bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3068: Identify targetable molecular drivers of chemotherapy resistance in gastroesophageal adenocarcinoma
Authors: Kong Mingyang , Bailey Swneke , Sangwan Veena , Ferri Lorenzo 
Published: June 2022

Abstract
Introduction: Gastroesophageal adenocarcinoma (GEA) is one of the most lethal malignancies worldwide. Even with the standard-of-care chemotherapy, 40% of the patients are innately resistant and half of the initial responders develop acquired resistance. The molecular mechanisms underlying the development of resistance in GEA remain largely unknown.
Methods: 30 GEA patients who received chemotherapy were included in this cohort. Both pre-and post-treatment primary tissues were collected to generate patient-derived organoids (PDOs). 29 PDOs were treated with chemotherapeutic agents and the cell viability was measured. We also evaluated the correlation between ex-vivo drug responses of PDOs and in-patient clinical responses. Data obtained from whole-exome (WES) and RNA sequencing of the primary tumor and their PDOs were analyzed to identify targetable molecules associated with chemo-resistance.
Results: After treatment, the cell viability of the PDOs obtained from chemo-resistant patients was significantly higher than that of chemo-sensitive patients. The variant allele frequency of the PDOs recapitulated their parental tumors. WES of one patient tumor revealed an increased copy number of EGFR, and their PDOs showed high sensitivity to an EGFR inhibitor in the subsequent drug screens. Furthermore, 40% of chemo-sensitive patients had mutations in one or more genes belonging to the adhesion G protein-coupled receptors (GPCRs) family. The adenylate cyclase-activating G protein-coupled receptor signaling pathway was found to be significantly activated only in chemo-sensitive patients. Single-cell RNA sequencing of pre-and post-treatment tissue revealed a broadly shifted transcriptome in epithelial cells. Patients with upregulated cell stemness genes including CTNNB1, MYC, ETS2, and KLF4 had disease recurrence 6 months post-surgery, while patients with unaltered or downregulated stemness genes remain disease-free 18 months until today.
Conclusion: Our PDOs not only reflected the genetic profile of primary tumors but also recapitulated patient responses to chemotherapy. Genomic analysis revealed that mutations in a few GPCR genes might have a role in increased sensitivity to chemotherapy. In addition, the transcriptomic analysis showed stemness genes were associated with disease recurrence. Our GEA PDO platform allows the identification and the subsequent verification of resistant-conferring targets, providing insight for novel therapeutic combinations.
Funding: This project is supported by the Cancer Research Society (CCS), and the Department of Defence (DoD), USA.
Citation Format: Mingyang Kong, Swneke Bailey, Veena Sangwan, Lorenzo Ferri. Identify targetable molecular drivers of chemotherapy resistance in gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3068.
Abstract 3095: Breaking the crosstalk of the cellular tumorigenic network in NSCLC by a highly effective drug combination
Authors: Gürgen Dennis , Conrad Theresia , Becker Michael , Sebens Susanne , Röcken Christoph , Hoffmann Jens , Langhammer Stefan 
Published: June 2022

Abstract
Background: Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages with limited treatment options particularly in tumors without targetable driver mutations.
Methods: Considering previously published criteria for selecting drug combinations for overcoming drug resistances1, we have established a low dose combination therapy with cabozantinib, afatinib, etoricoxib and plerixafor. Utilizing NSCLC patient-derived xenograft (PDX) models we aimed to use this drug regimen to disrupt paracrine substitutional signaling within the tumorigenic network in order to circumvent pre-existing and adaptive drug resistances. In contrast to daily dosing for respective monotherapies the low dose treatment was paused every five days for two days.
Result: All PDX tumors treated, including highly therapy-resistant adeno- and squamous cell carcinomas without identifiable driver mutations, were completely suppressed by this drug regimen leading to an Objective Response Rate of 81% and a Clinical Benefit Rate of 100%. After treatment discontinuation growth suppression remained until the end of the follow-up period with only slight increase in tumor growth. The application and the safety profile of this low dose therapy regimen was well manageable and without pronounced side effects in this pre-clinical setting.
Discussion: For the first time we show that simultaneous inhibition of pathways forming the cellular tumorigenic network in NSCLC tumors is highly effective and overcomes drug resistances for monotherapies. All of the drugs used in this combination regimen are approved for different indications and therefore readily available. Conclusion: Our results emphatically encourage a setup for a clinical study in advanced stage NSCLC patients without targetable driver mutations combining the drugs cabozantinib, afatinib, plerixafor and etoricoxib in a low dose treatment regimen as novel therapy strategy.
Indication of Source: 1. Langhammer S and Scheerer J. Oncotarget 8, 43555-43570 (2017).
Citation Format: Dennis Gürgen, Theresia Conrad, Michael Becker, Susanne Sebens, Christoph Röcken, Jens Hoffmann, Stefan Langhammer. Breaking the crosstalk of the cellular tumorigenic network in NSCLC by a highly effective drug combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3095.
Abstract 310: Harness small peptide to improve anti-cancer effect of PD-1 checkpoint inhibitor in melanoma-bearing obese mice
Authors: Han Seungmin , Decker Kelsey E. , Won Young-Wook 
Published: June 2022

Abstract
Obesity-associated chronic inflammation and adipokine increase the cancer risk through promotion of tumor growth and malfunction of immune cells. Leptin, an adipokine abundantly found in obesity, is positively correlated with PD-1 expression and up-regulation of PD-1 on immune cells leads to immune cell exhaustion. PD-1 blockade (checkpoint inhibitor) has shown promising anti-tumor efficacy in patients with obesity through direct effects on the up-regulated PD-1. However, there are still need for improving the response rate and the efficacy of PD-1 blockage. In our previous study, we have verified that prohibitin binding peptide (PBP) inhibits glucose metabolism of cancer cells, resulting in alterations in pro-tumor tumor microenvironment (TME) to pro-immune TME. The pro-immune TME reinvigorates anti-cancer activity of immune cells and results in better suppression of tumor growth. Based these findings, we hypothesized that PBP would improve the anti-cancer effect of PD-1 checkpoint inhibitor on cancer with obesity. Melanoma was embedded in lean or obese mice, then the mice were assigned to one of following groups: i) PBS, ii) PBP, iii) anti-PD-1 antibody (aPD-1) and iv) combination of PBP and aPD-1 (PBP+aPD-1). The PBP+aPD-1 group showed improved anti-cancer efficacy in tumor-bearing obese mice (not in lean mice) compared to single aPD-1 injection. Immune cells in PBP+aPD-1 injected obese mice showed the more activated characteristics in terms of its cytokine secretion and phenotype. In addition, the serum leptin level was decreased upon PBP treatment, indicating that the PBP-mediated decrease in the serum leptin level attributed the rejuvenation of immune cells through the balanced PD-1 expression on immune cells. PBP improves the anti-cancer efficacy of aPD-1 on tumor with obesity through recovering anti-cancer activity of immune cells that is driven, at least in part, by a decrease in the glucose metabolism of cancer cells and the circulating leptin levels. Consequently, combination of PBP and aPD-1 would have the great potential to treat cancer patients with obesity.
Citation Format: Seungmin Han, Kelsey E. Decker, Young-Wook Won. Harness small peptide to improve anti-cancer effect of PD-1 checkpoint inhibitor in melanoma-bearing obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 310.
Abstract 3102: MiniPDX and omics analysis for clinical indication and biomarker identification
Authors: Wang Shuai , Di Yu , Li Rongyu , Liu Yang , Gu Xiaorong , Hu Kaimeng , Wen Danyi 
Published: June 2022

Abstract
MiniPDX as an in vivo version of the organoid assay represents a novel platform of fast turnaround (7 days) in vivo drug sensitivity test, using either fresh patient tumor samples or tissues from established PDX models. We systematically evaluated and compared the response rates of MiniPDX assays and PDX assays pair-wise in 26 PDX models involving 3 types of cancers to 12 clinical relevant regimens, and found a high correlation between drug responses between the two assays, with sensitivity and specificity of 80% and 93%, respectively. LIDE has completed over 2,400 MiniPDX assays for precision medicine in clinical, including over 50 indications. Using MiniPDX for ranking the drug/treatment approved in clinical practice facilitates prioritization of the best strategy for benefiting patient in precision medicine, while screening a series of small/large molecules within the similar scaffold enables selection of the best candidate for further drug R&D. Importantly, performing MiniPDX Mouse Trial using fresh tumor samples generated from clinic is beneficial for determination of potential clinical indication that would be fit for the investigating new drug. RNA or DNA can be extracted and enriched from only thousands of cells left from MiniPDX preparation by K cell technology, while RNAseq can be further analyzed via functional genomic imaging (FGI). The Omics data would be useful for determination of potential biomarkers to distinguish responders vs non-responders in population with certain indication(s) and further application in patient stratification to confirm inclusive/exclusive criteria in clinical trials.
Citation Format: Shuai Wang, Yu Di, Rongyu Li, Yang Liu, Xiaorong Gu, Kaimeng Hu, Danyi Wen. MiniPDX and omics analysis for clinical indication and biomarker identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3102.
Abstract 3108: Preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities
Authors: Zhang Hongyong , Estrada-Florez Ana Patricia , Lott Paul , Toal Ted William , Morales-Arana Alexa , Poceros-Coba Alma ,   UCaMP Consortium, Ma Ai-Hong , Halmai Nicole Britney , Carvajal-Carmona Luis 
Published: June 2022

Abstract
Gastric cancer (GC) is one of the most common malignant tumors of the digestive system, and its prognosis remains poor because most tumors were detected in late stages and the 5-year survival is less than 5%. The Cancer Genome Atlas (TCGA) study found that 70% of all GCs have mutations that can be targeted with existing drugs, yet only four molecularly-guided therapies have been approved. GCs have strong disparities in incidence, mortality and survival that disproportionately affect different populations of color. No large-scale cancer genomic research has been carried out in U.S. minority populations. GC molecular data from U.S. minority residents is crucial to improve outcomes, as genomic phenotypes have been associated with differential prognosis and response to treatments. To our knowledge, minority patient-derived models have not been used to test GC therapies. In this study, several organoids lines from minority patients were established and used as an in vitro platform for screening effective therapies. After genomic data analyses, six minority patient-derived organoids with or without cell cycle regulator or PI3K/AKT/mTOR pathway gene alterations were tested for responses to first-line therapies, targeted drugs and combination treatments. Among the 24 PDX models established, the efficacy study of PDX model PDX015 which has amplifications of CDK and AKT genes showed the targeting therapy (a CDKi) can effectively prolong overall survival of mice bearing xenograft treated with the CDKi (60 days), compared with those mice in control group (22 days). In addition, an AKT inhibitor was found significantly inhibited tumor growth in CDKi-resistant mice treated with the CDKi/AKTi combination. In conclusion, investigating the efficacy of targeted therapies in these U.S. minorities will empower precision medicine applications in GC patients and improve GC treatment outcomes. Minority-patient derived tumor models have great potential in preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities.
Citation Format: Hongyong Zhang, Ana Patricia Estrada-Florez, Paul Lott, Ted William Toal, Alexa Morales-Arana, Alma Poceros-Coba, UCaMP Consortium, Ai-Hong Ma, Nicole Britney Halmai, Luis Carvajal-Carmona. Preclinical studies of chemotherapies and targeted therapies to address gastric cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3108.
Abstract 3110: Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1]
Authors: Xu Xiaoxi , Tognetti Marco , Feng Yuehan , Shang Limei , Chen Leilei , Wang Jessie , Bruderer Roland , Bourré Ludovic , Li Henry 
Published: June 2022

Abstract
In precision medicine, genomic, transcriptomic, and proteomic data has contributed to the identification of novel driver genes and the molecular-level characterization of cancers. This data has led to a better understanding of drug modulation and resistance mechanisms. Patient-derived tumor models, including patient-derived xenograft (PDX) and organoid counterparts (PDXO), have been increasingly viewed as predictive preclinical cancer models. These models closely recapitulate tumor complexity, enabling the study of tumor identity for personalized medicine. Leveraging our large PDX collection models which are genomically and phenotypically annotated and validated, we have established and characterized a series of PDXO models to be used as scalable and high throughput compatible drug screening platforms. Here we conducted methodical analysis of drug response in paired PDX and PDXO models. In addition, trough deep whole- and phospho-proteomic analysis, we have analyzed and compared the effect of targeted therapies on protein expression and phosphorylation in both PDX and PDXO tumor models. Indeed, one of the most common post-translational modifications that is involved in cell regulation and intracellular signal transduction is reversible protein phosphorylation catalyzed by protein kinases. For this purpose, we have tested a KRAS inhibitor (AMG510), BCR-ABL TKI (Ponatinib) and EGFR TKI (Afatinib) respectively in lung NSCLC model carrying KRAS G12C mutation, colorectal model with RET fusion and Lung NSCLC model with EGFR exon 19 deletion. According to our historical data, a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth has been observed, irrespective of the drug treatment. Furthermore, comparison between PDX and PDXO models deploying quantitative proteomic data enabled deep characterization of both global expression and signaling cascades modulated through small molecule inhibitors. Thus, we demonstrate the predictivity of organoid cultures to not only model in vivo drug responses but also to serve as a powerful platform to investigate target identification, mechanism of action and resistance mechanism via deep proteomics analysis.
Citation Format: Xiaoxi Xu, Marco Tognetti, Yuehan Feng, Limei Shang, Leilei Chen, Jessie Wang, Roland Bruderer, Ludovic Bourré, Henry Li. Identification of the phosphorylation network in PDX and corresponding organoid (PDXO) models upon targeted therapy treatment using deep phosphoproteomic analysis[MB1] [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3110.
Abstract 3116: Development of bioluminescent PDX models to study metastasis and evaluate therapeutic interventions
Authors: Nakashima Jonathan , Sperry Jantzen , Pedros Christophe , Carapia Bianca , Yan Deborah , Rivera Giovanni , Federman Noah , Singh Arun , Eilber Fritz C. , Datnow Brian 
Published: June 2022

Abstract
Metastatic disease continues to be a significant cause of mortality among cancer patients. Despite advancements in patient-derived xenografts (PDXs), translational models of metastasis are lacking. To overcome this challenge, we have developed luciferase tagged PDX cultures and utilized optical imaging to create robust translational in vivo models of metastasis. Here, we show that these models can be implanted orthotopically into common metastatic sites, or injected intravenously or intracardiacally to study spontaneous metastasis. Furthermore, we apply these models in humanized NOG-EXL mice to demonstrate immunophenotypic differences among tumors in different anatomical sites.
Citation Format: Jonathan Nakashima, Jantzen Sperry, Christophe Pedros, Bianca Carapia, Deborah Yan, Giovanni Rivera, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Development of bioluminescent PDX models to study metastasis and evaluate therapeutic interventions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3116.
Abstract 3129: TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse
Authors: Stevenson Denay N. , Holmberg Ryne M. , Gilbert Samuel F. , Robinson Mikella , House Carrie D. 
Published: June 2022

Abstract
Ovarian cancer is the deadliest gynecological cancer with over 13,000 deaths estimated in the United States this year. While there is an initial high response rate to cytotoxic chemotherapy, over 80% of advanced cases relapse within 24 months, presenting an urgent need to better understand the molecular mechanisms permitting relapse. Current research suggests that cancer recurrence can be attributed to a small subpopulation of cancer stem-like tumor-initiating cells (TICs) that possess the ability to both resist chemotherapy and initiate tumorigenesis. Our lab previously demonstrated an essential role for alternative NF-kB signaling in maintaining ovarian TICs, yet it is not fully understood how this pathway becomes activated in ovarian cancer. To begin to address this, we used an NF-kB reporter system to screen soluble factors known to be in the ovarian tumor microenvironment (TME) to identify the strongest inducers of NF-kB activation in ovarian cancer cells. We found that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a strong inducer of alternative NF-kB signaling. In vitro experiments demonstrate enhanced expression of stemness genes including SOX2, OCT4 and NANOG and increased spheroid formation ability after stimulation with TWEAK. Moreover, flow cytometry analysis of several TIC markers shows a significant enrichment of TICs when chemotherapy was combined with TWEAK, relative to chemotherapy alone. Stimulation of CD117+ cells led to higher expression of stemness genes relative to stimulation of CD117- cells, suggesting TWEAK activity may be specific to TICs and enhances their stem-like phenotype. In support of this, we found that CD117+ cells have higher expression of the TWEAK receptor FN14. We investigated the role of TWEAK in aiding relapse in vivo using an intraperitoneal xenograft mouse model and found that administration of a small molecule inhibitor of TWEAK-FN14 signaling as a maintenance treatment following chemotherapy significantly prolonged survival. These findings highlight a potential mechanism of TIC enrichment in response to chemotherapy that contributes to relapse.
Citation Format: Denay N. Stevenson, Ryne M. Holmberg, Samuel F. Gilbert, Mikella Robinson, Carrie D. House. TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3129.
Abstract 314: Amplifying STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy
Authors: Zhou Xingwu , Sun Xiaoqi , Gong Wang , Lei Yu Leo , Moon James J. 
Published: June 2022

Abstract
Background: Innate immune pathway of stimulator of interferon genes (STING) orchestrates antitumor immune responses and can elicit potent antitumor efficacy. However, clinical development of cyclic-dinucleotide (CDN) STING agonists is mostly limited to intratumoral administration because of the undesirable pharmacological properties of CDN. This limits their applications in treating metastasis, hematologic malignancies, and hard-to-reach solid tumor. Here, we aim to develop a pharmacological formulation that facilitate systemic delivery of CDN STING agonist to broaden its applications for cancer treatment.
Methods: Nutritional metal ions physiologically mediate various immune processes, which could potentially be utilized for modulating the STING pathway. By screening different nutritional metal ions, we discovered manganese ion (Mn2+) and cobalt ion (Co2+) synergize with CDN STING agonists and significantly enhance type-I interferon (IFN-I) responses. As Mn2+ has been used in FDA approved drugs, we further developed the formulation to enable systemic codelivery of Mn2+ and CDN.
Results: Mn2+ could significantly potentiate the STING activation by up to 77-fold. In addition, Mn2+ interact with CDNs and self-assemble into nanocrystals that could be stabilized as uniform nanoparticles (~120 nm) through lipid layer coating (CDN-Mn Particle, CMP). After either intratumoral or intravenous administrations, CMP effectively elevate the serum levels of inflammatory cytokines (IFN-β, TNF-α, CXCL-9, and CXCL-10), mitigates the suppressive functions of myeloid cells, relieve the immunosuppressive tumor microenvironment (TME), and induce antigen-specific CD8+ T cells expansion. Minute dose of CMP given intravenously exert remarkable antitumor efficacy in CT26, B16F10, and immune checkpoint blocker (ICB)-resistance tobacco-associated NOOC1 murine tumor models, leading to efficient tumor regression. Furthermore, the systemic biodistribution of CMP could be modulated by changing the composition of the lipid layer coating, allowing for organ-specific delivery of CMP to target tumor malignancies in certain organs.
Conclusions: CMP provides a novel and versatile platform for local and systemic cancer treatment. More importantly, it highlights the potential of harnessing metal ions in treating various immune-mediated diseases.
Citation Format: Xingwu Zhou, Xiaoqi Sun, Wang Gong, Yu Leo Lei, James J. Moon. Amplifying STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 314.