo tumor implantation site exhibits differential immune response in solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4672.
Abstract 4830: Uncoupling protein 2 (UCP2) loss of function mediates PDAC tumor suppression by mitochondrial fusion
Authors: Acevedo-Diaz Ariana Carolina , Caggiano Emily G. , Yu Meifang , Taniguchi Cullen 
Published: April 2023

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dependence on highly active mitochondria to grow and metastasize. We previously found that mitochondrial fusion suppressed PDAC growth and metastasis, leading to improved survival in a preclinical model. The tumor suppressive mechanisms of mitochondrial fusion remain unclear, and thus we explored the role of redox homeostasis through uncoupling protein 2 (UCP2).
Methods/Results: Murine pancreatic cancer cells (KPC) with enhanced mitochondrial fusion (sgDrp1) exhibited higher levels of mitochondrial ROS compared to controls targeting GFP (sgGFP), suggesting altered redox homeostasis. We performed RNAseq on these two cell lines and found that sgDRP1 cells exhibited reduced levels of UCP2. The UCP2 protein is known to have indirect antioxidant effects by reducing mitochondrial reactive oxygen species via uncoupling of ATP production from the electron transport chain. We found that abrogating UCP2 in KPC cells reduced its capacity for OXPHOS. Moreover, rescue of UCP2 in sgDrp1 cells restored their mitochondrial activity.
Conclusions: Mitochondrial fusion may suppress tumor growth and induce mitophagy by altering redox homeostasis. UCP2 may be a mediator of the tumor suppressive phenotype induced by mitochondrial fusion, thus linking mitochondrial dynamics and PDAC antioxidant strategies.
Future Work: These results will be explored for their translation in vivo and the effects of pharmacological inhibition of UCP2, both in vitro and in vivo, via the specific inhibitor Genipin, will be explored.
Citation Format: Ariana Carolina Acevedo-Diaz, Emily G. Caggiano, Meifang Yu, Cullen Taniguchi. Uncoupling protein 2 (UCP2) loss of function mediates PDAC tumor suppression by mitochondrial fusion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4830.
Abstract 4840: Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression
Authors: Zhang Qiongsi , Li Zhiguo , Rao Xiongjian , Allison Derek B. , Qiao Qi , Zhang Zhuangzhuang , Kong Yifan , Wang Ruixin , Fan Teresa W. , Higashi Richard M. , Lane Andrew N. , Liu Xiaoqi 
Published: April 2023

Abstract
Hexavalent chromium (Cr(VI)), an class I environmental carcinogen, not only induces lung epithelial cell transformation but also promotes lung cancer progression by alterations of the cell cycle and cellular energy metabolism. Using Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and parental BEAS-2B cells, we demonstrate that the level of polo-like kinase 1 (PLK1) is highly upregulated in CrT cells, which blocks mitochondrial function, and further promotes cell proliferation both in vitro and in vivo. Cells expressing a high level of PLK1 exhibited repressed mitochondrial activity due to defective modulation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which facilitates the carbon influx to TCA cycle via catalyzing pyruvate/Acetyl-CoA conversion. Mechanistically, we show that PDHA1 can be directly phosphorylated by PLK1 at T57, which triggers collapse of E1 and PDHA1 degradation via activation of mitophagy. These defects resulted in the inhibition of oxidative phosphorylation and reduction of mitochondrial reactive oxygen species (ROS) generation, eventually inhibiting mitochondrial-mediated apoptotic response. Defining the role of PLK1 in metabolic reprogramming in Cr(VI)-associated cancer progression may give us a new perspective and a target to inhibit Cr(VI)-induced cancer development. In addition, PLK1 inhibitors may be used to increase the chemo-sensitivity of cancer cells by restoring the normal function of mitochondria, thus alleviating the drug resistance caused by dysfunction and hyperpolarization of mitochondria.
Citation Format: Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Derek B. Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Ruixin Wang, Teresa W. Fan, Richard M. Higashi, Andrew N. Lane, Xiaoqi Liu. Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4840.
Abstract 4935: Cannabidiol and cannabis extract protect cells against platinum-based chemotherapy via cellular uptake
Authors: Buchtová Tereza , Beresova Lucie , Chroma Katarina , Mistrik Martin 
Published: April 2023

Abstract
Cannabinoids including cannabidiol belong between constituents of cannabis sp. (marijuana plant). Purified or as a part of cannabis products, the compounds are frequently used by cancer patients to attenuate chemotherapy-induced side effects such as pain, nausea, and vomiting. The presence of cannabis products on the public market expands each year while the illegality status weakens in an increasing number of countries. U.S. Food and Drug Administration has approved several cannabis-based drugs for seizures induced by Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex, also for the lost appetite of AIDS patients, and chemotherapy-induced nausea and vomiting. Oncological patients are further and strongly motivated to take the drugs in combination with chemotherapy by numerous reports demonstrating the anticancer effects of cannabinoids. Nevertheless, here we present unsettling data that cannabis extract together with CBD negatively interferes with worldwide approved platinum-based drugs cisplatin, carboplatin, and oxaliplatin. The phenomenon is proven across three cellular models including primary cells. Even low concentrations of cannabidiol or cannabis extract reduced the toxicity of platinum-based drugs using long-term colony forming assay and/or short-term crystal violet assay. Increased resistance of cells was also accompanied by decreased cellular stress as evaluated by quantitative immunofluorescence microscopy and immunoblotting. Most importantly, concomitant cannabidiol and cisplatin exposure results in the decreased presence of cisplatin-modified DNA. Following the information, we determined platinum content in cells by ICP-MS. The experiment uncovered significantly decreased intracellular platinum content indicating an effect on cellular transport. Furthermore, the mechanism is translational independent as shown by the experiment with cycloheximide. This study offers crucial information that patients and physicians should take into account regarding possible interactions between platinum-based drugs and cannabis-based products. Furthermore, the study on the contradictory effects of cannabis products in cancer treatment may be motivated by this project.
Citation Format: Tereza Buchtová, Lucie Beresova, Katarina Chroma, Martin Mistrik. Cannabidiol and cannabis extract protect cells against platinum-based chemotherapy via cellular uptake. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4935.
Abstract 4937: Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL
Authors: Kisselev Alexei F. , Jenkins Tyler W. , Fitzerald Elise , Maksimenko Andrey V. , Panizzi Peter , Fields Jennifer L. , Fiering Steven N. , Mitra Amit K. 
Published: April 2023

Abstract
The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib may be unacceptable to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues.
Citation Format: Alexei F. Kisselev, Tyler W. Jenkins, Elise Fitzerald, Andrey V. Maksimenko, Peter Panizzi, Jennifer L. Fields, Steven N. Fiering, Amit K. Mitra. Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4937.
Abstract 4939: Combinatorial approach using covalent menin inhibitor, BMF-219, and/or covalent FLT3 inhibitor, BMF-500, with MEK or BCL2 blockade potentiates therapeutic use in AML
Authors: Law Brian 
Published: April 2023

Abstract
Introduction:
Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease characterized by a highly diverse genomic landscape. Despite recent advances in therapies, treatment outcome remains variable and largely defined by genomic abnormalities such as gene fusions, copy number alterations and point mutations. Mutations in epigenic modifiers, nucleophosmin (NPM1c), signaling and kinase pathway such as KMT2A-re-arrangements (KMT2A-r), internal tandem duplication (ITD) insertions in FLT3, and NRAS mutations are amongst the highest alterations in AML patients with a propensity towards poor response to treatment and overall disease outcome. Such limitations impact the ability to achieve long-lasting response to treatment and result in therapy-induced resistance eventually leading to relapse. Combinatorial strategies are required to combat resistance and maximize duration of antitumor activity.
BCL2 and MEK blockade in combination with menin and/or FLT3 inhibitors potentiates an improved therapeutic strategy to achieve increased antitumor activity and overcome AML resistance. Here we explored the use of our clinical-stage covalent menin inhibitor, BMF-219, and BMF-500, a covalent FLT3 inhibitor, in combination with each other and in combination with BCL2 and MEK inhibitors in MV-4-11 and MOLM-13 cell lines for 4-days, then viability was measured using CellTiter Glo.
Results:
BMF-219 and BMF-500 as single agents induce effective antitumor activity on MOLM-13 and MV-4-11 cells lines. When dosed in combination, BMF-219 and BMF-500 show beneficial effects affording higher cell killing at lower concentrations. Repeated experiments revealed patterns of increased cell killing is achieved when trametinib, MEK inhibitor, and venetoclax, BCL2 inhibitor, are combined with BMF-219 treatment.
Conclusions:
Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Additionally, we show benefit of combinatorial approaches of menin and FLT3 covalent inhibitors with MEK and BCL2 blockade. These data provide initial pre-clinical evidence for combining pathway specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia.
Citation Format: Brian Law. Combinatorial approach using covalent menin inhibitor, BMF-219, and/or covalent FLT3 inhibitor, BMF-500, with MEK or BCL2 blockade potentiates therapeutic use in AML. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4939.
Abstract 4955: Kurarinone, a natural notch signaling inhibitor and modulator of breast cancer stemness
Authors: Kushwaha Prem Prakash , Shuaib Mohd , Prajapati Kumari Sunita , Singh Atul Kumar , Kulharia Mahesh , Kumar Shashank , Gupta Sanjay 
Published: April 2023

Abstract
Aberrant activation of Notch signaling pathway plays an important role in breast cancer development, progression, and stem cell renewal. Activation of Notch signaling is triggered by the interaction of Notch receptors with different ligands expressed on neighboring cells that bind and induce a second cleavage by a membrane-tethered metalloprotease. The remaining membrane-bound fragment is cleaved by γ-secretase (GS) releasing the Notch Intracellular Domain (NICD), which translocate to the nucleus to activate the expression of Notch target genes. Current indirect approaches to inhibit Notch signaling are based on agents that bind to GS substrates. In the search of novel Notch signaling inhibitor(s), we screened a number of plant flavonoids for their binding potential to GS substrate. Our in-silico study identified kurarinone (KU), a lavandulyl flavanone, having ability to bind to GS complex. The KU-GS complex was structurally and energetically stable during the molecular dynamics simulation period. Interestingly, dose and time dependent toxicity of KU was observed in T47D and MDA-MB-231 breast cancer cells at 1-25µM concentration. KU treatment of cells led to inhibition in cyclin D1 expression, arrest of cells in the G1 phase of the cell cycle and subsequently undergoes apoptosis. KU-mediated apoptosis was a result of altered mitochondria membrane potential and increased ROS production. In dual-luciferase Notch promoter assay, KU inhibited GS-mediated NICD production in transfected HEK293 cells. Furthermore, KU treatment decreased the mammosphere formation potential of MCF-7 cells through altered gene expression involved in self-renewal and stemness. KU treated MDA-MB-231 cells and MCF-7 derived mammosphere showed downregulation of Notch signaling through alteration in the expression of downstream genes such as Hey1, Hes1, and E-cadherin at both transcript and protein levels. Taken together, the present study identified KU as a novel natural Notch signaling inhibitor that could provide a novel and safer approach for the treatment of breast cancer through reduction in stemness and self-renewal properties.
Citation Format: Prem Prakash Kushwaha, Mohd Shuaib, Kumari Sunita Prajapati, Atul Kumar Singh, Mahesh Kulharia, Shashank Kumar, Sanjay Gupta. Kurarinone, a natural notch signaling inhibitor and modulator of breast cancer stemness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4955.
Abstract 4960: Fascin inhibitor decreases gynecological cancer cell growth through cell cycle regulation
Authors: Chen Wanyi , Wang Yufeng , Ji Liangliang , Li Ming O. , Huang Xin-Yun 
Published: April 2023

Abstract
The actin cytoskeleton is essential for maintaining cell morphology and architecture. Actin-bundling proteins such as fascin cross-link actin filaments into bundles and play critical roles in regulating cell protrusion and motility. Fascin protein expression is low or absent in normal human epithelial cells but high in cancer cells. Elevated fascin levels are correlated with aggressive clinical progression, poor prognosis, and shorter survival outcomes. It is regarded as a cancer progression biomarker and a therapeutic target. We have developed a small molecule fascin inhibitor and shown its efficacy in blocking tumor cell migration, invasion, and metastasis, as well as prolonging the overall survival of mice bearing different types of cancers. Our recent data reveals a new mechanism of this fascin inhibitor in cell cycle regulation of gynecological cancer cells. It blocks the G2/M progression and decreases the mitotic index. Fascin inhibitor treatment also results in aneuploidy, which is a well-known factor for triggering downstream apoptosis. Our data suggests that fascin is involved in maintaining the fidelity of chromosome segregation and cell division. This will advance our understanding of the interplay between actin and microtubule cytoskeleton during cell mitosis.
Citation Format: Wanyi Chen, Yufeng Wang, Liangliang Ji, Ming O. Li, Xin-Yun Huang. Fascin inhibitor decreases gynecological cancer cell growth through cell cycle regulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4960.
Abstract 5058: Impact of dexamethasone on chemotherapy response in ovarian cancer
Authors: Venkatachalam Annapoorna , Correia Cristina , Mcgehee Cordelia D. , Finstuen-Magro Sarah , VanBlaricom Jamison , Schneider Paula A. , Peterson Kevin L. , Heinzen Ethan P. , Larson Melissa C. , Hou Xiaonon , Oberg Ann L. , Weroha Saravut John , Kaufmann Scott H. 
Published: April 2023

Abstract
Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors.
Methods: Platinum-sensitive, glucocorticoid receptor (GRα) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo.
Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFα pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies.
Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted.
Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia D. Mcgehee, Sarah Finstuen-Magro, Jamison VanBlaricom, Paula A. Schneider, Kevin L. Peterson, Ethan P. Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut John Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5058.