bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4466: Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma
Authors: Tay Apple , Lundqvist Andreas , Sze Siu Kwan 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most hypoxic, lethal, and treatment resistant cancers. Due to its desmoplasias along with the hypoxic state and scarce infiltration of T cells, PDAC is considered a cold tumor. Using a proteomic approach, we previously identified that the expression of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) is induced by hypoxia and correlates with reduced survival in PDAC. Furthermore, we observed an increased kynurenine formation under hypoxia, suggesting a role of indoleamine 2,3-dioxygenases (IDO1) in PDAC. Since ERO1α and IDO are involved in driving immune suppression through influencing the generation of immature myeloid cells, we sought to investigate whether inhibition of these pathways modulates the myeloid cell composition in PDAC. Using MiaPaCa2 as a PDAC spheroid model with hypoxic core grown in serum-free defined media and immune cell infiltration, we assessed the functional role of ERO1a with IDO1 in modulating monocyte infiltration and differentiation into pro- and anti-inflammatory phenotypes, followed by characterizing the immunomodulatory factors secreted using tandem mass spectrometry. Inhibition of ERO1a and IDO1 significantly improved U937 monocyte infiltration (p-value = ****) and differentiation into dendritic cells (p-value = ****). Secretome analysis of proteins identified with high false discovery rate (q-value&lt;0.01) revealed a downregulation of hypoxia and pancreatic cancer pathways in PDAC spheroids. In the presence of monocytes, upregulation of immune-related pathways for antigen presentation (15-fold) and myeloid cell maintenance signaling (2-fold) were observed. Moreover, specific immune-modulatory factors involved in immune infiltration and migration including interleukin 8, lymphocyte cytosolic protein 1 and transgelin-2 were upregulated at 27-, 20-, and 14-fold respectively. Taken together, these results indicate that inhibition of ERO1a and IDO1 drives an inflamed tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially enable T cell infiltration and killing of PDAC tumors.
Citation Format: Apple Tay, Andreas Lundqvist, Siu Kwan Sze. Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma. [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 4466.
Abstract 4480: Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors
Authors: Delara Ritchie , McHale Cody , Pal Dhananjaya , Maddeboina Krishnaiah , Naumann R. Wendel , Crane Erin , Brown Jubilee , Durden Donald 
Published: April 2023

Abstract
Introduction: The objective of this study is to assess the feasibility and safety of treating endometrial adenocarcinoma (EC) with multitarget inhibitors which orthogonally target known oncogenic kinases and epigenetic regulators. The Molecular Targeted Therapeutics Laboratory has developed nanomolar potent multitarget small molecule chemotypes that inhibit the PI3K/Akt/mTOR pathway, cancer-associated kinases, and epigenetic regulatory proteins such as BRD4 in vitro and in vivo.
Methods: Two EC cell lines (AN3-CA, RL95-2) were treated with varying concentrations of triple PI3K/BRD4/CDK4/6/9 inhibitor LCI132 and dual PI3K/CDK4/6/9 inhibitors LCI133 and LCI136 for 48 hours; and cell viability assays were performed with IC50 determination. EC cells were treated with multitarget inhibitors and other indicated inhibitors of PI3K, BET, CDK4/6, and CDK9 for 24 hours; and lysates were prepared accordingly for Western blot (WB) and qRT-PCR analyses. Flow cytometry was conducted for cell cycle and apoptosis assays.
Results: In cell-free assays, LCI132 is a nanomolar inhibitor of PI3K/BRD4/CDK4/6/9, LCI133 is a picomolar inhibitor of CDK9, and LCI136 is a nanomolar inhibitor of PI3K and CDK9. LCI133 demonstrated nanomolar potency towards AN3-CA (IC50 248 nM) and RL95-2 (IC50 105 nM). LCI136 demonstrated nanomolar potency towards AN3-CA (IC50 631 nM) and RL95-2 (IC50 728 nM). WB demonstrated 24-hour treatment of FBXW7mut AN3-CA with LCI132 inhibited AKT phosphorylation but an increase in c-MYC protein expression. A corresponding increase in c-Myc gene expression at 24 hours was confirmed on qRT-PCR. In FBXW7wt RL95-2, LCI132 decreased c-Myc protein expression. LCI132 demonstrated dose-dependent G1 arrest, and dose-dependent pre-apoptotic and apoptotic activity.
Conclusions: Dual-target inhibitors LCI133 and LCI136 are nanomolar potent in AN3-CA and RL95-2 EC cell lines, suggesting a role of CDK9 inhibition of PTEN/PI3K co-mutated EC. Preliminary studies demonstrate an upregulation of MYC gene and protein expression in FBXW7mut EC but not FBXW7wt, and the role of FBXW7 as a predictive biomarker in treatment of PTEN/PIK3R1 co-mutated EC warrants further investigation.
Citation Format: Ritchie Delara, Cody McHale, Dhananjaya Pal, Krishnaiah Maddeboina, R. Wendel Naumann, Erin Crane, Jubilee Brown, Donald Durden. Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors. [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 4480.
Abstract 4481: Vrtx153, novel small molecule inhibitor of krasg12d
Authors: Bhavar Prashant Kashinath , Surampudi Uday Kumar , Sarma Partha Pratim , Kshirsagar Anuj Ramesh 
Published: April 2023

Abstract
Pancreatic cancer is an intractable malignancy and is the seventh leading cause of global cancer deaths in industrialized countries and the third most common in the USA. Despite advancement in the knowledge of potential risk factors that cause pancreatic cancer and newly available tools for early diagnosis, its incidence is estimated to increase and will include 0.35 mln new cases within 2040. KRAS is the predominant isoform mutated in cancer and are found in 92-95% of Pancreatic Cancer patients, dominated by somatic mutations of KRASG12D. KRASG12D, is one of the most frequently mutated oncogenes across adenocarcinoma of Pancreas (51%), Colon and Rectal (13.4%) and Lung (3%). With KRAS mutations found in nearly all PDAC, this cancer type is arguably the most RAS-addicted cancer. KRASG12D is a clinically relevant target but owing to structural complexity of the protein, poses challenges for its effective inhibition. Previously, we reported a series of compound including a proprietary tool compound VTRX144, with low nM potency in 2D (&lt;25 nM). Optimized lead from VRise de-novo platform has yielded an unparallel potent, highly selective, inhibitor, namely VRTX153. VRTX153 demonstrated high-affinity for KRASG12D in a GDP-loaded KRASG12D assay, with an IC50 value of less than 2 nM and more than1500 -fold selectivity over KRASWT, KRAS mutants and other RAS proteins including HRAS & NRAS. VRTX153 inhibited ERK1/2 phosphorylation (pERK) and cell viability in KRASG12D-mutant cell lines in both 2D and 3D, as evaluated by CellTiter-Glo®. In-vivo translation of activity in a mouse xenograft model representing PDAC is being investigated.
Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Anuj Ramesh Kshirsagar. Vrtx153, novel small molecule inhibitor of krasg12d. [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 4481.
Abstract 4611: Leveraging organotypic brain slice models to enhance adoptive cellular therapies
Authors: Reid Alexandra , Jin Dan , DiVita-Dean Bayli , Falceto-Font Laura , Figg John , Francis Connor , Flores Catherine 
Published: April 2023

Abstract
Glioblastoma (GBM) is an incredibly aggressive and prevalent primary CNS tumor with dismal survival outcomes. GBM’s intra-tumor heterogeneity and lack of anti-tumor immune cell infiltration have proved to be formidable challenges to the development of effective therapies. These hurdles may be overcome by garnering a better understanding of the cell-cell interactions occurring within the tumor microenvironment (TME). Accounting for the complexity and the spatial orientation of the components within the TME may offer insight into the multitiered layers of immunosuppression capitalized on by GBM tumors, thus elucidating the factors responsible for poor response to therapy and uncovering potential therapeutic targets that may offer more favorable therapeutic results for immunotherapies. Current in vitro and in vivo models, however, sorely limit our ability to probe these distinct attributes while preserving the intricate nature of the TME. To bridge this gap, we have devised a novel organotypic brain slice culture (BSC) model using tumor-bearing C57BL/6J mice, allowing us to characterize the tumor milieu in situ. We have identified infiltration of myeloid-derived suppressor cells (MDSC) and microglia polarized to the M2 anti-inflammatory phenotype within the TME. Leveraging this platform, we sought to define further the factors contributing to the dynamic impacts of GBM immunosuppression, such as the tolerogenic response in dendritic cells (DC) upon interaction with the TME. We have demonstrated outcomes similar to those seen in vivo following the introduction of DCs to tumor-bearing BSCs, further supporting the physiological relevancy of this model, and have since worked to unravel elements responsible for this response.
Citation Format: Alexandra Reid, Dan Jin, Bayli DiVita-Dean, Laura Falceto-Font, John Figg, Connor Francis, Catherine Flores. Leveraging organotypic brain slice models to enhance adoptive cellular therapies. [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 4611.
Abstract 4669: A patient derived xenograft model for lung adenocarcinoma using Obagel®, a human derived hydrogel
Authors: Sanchez Cecilia , Nakashima Jonathan , King Kristein , Frazier Trivia 
Published: April 2023

Abstract
Patient Derived Xenografts (PDXs) are valuable disease models as they preserve the tumor microenvironment’s structure, providing the most clinically relevant in vivo testing platform. Nevertheless, most of those models still use animal derived hydrogels as scaffolds for patient derived cells, reducing the potential to fully mimic the physiological microenvironment of the disease and human condition. ObaGel® is a human-derived hydrogel successfully deployed for supporting 3D cell culture, organoid, perfusion bioreactor, and/microphysiological system development for studying obesity, type II diabetes, and various forms of related cancers. Here we are investigating the use of Obagel® in the in-vivo development of a PDX-derived culture of lung adenocarcinoma and compare its performance to currently used animal derived hydrogels. Methods: 3 × 10^6 CRT00295 Non-small cell lung adenocarcinoma cells in 100ul 50:50 indicated Gel in PBS per injection site; the study used 10 NOG mice per condition. Results: The results indicated that ObaGel® performed similarly in terms of engraftment and tumor kinetics compared to animal derived hydrogels such as Cultrex, Geltrex, and Matrigel, using a patient-derived xenograft culture of lung adenocarcinoma. Conclusions: Our data supports the use of a human-derived hydrogel for PDX models, ObaGel® performs equivalently to animal derived hydrogels to support tumor volume over time. The use of a human derived hydrogels as scaffolds for PDX models provide a better humanized local microenvironment for lung adenocarcinoma. Obagel® can also be adapted for use as xenografts in other tissue/disease models
Citation Format: Cecilia Sanchez, Jonathan Nakashima, Kristein King, Trivia Frazier. A patient derived xenograft model for lung adenocarcinoma using Obagel®, a human derived hydrogel. [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 4669.
Abstract 470: A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice
Authors: Liu tao , Gu Lubing , Mui Anna , Wu Zhongzhi , Li Wei , Zhou Muxiang 
Published: April 2023

Abstract
The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression mainly through inhibition of the tumor suppressor p53. Here, we report a novel small-molecule chemical compound (MX69-114b) that we identified to induce MDM2 protein degradation resulting in reactivation of p53 and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL). We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modification of MX69 and selected analog MX69-114b showing increased MDM2-targeting activity. MX69-114b exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of 0.08-0.14 µM, representing a &gt;80-100-fold increase in activity compared to MX69. MX69-114b also showed inhibitory effects on xenografted human MDM2-overexpressing ALL in SCID mice at a much lower dose than did MX69. Importantly, MX69-114b had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-114b is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory ALL.
Citation Format: tao Liu, Lubing Gu, Anna Mui, Zhongzhi Wu, Wei Li, Muxiang Zhou. A MDM2 degrader inhibits cell proliferation and growth of MDM2-overexpressing acute lymphoblastic leukemia in SCID mice [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 470.
Abstract 471: A new synthetic peptide DS-2 enhanced anti-tumor activity by targeting human telomerase reverse transcriptase (hTERT) in prostate cancer cells
Authors: Park Jae Hyeon , Shin Joo Kyung , Han Joo Hee , Kim Hyung Sik 
Published: April 2023

Abstract
Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers. Therefore, hTERT is considered as an important target for cancer therapy. In the present study, we synthetized a new peptide, DS-2, based on the telomerase vaccine GV1001, a 16-mer peptide. The aim of this study is to evaluate the molecular mechanism of DS-2 on the anticancer activity by targeting hTERT in prostate cancer cells. The expression levels of hTERT in prostate cancer patients were measured. We compared the cytotoxic activity of GV1001 and DS-2 against different prostate cancer cell lines. Flow cytometry was used to evaluate the effects of DS-2 on apoptosis. The scratch-wound assay and matrigel invasion assay were performed to determine the metastasis ability of prostate cancer cells. We further measured the telomerase enzyme activity of DS-2 in LNCaP cells. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of GV1001 and DS-2. The cytotoxicity of human peripheral blood mononuclear cells (PBMC) on prostate cancer cells was determined by lactate-dehydrogenase (LDH)-release assay. The hTERT expression was directly correlated with telomerase activity in LNCaP cells, and DS-2 significantly inhibited telomerase enzyme activity, resulting in reducing LNCaP cells proliferation and metastasis. Furthermore, DS-2 exhibited the most substantial anti-cancer potential against prostate cancer cells compared with different cancer cell lines. In the tumor-bearing nude mice model, DS-2 significantly inhibited the growth of the prostate tumor and downregulated the expression of hTERT and Ki-67 in the tumor tissue as evidenced by western blot and immunohistochemistry analysis, respectively. Furthermore, the potent cytotoxicity was exhibited in LNCaP cells after treated with DS-2-activated PBMC plus IL-2. In addition, DS-2 synergistically enhanced IL-2 production from activated PBMC. These data indicated that the inhibition of hTERT expression by DS-2 suppressed prostate cancer cell growth and induced anti-cancer immunity. Therefore, DS-2 might be used as a novel therapeutic drug for cancer immunotherapy by targeting hTERT in prostate cancer.
Citation Format: Jae Hyeon Park, Joo Kyung Shin, Joo Hee Han, Hyung Sik Kim. A new synthetic peptide DS-2 enhanced anti-tumor activity by targeting human telomerase reverse transcriptase (hTERT) in prostate cancer cells [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 471.
Abstract 4766: Hypoxia increases the methylated histones to prevent histone clipping during Raf-induced senescence
Authors: Park Hyunsung , Chang Soojeong 
Published: April 2023

Abstract
Hypoxia increases methylated histones by inhibiting O2- and α-ketoglutarate-dependent histone lysine demethylases (KDMs). This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). Raf-activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated clipping of histone H3, H2B and H4. Hypoxia protects histones from CTSL by increasing histone methylation without reducing the amount and activity of CTSL. Forced enhancement of methylated histones protected histones from clipping during OIS, even under normoxia, but failed to block SAHFs. Altogether, these results suggest that maintenance of methylated histones is sufficient to protect histones from CTSL, not sufficient but necessary for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other mechanisms to inhibit SAHFs. Hypoxia protects histones and chromatin from dramatic epigenetic changes by increasing methylated histones.
Citation Format: Hyunsung Park, Soojeong Chang. Hypoxia increases the methylated histones to prevent histone clipping during Raf-induced senescence. [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 4766.
Abstract 4779: MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells
Authors: Perera Jeffrey Mario , Martinez Alicia K. Fleming , Storz Peter 
Published: April 2023

Abstract
Mitochondrially-generated reactive oxygen species (mROS) have been shown to induce acinar-to-ductal metaplasia (ADM). ADM, in presence of an oncogenic KRAS mutation, is an initiating step for progression to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic ductal adenocarcinoma (PDA). Here, we utilize primary murine cells as well as the p48Cre;LSL-KrasG12D (KC) mouse model to explore the use of the mitochondria-targeted mimetic of manganese superoxide dismutase MitoQ for targeting PDA initiation and progression. Previously published data by our laboratory has shown that treatment with MitoQ decreases the abundance of pancreatic low-grade lesions in KC mice. However, we here demonstrate that superoxide depletion by MitoQ at the same time increases formation of DCLK1+ cancer stem cells in such lesions. We here evaluate if the detoxification of mitochondrial superoxide results in a build-up of hydrogen peroxide, which is a major driver of the DCLK1+ cell type. We determine how altered expression of ROS detoxifying enzymes in different cell types contribute to PDA stem cell formation and PDA development. Eventually we test if the increase in DCLK1+ cancer stem cells can contribute to changes in the microenvironment and accelerated progression of abnormal tissue.
Citation Format: Jeffrey Mario Perera, Alicia K. Fleming Martinez, Peter Storz. MnSOD mimetic mitoquinone mesylate (MitoQ) increases DCLK1+pancreatic cancer stem cells. [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 4779.
Abstract 4923: Prostaglandin E2 receptor EP2: A novel target for high-risk neuroblastoma
Authors: Hou Ruida , Yu Ying , Yang Jun , Jiang Jianxiong 
Published: April 2023

Abstract
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. Based on tumor stage and histological features, 50% of NBs are classified as high-risk diseases, a subtype characterized by a quite unsatisfactory long-term survival even with the striking advances in NB management that have been achieved in the past decades. Cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) cascade has been reported to foster a proinflammatory tumor-nourishing microenvironment in NB. However, the specific downstream PGE2 receptor (EP) subtype which directly mediates this tumor promoting effect remains elusive. Therefore, in our research, we aim to 1) elucidate the culprit EP receptor that is directly involved in NB development; 2) evaluate the feasibility of inhibiting the PGE2 receptor subtype as a novel treatment strategy for high-risk NB. To start with, we analyzed the gene expression profiles of the COX2/PGE2/EP pathway from four major NB datasets (Versteeg, Kocak, SEQC, and NRC) on R2 platform. It indicates that the COX-2/PGE2/EP2 signaling axis is highly associated with the expression of high-risk NB markers, as well as an abysmal overall survival rate. Moreover, a time resolved fluorescence resonance energy transfer (TR-FRET) method was adopted to reveal that EP2 receptor is the key Gαs-coupled receptor that mediates PGE2-initiated cAMP signaling in high-risk NB cell lines. Genetic interference of EP2 receptor expression by CRISPR/Cas9-mediated genome editing and doxycycline induced conditional knockdown significantly inhibited high-risk NB development and progression both in neuro-sphere formation assay and in nude mice xenograft models. Finally, we tested the anti-NB efficacy of our recently developed selective and bioavailable small-molecule EP2 antagonists. With a consecutive treatment of three weeks, decreased tumor size and weight have been observed in both high-risk NB xenograft model and immunocompetent allograft model, simultaneously with decreased inflammation, angiogenesis, and enhanced apoptosis. Collectively, our results suggest that the PGE2/EP2 pathway contributes to the growth and malignant potential of high-risk NB; pharmacological inhibition on EP2 receptor by our drug-like compounds might provide a novel therapeutic strategy for this deadly pediatric cancer.
Citation Format: Ruida Hou, Ying Yu, Jun Yang, Jianxiong Jiang. Prostaglandin E2 receptor EP2: A novel target for high-risk neuroblastoma. [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 4923.