bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 382: Synergistic anti-tumor effect of ABN401 in combination with KRAS inhibitor in a c-MET-altered KRASG12C non-small cell lung cancer model
Authors: Lee Saehyung , Cho Sunghwan , Kim Na Young , Nirmal Rajasekaran , Park Kyung Eui , Choi Jun Young 
Published: April 2023

Abstract
ABN401, a highly selective c-MET inhibitor, is being evaluated for the treatment of non-small cell lung cancer (NSCLC) in clinical trials. NSCLC is a heterogeneous in nature and leading cause in cancer related mortality. Numerous studies are still ongoing to identify the key oncogenic mutations that promote tumor progression. Various actionable genetic mutations such as EGFR, ALK, BRAF, MET, RET, and NTRK/ROS1 have been identified, and the targeted therapies are being developed. It is known that targeted therapies can control disease progression in NSCLC patients and drug resistance due to their heterogeneity remains a clinical hurdle. Among the targets, KRAS gene mutations, an unactionable and is now considered a promising therapeutic approach for NSCLC. Currently, co-occurrence of KRASG12C mutation has been reported in NSCLC patients with MET alterations. Moreover, oncogenic KRAS protein can induce c-MET expression levels by signaling pathways. In this study, we aim to provide an alternative therapeutic strategy for NSCLC patients with KRASG12C mutation harboring MET alterations. We have performed several in vitro and in vivo efficacy studies for the combination of ABN401, c-MET inhibitor, and sotorasib, KRASG12C variant inhibitor, including a PDX model of c-MET-altered KRASG12C NSCLC. Our results suggest that the combination of ABN401 and KRAS inhibitor could be an alternative treatment option for c-MET-altered KRASG12C NSCLC patients.
Citation Format: Saehyung Lee, Sunghwan Cho, Na Young Kim, Rajasekaran Nirmal, Kyung Eui Park, Jun Young Choi. Synergistic anti-tumor effect of ABN401 in combination with KRAS inhibitor in a c-MET-altered KRASG12C non-small cell lung cancer model [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 382.
Abstract 3928: Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia
Authors: Bertulfo Carla , Perez-Duran Pablo , Palomero Teresa , Ferrando Adolfo 
Published: April 2023

Abstract
T-cell Acute Lymphoblastic Leukemia (T-ALL) is hematologic tumor characterized by the diffuse infiltration of the bone marrow by malignant hematopoietic cells expressing immature T cell markers. Although T-ALL currently has better cure rates primarily due to multiagent or intensified chemotherapy, the prognosis for patients who are resistant or develop relapse to therapy remains very poor. Aberrant Notch homolog-1 (NOTCH1) signaling is a major driver of T-ALL pathogenesis as more than 60% of T-ALL cases harbor activating mutations in the NOTCH1 gene. Gamma Secretase Inhibitors (GSIs) which effectively block the activation of oncogenic protein NOTCH1 are potential candidates for the treatment of T-ALL. However, the clinical application of GSIs is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling in the gut. Here we demonstrate that combination therapy of GSIs and a small molecule inhibitor of the neddylation pathway circumvents the GSI-induced gut toxicity in vitro and in vivo. Genome-wide CRISPR loss-of-function screen in LS174T adenocarcinoma cells revealed neddylation pathway as a main regulator of massive goblet cell differentiation upon NOTCH1 inhibition. Genetic and pharmacologic inhibition of the neddylation pathway in LS174T cells rescued GSI-induced differentiation and cell death. Mechanistically, neddylation inhibition increases the protein stability of Hairy and enhancer of split-1 (HES1), a known regulator of absorptive and secretory cell fate decisions. Combination treatment of GSI and neddylation inhibitor in C57/BL6 mice showed a profound decrease in the number of goblet cells and maintained HES1 protein levels in the intestinal epithelium compared to GSI treatment alone. Remarkably, combined treatment of GSI and neddylation inhibitor in NOTCH1-induced T-ALL mice showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL.
Citation Format: Carla Bertulfo, Pablo Perez-Duran, Teresa Palomero, Adolfo Ferrando. Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia. [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 3928.
Abstract 3973: Precision RNAi using synthetic shRNAmir target sites
Authors: Neumüller Ralph , Hoffmann Thomas , Hörmann Alexandra , Corcokovic Maja , Zuber Johannes 
Published: April 2023

Abstract
Genetic loss-of-function methods including short-hairpin RNAs (shRNAs) and CRISPR are key methods for target gene validation across a variety of different disease areas. While these methods have revolutionized target gene discovery and characterization, both methods suffer from limitations in the context of in vivo target validation due to off-target effects and insufficient knock-down for shRNAs and resistant clones for CRISPR. In this study, we describe a method, artificial RNA interference (ARTi) that overcomes these limitations by fundamentally changing the basic experimental strategy of RNAi-based loss-of-function studies. Instead of newly designing gene-specific shRNA for individual target genes, ARTi utilizes ultra-effective and selective artificial miRNA-based shRNAs that do not match any transcribed gene in the target genome. In addition, these sequences are optimized for ultra-efficient miRNA processing and knockdown of synthetic target genes, and are deeply characterized to not trigger major off-target effects, enabling highly stringent target validation in vivo with unprecedented temporal control, selectivity and potency. We validate the approach by studying the in vitro and in vivo phenotypes of EGFR, KRAS and STAG1, genes relevant to cancer biology. This loss-of-function strategy will enable novel experimental strategies in therapeutic target validation and will be instrumental in guiding the lead optimization process by establishing genetic benchmark phenotypes.
Citation Format: Ralph Neumüller, Thomas Hoffmann, Alexandra Hörmann, Maja Corcokovic, Johannes Zuber. Precision RNAi using synthetic shRNAmir target sites. [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 3973.
Abstract 3987: Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer
Authors: Liu Yue , Xu Mingjing , Wan Ho Lee , Wong Alissa M. , Ding Xiaofan , Ng Kelvin K. , Wong Nathalie 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has an overall 5-year survival rate of around 20%, making it the third leading cause of cancer-related death worldwide. Upregulated nucleotide metabolism is frequently identified in HCC and represents a metabolic weakness of tumor cells. The enzyme dUTPase (DUT) catalyzes the synthesis of nucleotide precursor and prevents undesired uracil misincorporation into DNA, and thus plays an important role in the maintenance of DNA integrity and cell viability. Although common upregulation of DUT has been reported in cancers, its role in HCC remains largely unknown. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC cases and significantly correlated with advanced stage tumors. CRISPR-Cas9 mediated knockout of DUT resulted in growth retardation, cell cycle arrest and a spontaneous induction of DNA damage in multiple HCC cell lines. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Metabolomics analysis showed altered DUT expression in HCC cells resulted in profound impact on pyrimidine and purine metabolism. In addition, levels of DUT protein strongly correlate with cellular level of dUTP and dTDP, which suggested its critical role in dNTP homeostasis. Interestingly, hepatic organoids overexpressing DUT showed drug resistance to tyrosine kinase inhibitor (TKI) Sorafenib. Both in vitro and in vivo assays confirmed that targeting dUTPase activity with TAS-114 synergized the effect of Sorafenib in suppressing HCC growth. In conclusion, our study showed that upregulated DUT conferred growth advantage to HCC cells by reducing uracil misincorporation and favoring nucleotide synthesis. Targeting DUT with its first-in-class inhibitor TAS-114 in combination with Sorafenib represents an effective treatment regime for HCC.
Citation Format: Yue Liu, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Xiaofan Ding, Kelvin K. Ng, Nathalie Wong. Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver 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 3987.
Abstract 4021: CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors
Authors: Shi Hui , Wang Meng , Huang Jiaxin , Ouyang Qiugeng , Guo Jiannan , Wang Youzhen , Mi Yuan , Wu Haiping 
Published: April 2023

Abstract
We identified CTS2016 as a novel, selective, orally bioavailable small molecule inhibitor with single-digit nanomolar enzymatic activity to AXL and FLT3. Overexpression of AXL is associated with metastasis, drug resistance, and poor prognosis of various hematological and solid tumors, which are all broadly modulated with epigenetic regulation. In addition, inhibition of AXL phosphorylation may overcome drug resistance to current FLT3 inhibitors in FLT3-ITD+ Acute Myeloid Leukemia (AML) (Park et al., 2015). We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models
CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD)
CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. The anti-tumor activity was correlated with the inhibition of receptor tyrosine kinase signaling, as measured by decreased phosphorylation of key downstream signaling targets of FLT3. In a tail vein injection of mouse LLC-Luciferase model, CTS2016 treatment could significantly reduce tumor metastasis. A combination of CTS2016 with venetoclax or azacitidine provides a therapeutic benefit over monotherapy and supports a rationale for testing these combination therapies in patients with relapsed or refractory (R/R) AML and myelodysplastic syndromes (MDS). In addition, CTS2016 significantly reduced the tumor burden of a leukemia model harboring FLT3-ITD-F691L, a drug-resistant mutation of FLT3. Notably, the selectivity of CTS2016 over other kinases (such as c-KIT) mitigates the off-target toxicity effects on normal hematological differentiation which is common in clinics for other FLT3 inhibitors. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial.
Citation Format: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu. CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors. [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 4021.
Abstract 4102: attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models
Authors: Hu Jiemiao , Lazar Alexander , Ingram Davis , Wang Wei-Lien , Zhang Wendong , Jia Zhiliang , Ragoonanan Dristhi , Wang Jian , Xia Xueqing , Mahadeo Kris , Gorlick Richard , Li Shulin 
Published: April 2023

Abstract
The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted CAR-T cell therapy does not impair ECM components such as collagen. In this study, we investigated whether the recently invented attIL12-T cells could destroy CAFs to disrupt the ECM and uncovered the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment and that CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL12-T or ttIL12-T cells, did not disrupt the ECM because this effect depended on the engagement between cell-surface vimentin (CSV) on the tumor cell surface and its ligand on the attIL12 -T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production upon interacting with CSV+ tumor cells to suppress TGFβ secretion and in turn upregulate FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T cell infiltration and tumor destruction. Thus, this study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.
Citation Format: Jiemiao Hu, Alexander Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li. attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft 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 4102.
Abstract 4116: Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer
Authors: Qi Xiaogiang , Yang Ming , Ma Lixin , Mitchem Jonathan , Kaifi Jussuf , Chen Shiyou , Ericsson Aaron , Kimchi Eric , Staveley-O’Carroll Kevin , Li Guangfu 
Published: April 2023

Abstract
Gut microbiota plays a pivotal role in the pathogenesis of hepatocellular cancer (HCC), significantly affecting the HCC treatment. It has been reported that the HCC patients’ response to the immunotherapy of PD-1/PD-L1 blockade was associated with their gut microbiota profiles. However, the impact of gut microbiota on anti-HCC immunity and its underlying mechanism are poorly understood. Treating HCC-bearing mice with a specific and non-hepatotoxic antibiotic cocktail caused the increased relative abundance of specific commensal bacteria such as Bacteroides, resulting in suppression of HCC growth and development which was involved in the activation of intrahepatic antitumor immune responses. Gut microbiota recolonization of Bacteroides thetaiotaomicron (B. th) in gut-sterilized HCC-bearing mice significantly improved the therapeutic efficacy of anti-PD-1 antibody (αPD-1 Ab) against HCC. Fecal microbiota transplantation (FMT) from HCC patients who received and responded to αPD-1 Ab treatment improved the efficacy of αPD-1 Ab treatment against HCC in mice model. Mechanistic studies demonstrated that the modulation of Krüppel-like factor 2 (KLF2)/Toll-like receptor 9 (TLR9) signaling and the accumulation of CpG-enriched genomic DNAs of B. th in livers/tumors activated the tumor antigen-specific CD8+ T cells through the dendritic cell in a TLR9-dependent manner. In conclusion, gut microbiota as a causative factor can be targeted to improve anti-HCC immunotherapy.
Citation Format: Xiaogiang Qi, Ming Yang, Lixin Ma, Jonathan Mitchem, Jussuf Kaifi, Shiyou Chen, Aaron Ericsson, Eric Kimchi, Kevin Staveley-O’Carroll, Guangfu Li. Modulating gut microbiota to improve intrahepatic immunity against hepatocellular 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 4116.
Abstract 4134: Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism
Authors: An Disi , Chen Guoying , Wang Wei , Mohrs Katja , DiLillo David , Daly Christopher , Thurston Gavin , Lin John , Gupta Namita , Atwal Mickey , Kuhnert Frank 
Published: April 2023

Abstract
High endothelial venules (HEV) are specialized blood vessels that mediate lymphocyte trafficking to lymph nodes. Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that develop in inflamed, infected or tumoral tissues. TLS contain HEV and B cell follicles surrounded by a T-cell zone and are characterized by abundant chemokine expression. The presence of TLS and HEV in solid tumors is positively correlated with patient survival in many cancer types, and may even be predictive of better response to immune-checkpoint blockade. However, the molecular mechanisms underlying the intratumoral HEV and TLS formation remain unclear. Using murine syngeneic tumor models, we found that systemic activation of lymphotoxin beta receptor (LTBR) with an agonistic antibody induced tumor-specific HEV formation, increased dendritic cell (DC) and T cell infiltration, and enhanced T cell activation in the tumor. In vitro assays revealed that LTBR agonism directly upregulated activation and maturation markers in bone marrow-derived DCs and promoted DC-mediated CD4 and CD8 T cell activation. Single agent LTBR agonist treatment attenuated Colon26 tumor growth in a CD8 T cell-dependent manner. In combination treatment studies, LTBR agonism further augmented anti-tumor efficacy of anti-PD1 and of CAR-T therapy. Notably, LTBR agonist mAb treatment upregulated the expression of TLS-related chemokines and induced TLS-like structures in approximately 20% of treated tumors. To enhance TLS induction, we generated syngeneic tumor models engineered to express several cytokines/chemokines and performed an in vivo screen for tumor-associated TLS formation. We identified some factors that in combination with LTBR agonism induced B cell enrichment and immature TLS formation, while others promoted robust TLS induction and anti-tumor effect. TLS formation induced by combined LTBR agonism and cytokine expression is associated with augmented anti-tumor responses to anti-CTLA-4 treatment. By studying anti-tumor mechanisms of LTBR agonism-mediated HEV and TLS formation, this work informs the future therapeutic strategies to boost T cell infiltration and activation in solid tumors.
Citation Format: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert. Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism. [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 4134.
Abstract 4186: Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research
Authors: Eldridge Linsey , Garton Elise , Duncan Kalina , Gopal Satish 
Published: April 2023

Abstract
Introduction: We conducted a bibliometric analysis to assess authorship of recent publications involving collaborations in low- and middle-income countries (LMICs) supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH).
Methods: We identified active NCI grants awarded directly to LMIC institutions or to US institutions with a collaborator site or sites exclusively in LMICs between 2015-2019 in NIH Query View Report (QVR). Grants were linked to resulting publications using Dimensions for NIH. Because grants may have been active in 2015 while beginning in earlier years, we analyzed any linked publications from 2011 to 2020. Publications with missing author information were excluded. Author institutional affiliation was used to classify author country income level as defined by the World Bank. Authors with multiple institutional affiliations from a high-income country (HIC) and LMIC were classified as such. Relative citation ratio (RCR) and Altmetric data from Dimensions were used to compare citation impact measures using the Wilcoxon rank sum test.
Results: NCI funded 159 grants to US institutions exclusively with LMIC collaborators and five awards directly to institutions in LMICs from 2015 to 2019, resulting in 2,428 publications between 2011 and 2020, of which 49% had at least one author affiliated with an LMIC institution. Of all publications, 78% and 83% had a first and last author with high-income country (HIC) affiliation, respectively. Publications with HIC-affiliated last authors had significantly higher median RCR and Altmetric attention scores than publications with LMIC-affiliated last authors (p=0.0134 and p=0.0004, respectively). Publications with HIC-affiliated first authors had significantly higher Altmetric scores than publications with LMIC-affiliated first authors (p=0.001).
Conclusion: LMIC-affiliated authors are represented on only approximately half of publications resulting from NCI grants awarded directly to LMIC institutions or to US institutions with LMIC collaborators, and rarely in the first or last author position. LMIC-affiliated authors also receive less bibliometric attention when represented. Increased scientific capacity and more equitable collaboration should be critical priorities for the cancer research community working in LMICs moving forward.
Citation Format: Linsey Eldridge, Elise Garton, Kalina Duncan, Satish Gopal. Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research. [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 4186.