bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1582: Inhibition of autophagy by CAGE targeting peptide retard tumor growth in non-small cell lung cancer of EGFR TKI resistance
Authors: Shin Jung-Young , Kim Min-Young , Lee Mi-Ran , Lee Hankyu , Jeon Doyong , Baek Seung Ryel , Il Kim Joo , Koh Jaemoon , Jeoung Dooil , Kang Jin Hyoung 
Published: April 2023

Abstract
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard of care as 1st-line treatment for NSCLC patients with activating EGFR mutations (exon 19 deletion or L858R mutation). However, EGFR-TKI therapy eventually leads to acquired drug resistance approximately 1-2 years from the beginning of treatment. Multiple acquired resistance mechanisms including on-target EGFR mutations, phenotype transformation, and activation of bypass signaling molecules have been identified, but over 35% still remains unknown. CAGE, a cancer/testis antigen, was originally isolated from the sera of patients with gastric cancer and is known to regulate the autophagic flux in acquired resistance to EGFR TKI in NSCLC. Herein, the expression of CAGE was found in more than 50% of NSCLC patients using immunohistochemistry (IHC). Interestingly, the expression level was increased especially for the patients acquiring resistance to EGFR-TKIs. In addition, both PC-9/ER (Erlotinib-resistance cells) and H1975/OR (Osimertinib-resistant cells) cells demonstrated increased CAGE expression and autophagic flux, when compared with their parental cells. Thus, we developed the peptide drugs targeting the DEAD box domain of CAGE. This novel peptide effectively inhibited tumor cell proliferation in EGFR-TKI resistant cell line. Moreover, in Erlotinib-resistant patient-derived xenograft (PDX) mice, the peptide drug retarded tumor growth and enhanced anti-tumor efficacy. Collectively, our data suggest that CAGE plays a crucial role in the tumor progression and acquired resistance of EGFR TKI by the modulation of autophagic flux. Furthermore, we provided evidence that the inhibition of autophagy through CAGE- derived peptide could overcome the acquired resistance to EGFR TKIs in advanced/metastatic NSCLC patients.
Citation Format: Jung-Young Shin, Min-Young Kim, Mi-Ran Lee, Hankyu Lee, Doyong Jeon, Seung Ryel Baek, Kim Joo Il, Jaemoon Koh, Dooil Jeoung, Jin Hyoung Kang. Inhibition of autophagy by CAGE targeting peptide retard tumor growth in non-small cell lung cancer of EGFR TKI 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 1582.
Abstract 1599: Targeting tumor synthetic vulnerabilities and immune evasion mechanisms with CO-1002
Authors: Ciznadija Daniel , Degaga Gemechis , Mondal Abdul , Hillbert Maxwell , Chen Cong , Debnath Bikash , Mehrotra Sonam , Jones Brandon , Rivero Ralph , Komurov Kakajan 
Published: April 2023

Abstract
Cancer immunotherapy with immune checkpoint inhibitors (ICI) has shown durable clinical benefits in patients with immune-hot tumors. However, the majority of cancers are characterized by an immune-cold tumor microenvironment, which are refractory to ICI therapy. Targeting of tumor synthetic vulnerabilities due to genomic alterations is another promising approach that has proven effective in the clinic (e.g. PARP inhibitors in BRCA-mutant tumors). Here, we aimed to identify therapeutic targets that have dual liabilities in tumor cell survival and the evasion of anti-tumor innate immune responses. Applying machine learning approaches to a manually curated compendium of public and proprietary datasets, we identified and validated several genes with a high potential of conferring tumor-intrinsic cell survival and blocking of innate pro-inflammatory responses in immune-cold tumors. The targeting of these genes induced robust cell killing and activation of innate immune response pathways in specific molecularly-defined tumor populations, including immune-cold cells. A series of highly potent small molecule compounds were established against these targets using structure-based design, which shows robust in vitro and in vivo target engagement and favorable cytotoxic and phenotypic profiles across a large panel of cancer cell lines and PDXs. Collectively, this therapeutic program shows significant promise in treating a multitude of solid tumors as a monotherapy and in combination with currently approved immune therapies.
Citation Format: Daniel Ciznadija, Gemechis Degaga, Abdul Mondal, Maxwell Hillbert, Cong Chen, Bikash Debnath, Sonam Mehrotra, Brandon Jones, Ralph Rivero, Kakajan Komurov. Targeting tumor synthetic vulnerabilities and immune evasion mechanisms with CO-1002 [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 1599.
Abstract 1602: Co-targeting mitochondria and nucleotide metabolism in T315I-BCR-ABL myeloid leukemia for therapy
Authors: Huang Chang-Yu , Chung Yin-Hsuan , Wu Sheng-Yang , Wang Hsin-Yang , Lin Chih-Yu , Yang Tsung-Jung , Fang Jim-Ming , Chen Yu-Ju , Hu Chun-Mei , Chang Zee-Fen 
Published: April 2023

Abstract
T315I mutation of Bcr-Abl in chronic myeloid leukemia (CML) leads to therapeutic resistance. It is known that Bcr-Abl transformation causes ROS-induced DNA damage, which can be exploited for anti-nucleotide treatment. We developed a small compound, JMF4073, which inhibits pyrimidylate kinases. Intriguingly, treatment of JMF4073 selectively eliminated WT-, but not T315I-, Bcr-Abl-transformed cells. We found that the higher level of cellular glutathione(GSH) in T315I-Bcr-Abl cells confers replication fork progression and sustains dTTP pool, leading to JMF4073 insusceptibility. Blocking mitochondrial pyruvate carrier (MPC) by UK-5099 reduced GSH and induced DNA replication stress in T315I-Bcr-Abl cells, thus increasing JMF4073 sensitivity in vitro and in vivo. We also observed the increases in glutamine flux to GSH production in T315I-Bcr-Abl cells, and reductive carboxylation of glutamate metabolism, together with mitochondrial dysfunction. The proteomic assay revealed the deficiencies in respiration complex I, II, and IV proteins in T315I-Bcr-Abl cells. Most interestingly, calcineurin inhibition remarkably elevated mitochondrial oxidative stress to cause cytotoxicity specifically in T315I-Bcr-Abl cells. Our results demonstrate the metabolic shift by T315I mutation of Bcr-Abl CML and provide the therapeutic options by co-targeting mitochondria and pyrimidylate kinases.
Citation Format: Chang-Yu Huang, Yin-Hsuan Chung, Sheng-Yang Wu, Hsin-Yang Wang, Chih-Yu Lin, Tsung-Jung Yang, Jim-Ming Fang, Yu-Ju Chen, Chun-Mei Hu, Zee-Fen Chang. Co-targeting mitochondria and nucleotide metabolism in T315I-BCR-ABL myeloid leukemia for 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 1602.
Abstract 1649: Chemically induced chaperone-mediated protein degradation (CHAMP) of KRAS(G12C)
Authors: Foley Kevin P. , Ying Chenghao , Wang Yaya , Dai Yan , Wang Zhiyong , Li Jinhua , Yang Zimo , Sun Yuetong , Zhou Hao Xin , Prince Thomas L. , Wang Guoqiang , Ying Weiwen 
Published: April 2023

Abstract
Covalent KRAS(G12C) inhibitors have recently shown promising efficacy in the clinic. However, the rapid development of drug resistance compromises their long-term benefits, indicating the need for additional approaches to treat KRAS-mutated cancers. Targeted protein degradation represents one such potential approach. We have therefore explored applying Chaperone-mediated Protein Degradation (CHAMP) technology to degrade KRAS(G12C) protein. CHAMPs are heterobifunctional small molecules that mediate protein degradation by inducing proximity between a target protein and the HSP90 chaperone complex, resulting in target ubiquitination and degradation by the proteasome. Due HSP90 being highly activated in cancer cells, CHAMPs also preferentially accumulate in tumors relative to normal tissues, resulting in an improved therapeutic index relative to typical inhibitors. In order to chemically induce KRAS(G12C) degradation, CHAMP compounds were synthesized by covalently coupling KRAS(G12C)- and HSP90-binding moieties through a short linker. CHAMP treatment of KRAS(G12C)-mutated cell lines resulted in formation of a KRAS(G12C)-CHAMP-HSP90 ternary complex and subsequent proteasome-dependent KRAS(G12C) degradation and inhibition of cell proliferation. In contrast, combination treatment with KRAS(G12C) and HSP90 inhibitors did not result in substantial KRAS(G12C) degradation. Importantly, CHAMPs retained potency in cell line models of resistance to covalent KRAS(G12C) inhibitors. Further, in mouse xenograft models, CHAMPs displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues and strongly inhibited tumor growth at tolerated doses. Based on these findings, KRAS(G12C)-degrading CHAMPs represents a promising approach to the treatment of KRAS(G12C)-mutated cancers.
Citation Format: Kevin P. Foley, Chenghao Ying, Yaya Wang, Yan Dai, Zhiyong Wang, Jinhua Li, Zimo Yang, Yuetong Sun, Hao Xin Zhou, Thomas L. Prince, Guoqiang Wang, Weiwen Ying. Chemically induced chaperone-mediated protein degradation (CHAMP) of KRAS(G12C) [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 1649.
Abstract 1742: Cediranib reverses taxane resistance in CLIP-170S expressing gastric cancer
Authors: Stone William G. , Castillo Urko del , Thakkar Prashant V. , Shah Manish A. , Giannakakou Paraskevi 
Published: April 2023

Abstract
Taxane-based chemotherapy is a first-line treatment for patients with Gastric Cancer (GC), however, many will not respond due to mechanisms of resistance. Recently, we reported the discovery of a novel truncated variant of the microtubule plus-end binding protein CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane-resistant cell lines and in 65% of patients with GC, non-responsive to Cabazitaxel monotherapy. CLIP-170S knockdown reversed taxane resistance and its ectopic expression led to resistance, suggesting causation. Computational analysis of RNA-seq data in conjunction with the connectivity map from taxane-sensitive and -resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, experimentally confirming the prediction, and did so unexpectedly by selective depletion of CLIP-170S. Other RTK inhibitors, such as Sunitinib, Ponatinib, Axitinib, and Cediranib also depleted CLIP-170S, suggesting a class effect, however, the mechanism is unknown. To investigate the mechanism of RTKi induced depletion of CLIP-170S, we sought to investigate the involvement of proteasomal and lysosomal cellular compartments. Preliminary results indicated that treatment of CLIP-170S expressing cells with Imatinib or Cediranib led to an increase in lysosome size, suggesting increased lysosomal activity. In parallel, we are testing in-vivo the synergistic activity of the RTKi, Cediranib, in combination with docetaxel in GC tumors expressing CLIP-170S. Together, these results will allow us to implement a novel clinical trial for patients with GC by using Cediranib as a treatment to increase taxane efficacy through CLIP-170S depletion.
Citation Format: William G. Stone, Urko del Castillo, Prashant V. Thakkar, Manish A. Shah, Paraskevi Giannakakou. Cediranib reverses taxane resistance in CLIP-170S expressing gastric 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 1742.
Abstract 1754: Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells
Authors: Durán Alfonso M. , Yoo Christian H. , Tran Jennifer D. , Santiago Krystal , Mohammed Adil S. , Casiano Carlos A. , Almaguel Frankis A. 
Published: April 2023

Abstract
Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED.
Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate 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 1754.
Abstract 1805: Identification of a small molecule that induces targeted protein degradation of ADAR1
Authors: Liu Yuan , Larsen Mads B. , Lin Bo , Kennerdell Jason R. , Alfaras Irene , Camarco Daniel P. , Tuncer Ferhan , Finkel Toren , Chen Bill B. 
Published: April 2023

Abstract
Adenosine deaminase acting on RNA (ADAR) are a family of enzymes that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Recent evidence suggests that genetic deletion of ADAR1 render tumors cells substantially more vulnerable to immunotherapy. In cells, ADAR1 is expressed as two different isoforms, the constitutively expressed ADAR1p110 and the inducible ADAR1p150. Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in most tumors. Of note, many of the effects of ADAR1p150 appear to be independent of the protein’s RNA editing function suggesting that a small molecule which induces ADAR1p150 targeted protein degradation might be preferable to agents that simply block deaminase activity. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bind to the unique N-terminal region of ADAR1p150. One such molecule, CL-AD-100, directly bound to ADAR1p150 but not ADAR1p110. Moreover, sub-micromolar concentrations of CL-AD-100, induced proteasomal mediated degradation of ADAR1p150, without effecting ADAR1p110 expression. Cells treated with CL-AD-100 exhibited a signature consistent with what has been observed with ADAR1p150 genetic deletion, namely accumulation of dsRNA, an inflammatory gene expression profile and interferon-dependent cell death. These results therefore demonstrate the feasibility of generating a small molecule that induces the specific targeted protein degradation of ADAR1p150. Such a molecule should have wide applicability in ADAR1-addicted tumors, as well as more broadly, in immuno-oncology.
Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Jason R. Kennerdell, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a small molecule that induces targeted protein degradation of ADAR1 [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 1805.
Abstract 1819: Integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling
Authors: Verschleiser Brooke , MacDonald William , Carlsen Lindsey , Huntington Kelsey E. , Zhou Lanlan , El-Deiry Wafik 
Published: April 2023

Abstract
Colorectal cancer is the third leading cause of cancer-related death and the third most common cause of cancer. As the five-year survival with advanced metastatic colorectal cancer (mCRC) is 14%, new treatment strategies are needed. Immune checkpoint blockade which takes advantage of an individual's immune system in order to fight cancer, is a promising future direction of research, although it is only effective and approved for the treatment of mismatch repair (MMR)-deficient CRCs. Long-term outcomes even in MMR-deficient mCRC suggest that most patients are not cured but eventually develop therapy resistance. We hypothesized that targeting TGF- β signaling may enhance immune-mediated T-cell killing by MMR-deficient CRC cells. Using GLPG-0187, an inhibitor of multiple integrin receptors and TGF- β, we demonstrate minimal cytotoxicity against MMR-deficient HCT116 or p53-null HCT116 human CRC cells. However, GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells. GLPG-0187 reduced pSMAD2 in HCT116 p53-null cells either in the absence or presence of exogenous TGF- β. We observed a reduction in CCL20, CXCL5, prolactin, and TRAIL-R3 while GDF-15 was increased in TALL-104 cells treated with a T-cell activating dose of GLPG-0187 (4 μM). Our results suggest that TGF- signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells, and suggest that a combination of anti-GDF-15 in combination with TGF- β blockade should be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade.
Citation Format: Brooke Verschleiser, William MacDonald, Lindsey Carlsen, Kelsey E. Huntington, Lanlan Zhou, Wafik El-Deiry. Integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling [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 1819.
Abstract 1824: Discovery and evaluation of an anti-IL18BP antibody to enhance anti-tumor immunity
Authors: Jun H. Toni , Witherden Deborah A. , Elliot Eric K. , Chidester Christine M. , Willen Maggie , Peguero Bryan R. , Chai Merrick , Horlick Robert A. , King David J. 
Published: April 2023

Abstract
Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Although recombinant mIL18 has demonstrated efficacy in mouse tumor models, recombinant human IL18 has not been efficacious in clinical studies, likely due to upregulation of IL18 binding protein (IL18BP), a negative regulator of the IL18 signaling axis. IL18BP is induced 10 - 100 fold after IL18 administration, binds to IL18 with high affinity, and prevents IL18 binding to the IL18 receptor. Analysis of expression data from the TCGA database as well as archived patient samples from select indications revealed that both IL18 and IL18BP are co-expressed in a number of tumor types, suggesting there may be a preexisting pool of IL18/IL18BP complex at the site of the tumor in some patients. Inhibition of IL18/IL18BP binding using a monoclonal antibody may therefore allow release of IL18 in situ, leading to IL18-mediated proinflammatory effects and enhanced anti-tumor immunity. Although the interaction of IL18 with IL18BP is a high affinity interaction, we have been able to identify very high affinity antibodies which can both inhibit complex formation and disrupt existing mouse IL18/IL18BP complexes. These antibodies are active in a number of cell-based functional assays, resulting in potent stimulation of interferon gamma production from cell lines or splenocytes. In vivo, we observed efficacy in a mouse syngeneic tumor model using an anti-mIL18BP antibody. RNA and protein analysis demonstrated expression of both IL18BP and IL18 within the tumors. Combined, these data suggest that inhibition of IL18/IL18BP binding may prove efficacious in the treatment of cancers where existing pools of IL18/IL18BP complexes prevent an IL18-mediated proinflammatory response. Experiments exploring anti-IL18BP therapy in combination with other checkpoint inhibitors such as anti-PD-1 are under current investigation.
Citation Format: H. Toni Jun, Deborah A. Witherden, Eric K. Elliot, Christine M. Chidester, Maggie Willen, Bryan R. Peguero, Merrick Chai, Robert A. Horlick, David J. King. Discovery and evaluation of an anti-IL18BP antibody to enhance anti-tumor immunity [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 1824.