bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 936: Developing a sex-biased model for LKB1-mutant lung adenocarcinoma
Authors: Fan Yijian , Jin Rui , Liu Xiuju , Liu Yuan , Huang Chunzi , Gilbert-Ross Mellissa , Marcus Adam , Zhou Wei 
Published: June 2022

Abstract
Liver kinase B1 (LKB1) is the third most frequently mutated gene in lung adenocarcinoma (LUAD), and LKB1-mutant lung cancers are resistant to existing targeted therapy or immune checkpoint blockade therapy. In the TCGA-LUAD dataset, LKB1 was found to be more frequently mutated in males than in females even after correcting for potential confounders (male versus female: 22.8% versus 11.3%, p &lt; 6.9x 10-4, FDR = 0.033). Similar trends can be found in all other large LUAD datasets. However, the mechanistic basis of this bias is unknown because the existing mouse models of lung cancers either did not exhibit sex bias or showed female mice being more susceptible to the development of lung cancers. Here, we demonstrate that our lentivirus-inducing Kras/LKB1-mutant genetically engineered mouse model (GEMM) and tail-vein injection syngeneic model exhibit sex bias against the tumor formation in the female host. In our KRASLSL-G12D/LKB1fl/fl/Rosa-Luc GEMM mice, the lung tumor formation was monitored by bioluminescence imaging (BLI) and validated by immunohistochemistry of tumor bearing-lung. The sex bias of time to lung adenocarcinoma formation in males and females was determined by the Kaplan-Meier method. 97% (31/32) male GEMM developed LUAD after the induction, whereas only 58% (15/26) female GEMM developed LUAD (p=0.0001, log-rank). The tail-vein injection method used the WRJ388-AD1 cell line, which was derived from WRJ388. Tumor growth in the chest area was monitored by BLI and evaluated by the mixed-effects model. Sex bias preference for developing lung tumors in the male host reached significance on day 14 post-injection (p=0.0037) and lasted during the study (day 21, p=0.0021). On day 21, with the cutoff as 1x106 p/sec/cm2/sr in lung region, 100% male GEMM formed lung tumor while only 36% female GEMM formed lung tumor after the injection. Collectively, this KRAS/LKB1-mutant lung adenocarcinoma exhibits sex-biased tumor formation and growth, which are consistent with clinical data among LUAD patients. This model will provide researchers with opportunities to understand the mechanistic basis of this sex bias and to develop novel personalized therapies.
Citation Format: Yijian Fan, Rui Jin, Xiuju Liu, Yuan Liu, Chunzi Huang, Mellissa Gilbert-Ross, Adam Marcus, Wei Zhou. Developing a sex-biased model for LKB1-mutant lung 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 936.
Abstract 937: Novel role of deubiquitylase USP13 in lineage plasticity and drug resistance of non-small cell lung cancer
Authors: Kwon Juntae , Han Cecil 
Published: June 2022

Abstract
Lineage plasticity, the ability of cells to transition from one defined cell type to another, has been proposed as a source of intertumoral heterogeneity and therapeutic resistance.However, molecular drivers and underlying mechanisms of lineage plasticity remain largely unknown. Here, we found a novel role of deubiquitylase USP13 in lineage transition of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) using mouse model: Usp13-overexpressing (Usp13OE) ADC loses its characteristics while gaining SCC features are enhanced. Transcriptomic analysis showed that Usp13OE lung cancers were heterogeneous and epithelial-mesenchymal transition (EMT), hypoxia, and PI3K-Akt-mTOR signaling pathway were enriched. Furthermore, development disease pathways including neurological and gastrointestinal diseases were overrepresented in Usp13OE tumors. Notably, Usp13OE primary tumor cell lines showed higher drug resistance against first-line therapy. Collectively, our findings demonstrate the novel role of USP13 in lineage transition of lung cancer and suggest that targeting USP13 is a promising strategy for the further treatment of lung cancer patients.
Citation Format: Juntae Kwon, Cecil Han. Novel role of deubiquitylase USP13 in lineage plasticity and drug resistance of non-small cell lung cancer [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 937.
Abstract 94: PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers
Authors: Mulvaney Kathleen M. , McMillan Brian , Blomquist Christa , Acharya Nischal , Ranaghan Matthew , Kesar Devishi , Ianari Alessandra , Sellers William 
Published: June 2022

Abstract
PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5. Current efforts are focused on understanding whether PRMT5-substrate adaptor disruption synergizes with immune therapies or new classes of PRMT5 inhibitors in CDKN2A/MTAP null cancer.
Citation Format: Kathleen M. Mulvaney, Brian McMillan, Christa Blomquist, Nischal Acharya, Matthew Ranaghan, Devishi Kesar, Alessandra Ianari, William Sellers. PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers [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 94.
Abstract 943: Modeling and dissecting of esophageal squamous cell carcinoma initiation
Authors: Ko Kyung Pil , Zou Gengyi , Huang Yuanjian , Kim Bongjun , Zhang Jie , Jun Sohee , Park Jae-Il 
Published: June 2022

Abstract
Esophageal cancer is the 7th common cancer with the 6th highest cancer mortality rate worldwide. The 5-year survival rate of esophageal cancer is 10 ~ 25%. Esophageal cancer is mainly divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC accounts for 80% of all esophageal cancer cases and shows a poor prognosis due to a lack of symptoms at early stages. Given that early diagnosis of ESCC may lead to better outcomes, understanding the biology of ESCC initiation is imperative. To recapitulate the early events of ESCC, we employed the murine esophageal organoid (EO) system recently developed. Based on in silico analyses, we selected nine candidate genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) frequently mutated in ESCC patients. The EOs were then genetically manipulated with the combinatorial ablation of nine genes by CRISPR/Cas9 system. The EOs carrying PN (Trp53 and Notch1 KO), PC (Trp53 and Cdkn2a KO), and PCN (Trp53, Cdkn2a, and Notch1 KO) showed hyperplastic and neoplastic properties with impaired squamous cell differentiation and organoid integrity, compared to the wild-type (WT) EOs. Single-cell RNA-seq (scRNA-seq) analyses of WT, PC, PN, and PCN organoids showed the highest enrichment of ESCC cancer stem cell markers in PCN organoids. Unlike the cell lineage in WT EOs, neoplastic EOs (PC, PN, and PCN) exhibited distinct cell lineage along with multiple root cell clusters. While WT EOs failed to become neoplastic, PN, PC, and PCN EOs displayed the transforming activity in vitro and in vivo xenograft transplantation assays. Intriguingly, in allograft mouse models, while PN organoids-derived cells barely developed tumors, PC and PCN organoids-derived cells developed tumors with marked downregulation of genes related to antigen processing and presentation. These results suggest that combinatorial loss of P53, CDKN2A, and NOTCH1 play a pivotal role in ESCC neoplasia, stemness, and immune checkpoint, unveiling the biology of ESCC initiation.
Citation Format: Kyung Pil Ko, Gengyi Zou, Yuanjian Huang, Bongjun Kim, Jie Zhang, Sohee Jun, Jae-Il Park. Modeling and dissecting of esophageal squamous cell carcinoma initiation [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 943.
Abstract 963: Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer
Authors: Ban Yi , Dong Wenjuan , Zou Yue , Lee Sharrell B. , Sheng Jianting , Cao Yuliang , Wong Stephen T.C. , Gao Dingcheng 
Published: June 2022

Abstract
Epithelial to mesenchymal transition (EMT) plays an important role in metastasis and chemoresistance. However, targeting EMT has been challenging due to the complex and redundant EMT signaling pathways. Moreover, EMT inhibition would unequivocally promote its reversed process, mesenchymal to epithelial transition (MET), which also favors malignancy progression. To solve this EMT targeting paradox, we proposed to target the ability of tumor cells to oscillate between epithelial and mesenchymal states, the epithelial to mesenchymal plasticity (EMP), which encompasses both EMT and MET. Using a SnailCre-ERT2 mediated EMT lineage-tracing model, we confirmed the involvement of EMP in chemoresistant metastasis of breast cancer. Single-cell transcriptome analyses of tumor cells in the transitioning phases of EMT or MET consistently revealed that ribosome biogenesis (RiBi) was specifically elevated regardless of their destined phenotypical fates. Further analyses delineated that the upregulation of RiBi and the subsequent nascent protein synthesis via the intensified ERK and mTOR signalings were vital for cancer cells to transit between epithelial and mesenchymal states. Importantly, inhibiting the excessive RiBi by either genetic or pharmacological means impaired EMP, as both EMT and MET processes were impeded, leading to significantly reduced metastatic outgrowth of chemoresistant tumor cells. Our studies revealed that elevated RiBi is required for tumor cells to “Ping Pong” between epithelial and mesenchymal states. Targeting the EMP via RiBi inhibition provides a feasible strategy to improve therapies for advanced breast cancers.
Citation Format: Yi Ban, Wenjuan Dong, Yue Zou, Sharrell B. Lee, Jianting Sheng, Yuliang Cao, Stephen T.C. Wong, Dingcheng Gao. Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer [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 963.
Abstract CT224: Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135)
Authors: Ranjan Tulika , Sengupta Soma , Yu Alexander , Howard Candace M. , Chen Ricky , Chaudhary Rekha , Marko Nicholas , Aregawi Dawit , Glantz Michael , Glass Jon , Green Richard M. , Lu-Emerson Christine , Mammoser Aaron , Moulding Hugh , Jubelirer Steven , Schroeder Jason , Anderson Mark , Chow Frances , Lirette Seth , Denning Krista , Alberico Anthony , Valluri Jagan , Claudio Pier Paolo 
Published: June 2022

Abstract
Background: Clinical outcomes in patients with recurrent high-grade glioma (HGG) remain poor. Cancer stem cells (CSCs) have been implicated in metastasis, treatment resistance and recurrence of HHGs. We have shown in several clinical studies that anti-CSC-directed therapy provides benefits in many cancer types; however, this is the first report of a randomized clinical trial evaluating it for recurrent HGGs. Objective: Determine whether CSC-targeted cytotoxic agents selected by ChemoID assay-guided therapy improves survival in patients with recurrent HGG.
Design, Settings, and Participants: In this parallel-group, randomized, phase-3 clinical trial, patients at 13 clinical sites in the USA with grade-III/IV recurrent glioma (2016 WHO guidelines) were randomized 1:1 to either ChemoID assay-guided therapy or physician-choice therapy, and then treated and followed until unacceptable toxic effects, hospice, or death.
Main Outcomes and Measures: The primary endpoint was overall survival (OS).
Results: Combined median follow-up was 9 months. Median OS (mOS) was 12.5 months (95% CI, 10.2-14.7) in the ChemoID assay-guided group vs 9 months (95% CI, 4.2-13.8) in the physician-choice group (log-rank P = .010). Risk of death was significantly lower in the ChemoID assay group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression free survival (PFS) was 10.1 vs 3.5 months (95% CI, 4.8-15.4 vs 1.9-5.1) (HR, 0.25; 95% CI, 0.14-0.44; P &lt; .001).
Conclusions and Relevance: Primary endpoint was met in this randomized clinical trial. The mOS was 3.5 months longer in the ChemoID assay-guided group vs the physician-choice group demonstrating the clinical advantage of treating HGG patients using CSC personalized therapy.
Citation Format: Tulika Ranjan, Soma Sengupta, Alexander Yu, Candace M. Howard, Ricky Chen, Rekha Chaudhary, Nicholas Marko, Dawit Aregawi, Michael Glantz, Jon Glass, Richard M. Green, Christine Lu-Emerson, Aaron Mammoser, Hugh Moulding, Steven Jubelirer, Jason Schroeder, Mark Anderson, Frances Chow, Seth Lirette, Krista Denning, Anthony Alberico, Jagan Valluri, Pier Paolo Claudio. Multi-institutional randomized phase-3 trial comparing cancer stem cell-targeted vs physician-choice treatments in patients with recurrent high-grade gliomas (NCT03632135) [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 CT224.
Abstract CT502: Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma
Authors: Leidner Rom S. , Taylor Matthew H. , Moudgil Tarsem L. , Christie Tanisha L. , Koguchi Yoshinobu , Dowdell Alexa , Redmond William L. , Jensen Shawn M. , Ballesteros-Merino Carmen , Vancampen Jake A. , Rajamanickam Venkatesh , Bernard Brady M. , Paustian Christopher , Hilton Traci L. , Hu Hong-Ming , Bell Richard B. , Urba Walter J. , Bifulco Carlo B. , Piening Brian , Fox Bernard A. 
Published: June 2022

Abstract
Background: Preclinical studies document that complex cancer vaccines, combined with T cell agonists and anti-PD-1, can augment therapeutic efficacy. Here we report preliminary immunological analyses of patients enrolled in a first-in-human immunotherapy-trio study of multivalent autophagosome vaccine (DPV-001), with sequenced checkpoint inhibition (anti-PD-1; retifanlimab), with/without anti-GITR agonist (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024).
Methods: Peripheral blood (PB) and sera are collected regularly and PB are evaluated by flow cytometry. Biopsies obtained at baseline, D15 and D45 are analyzed by multiplex IF and 10x Genomics scRNA-Seq. Sera are being analyzed by phage immunoprecipitation (PhIP) sequencing for reactivity against the human proteome.
Results: Preliminary results document increases in activated CD4 and CD8 effector memory T cells (TEM) with vaccine alone. Changes in tumor microenvironment (TEM) were also observed with increased infiltration of immune cells. Evaluation of changes to humoral immunity, T cell function and TCR analyses are ongoing.
Conclusions: We previously reported immunological monitoring of a phase I/II trial of an autophagosome cancer vaccine (DPV-001) containing more than 300 shared cancer antigens, as adjuvant therapy for NSCLC. Vaccination induced or augmented immune responses to more than 50 cancer antigens shared with head and neck squamous cell carcinoma (HNSCC). Preclinical studies combining this cancer vaccine with αGITR agonist and αPD-1 augmented therapeutic efficacy [PMID: 31747946], and provided the rationale for the current study. This is the first clinical trial to perform such a study with αGITR agonist (INCAGN-1949), in humans.
Support: Incyte, Providence Medical Foundation, The Harder Family, Nancy Lematta.
Citation Format: Rom S. Leidner, Matthew H. Taylor, Tarsem L. Moudgil, Tanisha L. Christie, Yoshinobu Koguchi, Alexa Dowdell, William L. Redmond, Shawn M. Jensen, Carmen Ballesteros-Merino, Jake A. Vancampen, Venkatesh Rajamanickam, Brady M. Bernard, Christopher Paustian, Traci L. Hilton, Hong-Ming Hu, Richard B. Bell, Walter J. Urba, Carlo B. Bifulco, Brian Piening, Bernard A. Fox. Preliminary immunological monitoring of first-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma [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 CT502.
Abstract CT526: A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A in patients with advanced solid tumors
Authors: Qin Xiaoli , Luo Lori , Ying-ying Li , Wang Yin , Sun Shuaijun , Hao Xiaolin , Yang Jinfu 
Published: June 2022

Abstract
ZX-101A is a next-generation PI3Kδ/γ dual inhibitor, exerting synergistic effects on PI3Kδ and PI3Kγ-mediated processes through multifaceted mechanisms of actions. Phase 1/2a study, ZX-101A-101 (NCT04504708) is ongoing to assess safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced hematologic malignancies. Furthermore, recent preclinical studies of ZX-101A showed that dual inhibition of PI3Kδ and PI3Kγ restored the immune surveillance to inhibit solid tumor growth. ZX-101A-201 is a phase 1/2a open-label, multiple-dose ascending study to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of once daily oral ZX-101A in 28-day cycles in patients with advanced solid tumors.ZX-101A had minimal effects on solid tumor-derived CT26, 4T1 and A20 cells in in vitro cell proliferation assay. In contrast, ZX-101A inhibited tumor growth when CT26 cells were grafted to wild-type syngeneic mice, while only showed a limited tumor growth inhibition when CT26 tumors grew on T-cell deficient nude mice. Thus, in vivo tumor growth inhibition in wild-type mice was attributed to the enhanced anti-tumor immunity by ZX-101A treatment. Flow cytometry analysis on ex vivo tumor tissues from syngeneic mouse demonstrated that ZX-101A decreased regulatory T cells and increased M1/M2 macrophage polarization in the tumor microenvironment. In A20 syngeneic model, ZX-101A in combination of anti-PD1 antibody achieved 99.7% TGI after 18 days of treatment, while anti-PD1 antibody alone only had TGI at 11.7%. Synergistic inhibitory effect of ZX-101A and anti-PD1 antibody was also observed in LLC, CT26 and humanized MC38 syngeneic mouse models. Safety assessment on the mouse spleen, thymus and colon organs indicated minimal side effects by the treatment of the ZX-101A alone and in combination with anti-PD1. These results suggested ZX-101A as a potential immunotherapeutic agent to treat appropriate solid tumor types. ZX-101A-201 study consists of 2 parts, Dose Escalation and Dose Expansion. Part 1 dose escalation is designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of ZX-101A monotherapy in patient with advanced solid tumors. Part 2 dose expansion will evaluate ZX-101A activity in up to three disease-specific cohorts. Inclusion of combination therapy is planned after obtaining the initial clinical assessment of ZX-101A on its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients.
Citation Format: Xiaoli Qin, Lori Luo, Li Ying-ying, Yin Wang, Shuaijun Sun, Xiaolin Hao, Jinfu Yang. A Phase 1/2a Study of a PI3Kδγ dual inhibitor ZX-101A in patients with advanced solid tumors [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 CT526.
Abstract LB005: ATAK receptors, a new class of chimeric antigen receptors that harness innate immunity in myeloid cells to target cancer
Authors: Diwanji Neha , Kieffer-Kwon Kyong-Rim , Prod’homme Thomas , McCreedy Bruce , Wang Yuxiao , Getts Daniel 
Published: June 2022

Abstract
For the majority of patients with advanced solid tumors, sustained clinical benefit with immunotherapy has yet to be achieved. Myeloid cells, including monocytes and macrophages are the primary orchestrators of immune responses and are found to accumulate in tumors, in some cases contributing up to 75% of the tumor mass. Myeloid cells express a wide range of innate immune sensors such as Toll-like receptors, RIG-I and cGAS-STING as well as co-stimulatory molecules like CD40. The activation of these innate immune pathways in myeloid cells can associated with anti-tumor immune response. Notwithstanding the ability of the myeloid cells to infiltrate tumors and elicit broad immune responses, technologies capable of harnessing these cells to target cancer remains elusive. Here we designed and engineered a new class of chimeric antigen receptors that couple tumor recognition with multiple innate immune signal domains, referred to as Activate, Target, Attack & Kill (ATAK) receptors. By combining cancer recognition domains with intracellular signaling domains from innate immune receptors such as Fc, TLR and cytokine receptors, we show that myeloid cells can be controlled and programmed to recognize cancer and elicit a broad and tunable immune response. Critically, in mice with established, highly immunosuppressive B16 melanoma tumors, delivery of monocytes engineered to express ATAK receptors results in anti-tumor activity. Our data show the versatility of building ATAK receptors by harnessing innate immune pathways and support their clinical development in cell therapies.
Citation Format: Neha Diwanji, Kyong-Rim Kieffer-Kwon, Thomas Prod’homme, Bruce McCreedy, Yuxiao Wang, Daniel Getts. ATAK receptors, a new class of chimeric antigen receptors that harness innate immunity in myeloid cells to target cancer [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 LB005.