bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1657: Discovery of a first-in-class multifunctional TYMS non-classical antifolate inhibitors with potent in vivo activity that prolongs survival
Authors: Dib Peter Elias , Guijarro Maria , Kellish Patrick , Paciaroni Nick , Nawab Akbar , Andring Jacob , Kulemina Lidia , Leas Derek , Borrero Nick , Modenutti Carlos , Bennett Richard , Licht Jonathan , McKenna Robert , Roitberg Adrian , Kaye Frederic , Zajac-Kaye Maria 
Published: April 2023

Abstract
Thymidylate synthase (TYMS/TS) is overexpressed in many cancer types and is commonly associated with advanced disease. TYMS catalyzes the de novo synthesis reaction of deoxythymidine monophosphate (dTMP), one of the building blocks of DNA. Although TYMS inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance limiting overall benefit. Here we report a small molecule TYMS inhibitor and its two analogues that exhibit i) enhanced anti-tumor activity as compared to current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) are structurally distinct from classical antifolates, iii) extend survival in both pancreatic xenograft tumor models and hTS/Ink4a/Arf null genetically engineered mouse tumor model, iv) and are well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we confirm the compound and its analogues are a multifunctional non-classical antifolate, and we identify structural features allowing direct TYMS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non-classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy.
Citation Format: Peter Elias Dib, Maria Guijarro, Patrick Kellish, Nick Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Derek Leas, Nick Borrero, Carlos Modenutti, Richard Bennett, Jonathan Licht, Robert McKenna, Adrian Roitberg, Frederic Kaye, Maria Zajac-Kaye. Discovery of a first-in-class multifunctional TYMS non-classical antifolate inhibitors with potent in vivo activity that prolongs survival [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 1657.
Abstract 1681: The alternative mechanism of Src inhibition in colon cancer cells
Authors: Lu Yi-Wen , Hou Xiang-Ling , Lu Yen-Tse , Lin Chia-Wen , Huang Chien-Chi , Chao Wei-Ting 
Published: April 2023

Abstract
In colon cancer, Src showed the high expression in tumor cells and was known as an important migration marker that plays the role in coordinate with many important cellular signal pathways. According to previous studies, cell viability and migration ability can be inhibited by Src inhibitor, Dasatinib. However, the clinical study demonstrated the survival rate has no significant increase in Dasatinib treatment. Therefore, we want to figure out what is the real function of Src in colon cancer cell in this study. HT-29, colon cancer cell with epithelial cell morphology was used in the study. After treated with Dasatinib, cells were followed by reattachment experiment. Then the cell growth, migration ability, signaling pathway transition, molecular localization and expressions were analyzed. The results showed Src inhibition can reduce EGFR activation on cell-cell contacts and increased Akt phosphorylation upon EGF stimulation. We further found Dasatinib has limited effect on cell toxicity, however, can be the selector to separate two cell populations, Dasatinib sensitive (DSTS) and Dasatinib resistance (DSTR) cells, interestingly, the DSTS cells were grown as colony phenotype efficiently and majorly through EGFR/AKT pathway. Meanwhile, DSTR was demonstrated the promotion of collective cell migration ability by EGFR/Ecad pathway. The results of this study suggested Src activity plays novel role in switch EGFR/Akt and EGFR/Ecad pathways in colon cancer cells and harboring different strategies to survive, therefore, the alternative resistance mechanism of Src inhibitor in colon cancer cells may need be concerned in clinical application.
Citation Format: Yi-Wen Lu, Xiang-Ling Hou, Yen-Tse Lu, Chia-Wen Lin, Chien-Chi Huang, Wei-Ting Chao. The alternative mechanism of Src inhibition in colon 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 1681.
Abstract 1683: Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance
Authors: Chen Ziheng , Ho I-Lin , Soeung Melinda , Yen Er-Yen , Rose Johnathon , Srinivasan Sanjana , Deem Angela , Gao Sisi , Ying Haoqiang , Draetta Giulio 
Published: April 2023

Abstract
Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monounsaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells.
Citation Format: Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Johnathon Rose, Sanjana Srinivasan, Angela Deem, Sisi Gao, Haoqiang Ying, Giulio Draetta. Ether phospholipids metabolism is a latent vulnerability for pancreatic cancer resistance [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 1683.
Abstract 1737: Genome-scale metabolic modeling reveals a metabolic switch that restores sensitivity to anticancer chemotherapy in drug-resistant breast cancer cells
Authors: Lim JinA , Jung Hae Deok , Lee Kyung-min , Jeon Moonhyeon , Ryu Han Suk , Kim Hyun Uk , Kim Yoosik 
Published: April 2023

Abstract
Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance due to continued drug usage remains a major hurdle. Among the multiple mechanisms behind the acquisition of drug resistance, metabolic plasticity is receiving increasing attention. Recent proteomic and transcriptomic studies identified metabolic enzymes as potential targets for overcoming the resistance. Yet, these studies mainly focused on differentially expressed genes and overlooked the complexity of the metabolic network, especially its ability to reorganize the metabolic state in response to gene downregulation. Here, we employ the genome-scale metabolic model (GEM) to simulate the metabolic flow and identify candidates that can act as a metabolic switch for drug resistance. Using adriamycin- and paclitaxel-resistant MCF-7 breast cancer cells as model systems, we perform proteomics analysis followed by GEM construction to analyze the differential metabolic flow in the resistant cells. Moreover, we perform GEM simulations after individually knocking out every metabolic enzyme and identify a metabolic switch whose knockout restores the metabolic state of drug-sensitive MCF-7 cells. Notably, downregulating the candidate metabolic switch predicted by our model results in sensitization to the drug. We further show that the cotreatment of adriamycin or paclitaxel with a small chemical inhibitor of the metabolic switch synergistically induces cell death in drug-resistant cells. Collectively, our study demonstrates the application of GEM simulation and subsequent modulation of metabolic state as a strategy to restore drug sensitivity to overcome drug-resistant cancer.
Citation Format: JinA Lim, Hae Deok Jung, Kyung-min Lee, Moonhyeon Jeon, Han Suk Ryu, Hyun Uk Kim, Yoosik Kim. Genome-scale metabolic modeling reveals a metabolic switch that restores sensitivity to anticancer chemotherapy in drug-resistant breast 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 1737.
Abstract 1748: Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma
Authors: Odat Omar S. Al , Gowda Krishne , Amin Shantu G. , Alpdogan Tulin Budak- , Jonnalagadda Subash C. , Pandey Manoj K. 
Published: April 2023

Abstract
Recent advancements in multiple myeloma (MM) therapy have not changed the fact that it is incurable, and all patients experience relapse or become refractory. Thus, more effective treatments are needed to prolong the survival of MM patients. Anti-apoptotic myeloid cell leukemia 1 (Mcl-1) overexpression is correlated with poor prognosis and drug resistance in MM. Nonetheless, there is a lack of effective Mcl-1 inhibitors. To address this unmet clinical need, we developed KS18, a Mcl-1 inhibitor. We generated respective resistant cells to investigate whether KS18 may overcome acquired resistance against various available drugs in the clinic including bortezomib, venetoclax, and ABT-737. KS18 was effective against all MM cells with IC50 values ranging between 1.5 to 2.5µM. KS18 showed significant Mcl-1 inhibition in various MM cells including resistant cells. Importantly, KS18 re-sensitizes resistant cells to bortezomib and other chemotherapeutic drugs. Moreover, KS18 was able to enhance the anti-myeloma activity of venetoclax and ABT-737 treatments toward bortezomib-resistant cells. These results indicate that KS18 possesses the potential to overcome resistance by targeting Mcl-1. Our future studies in patient samples and in vivo model are proposed for further preclinical assessment of this exciting molecule.
Citation Format: Omar S. Al Odat, Krishne Gowda, Shantu G. Amin, Tulin Budak- Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma [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 1748.
Abstract 175: Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma
Authors: Phuong Daryl J. , Armstrong Amanda P. , Flesken-Nikitin Andrea , Nikitin Alexander Y. , Schimenti John C. 
Published: April 2023

Abstract
High grade serous carcinoma (HGSC) is the most common and deadly form of ovarian cancer. Although HGSC can arise from cells in the ovarian surface epithelium (OSE) or fallopian (oviductal) tubal epithelium (TE), the cell state and genetic alterations for HGSC initiation and progression remains unclear. Previous studies with cell type-specific mouse knockouts found inconsistencies in tumorigenesis and chemoresistance. These data can be explained if specific gene signatures in specific cell types have varied tumorigenic potential and chemoresistance. To determine specific gene combinations necessary for OSE and TE malignant transformation, we designed a CRISPR knock out (KO) mini-library against commonly mutated genes of HGSC. Our previous results revealed efficient gene combinations for ex vivo OSE transformation events and a preference for OSE stem cell transformation. To build on our previous studies, we extended our screening methods into TE cells. Our studies utilize an organoid approach to identify the most cancer-prone cell populations. They also test if cell differentiation state determines a specific set of genetic alterations necessary for HGSC initiation. Our screening platform has the potential to determine whether specific genetic alterations in specific cell types are required for malignant transformation. Additionally, our results may improve on previous models of HGSC initiation and progression.
Citation Format: Daryl J. Phuong, Amanda P. Armstrong, Andrea Flesken-Nikitin, Alexander Y. Nikitin, John C. Schimenti. Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma [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 175.
Abstract 1750: Removal of mucin glycans by Bifidobacterium bifidum enhances chemotherapy-mediated cell death in mucinous adenocarcinomas
Authors: Stripe Leah K. , Engevik Amy C. , Engevik Mindy A. 
Published: April 2023

Abstract
Background: Mucinous colorectal adenocarcinoma, a subtype of colorectal cancer, is characterized by mucin production and increased resistance to several chemotherapeutic interventions; resulting in a poorer prognosis compared to non-mucus secreting cancers. Advances in treatment are stymied by the limited number of efficacious chemotherapeutic agents. The most common drug used to treat colorectal cancer is 5-Fluorouracil (5-FU), but less than 10% of mucinous tumors respond to this drug. The production of mucus has been theorized to limit the uptake of chemotherapeutic agents via charge repulsion and size exclusion, thereby promoting chemo-resistance and driving poor outcomes.
Hypothesis: We predict that mucin-degrading microbes secrete glycosyl hydrolase enzymes which cleave mucin glycans and promote the uptake of chemotherapeutic agents and enhance cell death.
Methods & Results: We queried the human gut microbiota and identified multiple diverse microbes which encode enzymes to degrade mucin glycans. Among the mucin-degrading bacteria, we found that Bifidobacterium bifidum harbored one of the most extensive repertoires of mucin-degrading enzymes. B. bifidum was grown in a chemically defined medium with or without porcine intestinal mucus and the secreted products were then added to mucus-producing adenocarcinoma cell lines: HT29-MTX and T84 cells. Supernatant from cultures with mucus removed sialic acid residues and enhanced 5-FU uptake after 48 hrs in both cell lines. Supernatant without mucus also promoted 5-FU mediated cell death; although to a lesser degree than supernatant from cultures incubated with mucus. Gene expression analysis and immunostaining revealed decreased MUC13 gene expression and protein in B. bifidum metabolite treated cell lines compared to media controls. In contrast, we found that secreted products from B. dentium, which is unable to degrade mucus, had no effect on 5-FU induced cell death.
Conclusions: Our data suggests that B. bifidum elicits chemo-sensitivity via the production of mucin-degrading enzymes, which cleave negatively charged sialic acid, increasing the activity of 5-FU in these cancers as well as by lowering the expression of adherent mucins. This work points to a novel role of mucin-degrading microbes to promote 5-FU penetration of mucinous colorectal adenocarcinoma. This strategy has the potential to provide unique treatment strategies for patients with mucinous colorectal cancer.
Citation Format: Leah K. Stripe, Amy C. Engevik, Mindy A. Engevik. Removal of mucin glycans by Bifidobacterium bifidum enhances chemotherapy-mediated cell death in mucinous adenocarcinomas [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 1750.
Abstract 1752: Darolutamide reverses osimertinib resistance in non-small cell lung cancer
Authors: Schmitz John C. , Zhang Guojing , Liu Zhentao , Huang Yufei , Sica Gabriel , Sun Shi-Yong , Owonikoko Taofeek K. 
Published: April 2023

Abstract
Targeted therapies, such as EGFR inhibitors, have improved survival for patients with non-small cell lung cancer (NSCLC). Overall cure rates remain low due to eventual development of resistance. Osimertinib is a third-generation EGFR inhibitor that overcomes T790M-mediated resistance to earlier generation EGFRi. However, resistance to osimertinib has also emerged through mechanisms that are EGFR-dependent and EGFR-independent. To uncover novel strategies to overcome osimertinib resistance, we explored androgen receptor (AR) antagonists in combination with osimertinib as recent studies have demonstrated AR inhibition enhanced TKI-targeted therapy. For these experiments, we utilized lab-derived osimertinib-resistant PC9-AR and HCC827-AR NSCLC cell lines and matching parental lines in both in vitro and in vivo model systems. Clonogenic assays revealed that darolutamide in combination with osimertinib synergistically suppressed clonal growth in resistant cell lines. Similar results were observed with the combination of enzalutamide and osimertinib. Given this result, we next wanted to establish whether the promising in vitro activity of this combination translates into antitumor efficacy in vivo. Mice bearing either HCC827AR or PC9AR xenografts were treated orally daily with both drugs. At the doses administered, neither drug alone had antitumor activity. However, the combination significantly delayed tumor growth by more than 60%. We confirmed this ability to reverse resistance as a class effect using a different AR antagonist, enzalutamide in PC9AR-bearing mice. Significant tumor growth inhibition was observed with the combination of enzalutamide and osimertinib. To investigate the mechanism by which this combination may reverse osimertinib-resistance, RNA-seq studies were performed following drug exposure in vitro using parental and resistant cell lines under various experimental conditions. Comparison of gene expression profiles between parental and resistant cell lines under different therapeutic pressure and pathway enrichment analysis revealed important differentially expressed genes pointing plausible activated pathways that underline osimertinib resistance. AR antagonists have the potential to reverse EGFR inhibitor resistance in treatment of EGFR-mutant NSCLC.
Citation Format: John C. Schmitz, Guojing Zhang, Zhentao Liu, Yufei Huang, Gabriel Sica, Shi-Yong Sun, Taofeek K. Owonikoko. Darolutamide reverses osimertinib resistance in non-small cell lung 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 1752.
Abstract 1820: Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models
Authors: Jensen Simon Skjøde , Christensen Esben , Winther Martin Bak , Hansen Anders Elias , Henriksen Jonas Rosager , Andersen Thomas Lars , Petersen Morten Just , Panina Svetlana 
Published: April 2023

Abstract
TLR7 agonists have shown efficacy in pre-clinical cancer models, however, their clinical use is restricted to topical treatment due to a high systemic toxicity. We have developed a micellar formulation of the TLR7 agonist MBS8(1V270) which demonstrated low toxicity and high efficacy in multiple murine cancer models when administered intravenously as monotherapy. In combination treatment, MBS8(1V270) showed a synergistic effect with PD-1 and PD-L1 inhibitors. Moreover, in several models resistant to anti-PD-1 treatment, MBS8(1V270) co-administration restored sensitivity to anti-PD-1 thus indicating potential for combination treatment in clinical setting. GLP toxicology studies in SD rats and cynomolgus monkeys did not reveal significant toxicities up to the human equivalent dose level of ~1.3 mg/kg which is above anticipated therapeutic dose. Additionally, ex vivo stimulation of human whole blood demonstrated significantly lower IL-6 induction by MBS8(1V270) as compared to the benchmark drug resiquimod. Tissue distribution and excretion of MBS8(1V270) was investigated in SD rats. No signs of drug accumulation were observed in any of the analyzed organs with nearly complete clearance of the drug 24 hours post-end of infusion. The major route of the MBS8(1V270) elimination was via faeces. Cellular uptake of MBS8(1V270) by human blood cells was investigated ex vivo using whole blood from healthy donors. The main cell populations taking up the drug were monocytes and B cells followed by NK cells. No MBS8(1V270) was detected in neutrophils or T cells.In conclusion, MBS8(1V270) was well tolerated in rodents and cynomolgus monkeys at dose levels above therapeutic effective doses identified in mice, thus providing a good therapeutic window. It showed significant anti-cancer activity in multiple murine tumor models when administered either alone or in combination with PD-1/PD-L1 inhibitors. Together, these data provide a rationale for clinical studies of MBS8(1V270) as monotherapy and in combination with immune checkpoint inhibitors. MBS8(1V270) is currently under clinical investigation in the clinical trial MBS8-101 (ClinicalTrials.gov identifier NCT04855435).
Citation Format: Simon Skjøde Jensen, Esben Christensen, Martin Bak Winther, Anders Elias Hansen, Jonas Rosager Henriksen, Thomas Lars Andersen, Morten Just Petersen, Svetlana Panina. Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models [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 1820.