bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3932: Targeting cyclin K in pancreatic cancer
Authors: Xiao Yi , Dong Jixin , Chen Yuanhong 
Published: April 2023

Abstract
This study focuses on investigating the role of Cyclin K in pancreatic cancer growth and chemotherapeutic sensitivity, aiming to provide pre-clinical evidence for Cyclin K-targeted therapy in pancreatic cancer. Unlike other well-known cyclins, Cyclin K is largely understudied in cancers. Data extracted from the TCGA database indicated that Cyclin K was overexpressed in pancreatic ductal adenocarcinoma (PDAC) and associated with reduced overall survival. Consistently, western blotting showed that Cyclin K was abundantly expressed in human and mouse PDAC cell lines. By using a Tet-On inducible system, we established Cyclin K-depleted and Cyclin K-overexpressed cell lines to evaluate the function of Cyclin K in pancreatic cancer. The proliferation assay showed that Cyclin K depletion led to retarded PDAC cell proliferation, whereas Cyclin K overexpression boosted cell growth. We further confirmed that Cyclin K was required for pancreatic cancer growth in vivo. In addition, cell cycle analysis showed that Cyclin K deficiency resulted in G1-S arrest, while Cyclin K overexpression promoted G1-S progression. By using an RT2 cell cycler array, we identified CDC20 as an important target of Cyclin K that mediated Cyclin K-induced PDAC cell proliferation. To investigate the influence of Cyclin K on chemo-sensitivity, we treated the PDAC cell lines with two newly synthesized Cyclin K molecular glue degraders (HQ461 and NCT02). We found that these degraders specifically ablated Cyclin K and its cognate kinase CDK12 in a very efficient manner. Importantly, we demonstrated that Cyclin K abrogation, either by Cyclin K degrader or Cyclin K knockdown, rendered PDAC cells more sensitive to GemTaxol (gemcitabine plus Taxol) treatment and PARP inhibitors (olaparib or niraparib), as indicated by increased cleavage of PARP or caspase 3. Together, our current results suggest: 1. Cyclin K promotes cell proliferation and G1-S transition in pancreatic cancer; 2. CDC20 mediates the function of Cyclin K on pancreatic cancer cell proliferation; 3. Cyclin K depletion synergizes with GemTaxol or PARP inhibitor in pancreatic cancer treatment. Our study revealed for the first time that Cyclin K plays an essential role in pancreatic cancer growth and chemo-sensitivity, and targeting Cyclin K may offer a great therapeutic avenue for pancreatic cancer patients.
Citation Format: Yi Xiao, Jixin Dong, Yuanhong Chen. Targeting cyclin K in pancreatic 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 3932.
Abstract 4074: Cellular immunotherapy targeting kappa myeloma antigen for the treatment of multiple myeloma
Authors: Li Jessica , Haynes Nicole , Cummins Katherine , Gowrishankar Kavitha , Micklewaithe Kenneth , Hilton Halley , Dunn Rosanne , Oliaro Jane , Harrison Simon 
Published: April 2023

Abstract
Multiple myeloma (MM), the second most common blood cancer, is characterized by the accumulation of malignant plasma cells in the bone marrow. Chimeric Antigen Receptor (CAR)-T cell therapy has recently entered the standard of care for relapsed and refractory MM, following the recent FDA-approval of two CAR-T cell products, ide-cel® and cilta-cel®, which target the B cell maturation antigen (BCMA). However, despite impressive response rates, most patients relapse within 1-3 years. Kappa (κ) myeloma antigen (KMA) is a tumour specific membrane associated protein expressed on malignant plasma cells in patients with kappa light-chain restricted (κ-type) MM. KMA is absent on normal plasma cells and haematopoietic stem cells, making it an attractive and alternative target antigen for CAR-T cell therapy for MM. The monoclonal antibody, KappaMab (MDX-1097), binds to a conformational epitope on KMA, and has been assessed in phase I, IIa and IIb clinical trials in relapse refractory myeloma patients (1). Here, we have engineered a lentiviral vector encoding a second-generation CAR expressing a scFv from MDX-1097, fused to a 4-1BB co-stimulatory domain and CD3 zeta chain. We successfully generated human anti-KMA CAR-T cells with high and stable CAR expression and a predominately memory T cell phenotype. The CAR-T cells selectively killed KMA-expressing tumour lines, secreted interferon-gamma upon target recognition, and demonstrated potent anti-tumour activity in a xenograft model. Anti-KMA CAR-T cell therapy therefore represents a novel and potent treatment ready to enter a phase I clinical trial for patients with myeloma. (1) Spencer et al. Blood Cancer Journal (2019) 9:58
Citation Format: Jessica Li, Nicole Haynes, Katherine Cummins, Kavitha Gowrishankar, Kenneth Micklewaithe, Halley Hilton, Rosanne Dunn, Jane Oliaro, Simon Harrison. Cellular immunotherapy targeting kappa myeloma antigen for the treatment of 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 4074.
Abstract 4105: Improvement of CD133-specific chimeric antigen receptor T cells by secreting anti-PD-L1 single-chain variable fragment against cholangiocarcinoma
Authors: Sangsuwannukul Thanich , Supimon Kamonlapat , Chieochansin Thaweesak , Choomee Kornkan , Sujjitjoon Jatuporn , Junking Mutita , Yenchitsomanus Pa-thai 
Published: April 2023

Abstract
Cholangiocarcinoma (CCA) is rare but hard-to-treat solid cancer affecting people worldwide. Cancer stem cells (CSCs) in CCA contribute to tumor heterogeneity and resistance to conventional therapies. Thus, CSCs are notable targets for cancer immunotherapy. CD133 is a potential CSC surface marker overexpressed in various cancers. T cell-based immunotherapy, namely chimeric antigen receptor (CAR) T-cell targeting CD133 has shown potential in eradication of some solid tumors including CCA. Nevertheless, anti-tumor function of CAR T cell could be decreased under immunosuppressive tumor microenvironment (TME). Thus, to improve its function under TME, the next-generation of CD133-specific CAR T-cell is required. We therefore constructed two lentiviral vectors containing: (i) anti-CD133 single-chain variable fragment (scFv), 4-1BB costimulatory molecule, and CD3ζ (133CAR), and (ii) anti-CD133 scFv, 4-1BB, and CD3ζ in tandem with anti-PD-L1 scFv (133CARsL). The lentiviruses were transduced to generate CD133-specific CAR T cells expressing the second-generation (133CART) or anti-CD133 CAR with self-secreting anti-PD-L1 scFv (133CARTsL). The latter was able to simultaneously target CD133 and PD-L1 molecules on CCA cells. CCA cells endogenously expressing CD133 and PD-L1 were cocultured with either 133CART or 133CARTsL. In short-term coculture, the antitumor effects of 133CARTsL were not different from that of 133CART. However, in long-term coculture and after tumor re-challenge, 133CARTsL showed lower expression of programmed cell death protein (PD-1) and better cytotoxic function against high CD133 and PD-L1 CCA cells. The higher potential of 133CARTsL with reduced exhaustion profile would offer great promise for application of CD133-targeting CAR T cells in solid tumors.
Citation Format: Thanich Sangsuwannukul, Kamonlapat Supimon, Thaweesak Chieochansin, Kornkan Choomee, Jatuporn Sujjitjoon, Mutita Junking, Pa-thai Yenchitsomanus. Improvement of CD133-specific chimeric antigen receptor T cells by secreting anti-PD-L1 single-chain variable fragment against cholangiocarcinoma. [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 4105.
Abstract 4107: Cytotoxic T cells armed with IL-4 receptor-targeting and PD-L1-blocking peptides inhibits lung tumor growth
Authors: Jo Dong Gyun , Rangaswamy Gunassekaran Gowri , Murugan Poongkavithai Vadevoo Sri , Lee Byungheon 
Published: April 2023

Abstract
Tumor homing of adoptively transferred cytotoxic T cells (CTLs) to solid tumors is still inefficient. In addition, CTLs that arrive at tumor tissues meet the immune-suppressive tumor microenvironment. To reduce these limitations in adoptive T-cell therapy against solid tumors, we here exploited CTLs dual-labeled with IL-4 receptor (IL4R)-targeting peptide and programmed cell death-ligand 1 (PD-L1)-blocking peptide. IL4R is commonly upregulated in many solid tumors including lung tumor. PD-L1, an immune checkpoint, is frequently upregulated in tumor cells and contributes to the suppression of CTLs in the tumor microenvironment. CTLs were isolated from the splenocytes of LLC lung tumor-bearing mice and non-genetically labeled with IL4RPep-1, an IL4R-targeting peptide, and PD-L1Pep2, a PD-L1-blocking peptide, using a sulfhydryl-reactive cross linker. Compared to unlabeled CTLs, IL4R-targeted, PD-L1-blocking CTLs showed more robust cytokine secretion and tumor cell lysis during co-culture with LLC tumor cells. The CTLs armed with the dual-acting peptides exerted higher levels of tumor homing and anti-tumor growth activity in LLC lung tumor-bearing mice, which was accompanied by decrease of immune-suppressive cells in the tumor tissues. These results suggest that the IL4R-targeted, PD-L1-blocking CTLs can be a promising strategy in adoptive T-cell therapy against solid tumors.
Key words: Adoptive T-cell therapy, CTLs, IL-4 receptor, lung tumor, PD-L1
Citation Format: Dong Gyun Jo, Gunassekaran Gowri Rangaswamy, Poongkavithai Vadevoo Sri Murugan, Byungheon Lee. Cytotoxic T cells armed with IL-4 receptor-targeting and PD-L1-blocking peptides inhibits lung tumor growth. [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 4107.
Abstract 4178: Lysosomal storage dysfunction as a risk factor in pancreatic cancer
Authors: Kim Hyemin , Koh Youngil , Park Joo Kyung 
Published: April 2023

Abstract
Background: Lysosome is closely linked to autophagy activity which has an important role in pancreatic adenocarcinoma (PDAC). We investigated whether lysosome storage dysfunction (LSD) contributes to PDAC development.
Materials and Methods: Comparison of germline putative pathogenic variants (PPV) in genes involved in lysosome functions was performed between PDAC patients (N=418) and healthy controls (N=745) using next generation sequencing. Using mouse pancreas organoid, consequences of GALC downregulation in PDAC development was evaluated. Transcriptome data analysis of human PDAC organoid according to PPV status was followed.
Results: PPV in LSD related genes were enriched in PDAC patients compared to healthy controls (Log2OR = 1.65, P = 3.08  ×  10−3). For limited stage PDAC patients, PPV carriers were diagnosed with PDAC in younger age compared to non-carriers (mean age 61.5 vs. 65.1 years, p=0.038). In mouse pancreas organoid, Ki-67 index significantly increased as GALC was downregulated. Altered autophagy activity with increased autophagy flux following GALC dysfunction was observed in both human cancer cell line and mouse organoid. mTOR downregulation was noted in mouse pancreas organoid. RNA sequencing analysis of human PDAC organoid revealed metabolism alteration related to LSD.
Conclusion: Genetically defined lysosome dysfunction is frequently observed in young age onset PDACs. Lysosome dysfunction might contribute to PDAC development via altered metabolism and autophagy activity.
Key words: lysosomal storage disease (LSD), germline, pancreatic ductal adenocarcinoma (PDAC)
Citation Format: Hyemin Kim, Youngil Koh, Joo Kyung Park. Lysosomal storage dysfunction as a risk factor in pancreatic 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 4178.
Abstract 4194: The FuSion Project of Pan-Cancer Early Screening in Chinese– An integrative study by Fudan University and Singlera
Authors: Suo Chen , Zhao Renjia , Jiang Yanfeng , Zhang Yunzhi , He Qiye , Su Zhixi , Liu Rui , Jin Li , Chen Xingdong 
Published: April 2023

Abstract
Background: Cancer is the leading cause of premature deaths. Screening in the population can effectively improve the prognosis by diagnosing cancer early. Previous studies have found that cancer biomarkers, for example, ctDNA methylation and protein biomarkers are clearly associated with the occurrence and development of cancer. To evaluate the performance of reported biomarkers for cancer early screening in real world, we launched an integrative study by Fudan University and SInglera for pan-cancer early detectiON (FuSion) project since 2021. Method: The FuSion Project (NCT05159544) is a prospective and multicenter cohort study of pan-cancer screening in Chinese population. We will construct a stepwise model of risk stratification for screening of multiple cancer types, including lung, esophagus, stomach, liver, pancreatic and colorectal cancers. A total of 50,137 individuals recruited in the Taizhou Longitudinal Study (TLS) between 2012 and 2021 are investigated. Eligible participants are aged 20-75 years and without history of cancer. They have completed a questionnaire and provided blood samples for baseline tests, which measure a total of about 50 indicators in the routine blood work, blood biochemistry, and serum cancer biomarkers, such as carbohydrate antigen 19-9 and carcinoembryonic antigen. Informed consent is obtained from all participants. We build risk stratification models based on risk factors collected in the questionnaire and from baseline test results for each cancer type, respectively. Then, 10,000 high-risk- and 5,000 low-risk individuals of cancers are identified by the cancer-specific risk stratification model. They will be screened by the PanSeerX assay using cancer-related DNA methylation markers, and medically followed-up for at least two years. Sensitivity, specificity, positive- and negative-predictive values of the screening models will be determined based on the true cancer incidences. Finally, we will validate the cancer screening strategies using 10,000 average-risk participants recruited from multiple centers by regular checkups and from other large-scale cohort studies.
Citation Format: Chen Suo, Renjia Zhao, Yanfeng Jiang, Yunzhi Zhang, Qiye He, Zhixi Su, Rui Liu, Li Jin, Xingdong Chen. The FuSion Project of Pan-Cancer Early Screening in Chinese– An integrative study by Fudan University and Singlera. [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 4194.
Abstract 4309: Early apoptotic measurements of patient-derived organoids predict patient response to therapy
Authors: McQueeney Kelley E. , Bhola Patrick , Hill Sarah J. , Letai Anthony 
Published: April 2023

Abstract
The use of imperfect models and ex vivo culture systems to try to predict patient drug response represents an enormous bottle neck in cancer treatment. Nonetheless, determining how effective an approved drug will be for an individual cancer patient, as well as identifying novel compounds that may be beneficial to a specific population often requires the use of primary tumor cells. Patient-derived organoids represent an intermediate between primary tumor cells, whose limited supply may hinder reliable drug testing, and cell lines, which often do not reflect what happens in vivo. Herein, we describe the development of a novel assay platform, termed 3D-DBP (3D dynamic BH3 profiling), to detect early apoptotic measurements in ovarian cancer patient-derived organoids and present evidence that this method can be used to predict patient response to therapy. We have optimized the use of patient-derived organoids from 16 individual tumors in a microscopy-based imaging assay. We image the BH3 peptide-induced release of cytochrome c from mitochondria, which indicates permeabilization of the outer mitochondrial membrane, in intact organoids. The less cytochrome c retained in each organoid, the more primed that organoid is for apoptosis. By comparing results of drug-treated and untreated cells, we can identify drugs that cause a significant increase in apoptotic priming in organoids. In the 16 patient-derived organoids investigated this 3D DBP technique was an effective means of predicting patient response to carboplatin therapy. In summary, we have not only created a means of visualizing drug response in intact organoids, but also have demonstrated its clinical utility.
Citation Format: Kelley E. McQueeney, Patrick Bhola, Sarah J. Hill, Anthony Letai. Early apoptotic measurements of patient-derived organoids predict patient response to therapy. [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 4309.
Abstract 4440: Efficacy of Gen-1, an interleukin-12 immune gene therapy, at different dose frequencies
Authors: Sood Subeena , Boyer Jean D. , Kim Jessica , Matar Majed M. , Signer Olivia , Rice Jennifer S. , Smith Alanna M. , Borys Nicholas , Anwer Khursheed 
Published: April 2023

Abstract
Introduction: The purpose of this study was to investigate the effect of dosing frequency on the antitumor activity of intraperitoneal GEN-1, an interleukin-12 (IL-12) immune gene therapy in a mouse model of peritoneally disseminated ovarian cancer.
Procedures: Three GEN-1 dosing regimens were examined for efficacy in ID-8 tumor-bearing mice: weekly, every 2 weeks and every 3 weeks. 2.5 million cancer cells were bolus injected into 4 groups (B, C, and D) of 10 mice each. A control group (A) of 6 mice had PBS injected IP without tumor and an untreated control (E) of 15 mice were injected with 2.5 million cancer cells. Groups B, C, and D were injected with GEN-1 IP weekly, every 2 weeks, and every 3 weeks respectively. Six animals from each group B, C, and D were harvested for translational research (TR) after 5 weekly, 3 every 2-week and 2 every 3-week treatments respectively. The remaining 4 animals in each group were followed for weight change (tumor burden) and survival. Additionally, TR evaluated change in ascites T-cell, B-cell and myeloid cell populations.
Results: There was a gradual rise in tumor burden and mortality in all treatment groups with comparable rate between once every week and once every 2-week regimens. Once every 3-week regimen had relatively higher mortality rate and higher tumor burden. There were similar or higher increases in T-cell and B-cells with reduced treatment frequency with lesser increases in myeloid cell density with reduced treatment frequency.
Conclusions: Once every 2-week dosing of GEN-1 in human studies is warranted. Future combination studies of Gen-1 with immune checkpoint inhibitors will evaluate the safety and efficacy of this regimen.
Citation Format: Subeena Sood, Jean D. Boyer, Jessica Kim, Majed M. Matar, Olivia Signer, Jennifer S. Rice, Alanna M. Smith, Nicholas Borys, Khursheed Anwer. Efficacy of Gen-1, an interleukin-12 immune gene therapy, at different dose frequencies. [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 4440.
Abstract 446: LONP1 inhibition induces mitochondrial proteotoxic stress and is cytotoxic to acute myeloid leukemia cells
Authors: Tcheng Matthew 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the uncontrolled proliferation of abnormal myeloid precursors that fail to fully differentiate, resulting in the accumulation of malignant leukemic cells. High rates of nuclear-encoded protein synthesis, supporting increased proliferation rates, render leukemic cells reliant on increased proteolytic systems to clear misfolded proteins. Compared to non-transformed blood cells, AML cells and stem cells exhibit a unique metabolic phenotype characterized by increased mitochondrial mass and greater reliance on oxidative metabolism for survival and proliferation. To identify novel biological vulnerabilities in the mitochondrial proteome, we analyzed the DepMap (depmap.org) for essential mitochondrial genes in AML. Through this analysis, we identified the mitochondrial protease LONP1 as essential for a subset of AML and in the top 10% of essential genes for this disease. LONP1 is a nuclear-encoded AAA+ serine protease that resides in the mitochondrial matrix and maintains the mitochondrial proteome, mainly via the clearance of misfolded, unassembled or oxidatively-damaged proteins. However, its importance and function in AML has not been previously reported. Compared to normal hematopoietic cells, LONP1 mRNA was overexpressed in AML across three publicly available datasets while LONP1 protein was increased &gt;2 fold in tested AML primary samples (N=16). Using shRNA and CRISPR gRNA, LONP1 knockdown and knockout reduced the growth and viability of OCI-AML2, OCI-M2, and NB4 cells. Mechanistically, genetic knockdown or knockout of LONP1 increased levels of insoluble, aggregated mitochondrial proteins including ClpP, TUFM, and NDUFA9 as measured by immunoblotting of soluble and insoluble protein fractions as well as by the fluorescence of the protein aggregation dye PROTEOSTAT by confocal microscopy. The accumulation of insoluble mitochondrial protein aggregates through LONP1 inhibition exploits an increased reliance on chaperone and protease systems due to abnormally high protein synthesis. This novel therapeutic avenue targets a unique metabolic vulnerability to eliminate AML cells.
Citation Format: Matthew Tcheng. LONP1 inhibition induces mitochondrial proteotoxic stress and is cytotoxic to acute myeloid leukemia 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 446.