bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 663: Systemic targeting of therapeutic RNA to cancer via a novel, cell-penetrating and nucleic acid binding, monoclonal antibody
Authors: Quijano Elias , Saucedo Diana Martinez , Khang Minsoo , Liu Yanfeng , Ludwig Dale , Turner Bruce C. , Squinto Stephen , Bindra Ranjit , Saltzman W. Mark , Escobar-Hoyos Luisa , Glazer Peter M. 
Published: June 2022

Abstract
There is intense interest in the development of nucleic acid ligands for immune stimulation of the tumor microenvironment via pattern recognition receptors (PRRs), particularly for the treatment of “cold” tumors. However, delivery of these ligands in a tumor-specific manner to avoid systemic toxicity has been a challenge. Many current efforts rely on direct intra-tumoral injection of RNAs or other stimulatory immune ligands, which is therapeutically sub-optimal, especially for metastatic disease. Here we report studies evaluating the utility of a lupus-derived, cell-penetrating antibody, to deliver nucleic acids to tumors in vivo. This antibody, a modified version of 3E10-D31N, designated GMAB, forms non-covalent complexes with RNAs and can mediate highly specific delivery into tumors via intravenous injection by targeting the nucleoside transporter ENT2, which is highly expressed in tumor cells. Studies with labeled RNAs showed tumor specific delivery and functional expression by imaging, with minimal delivery to healthy tissues. Following these proof-of-concept studies, we investigated whether our antibody could be used to deliver RIG-I agonists to tumors. Using a known agonist of RIG-I, 3p-hpRNA, we demonstrated single agent activity of our GMAB/RNA complexes in multiple tumor models, including a mouse model of melanoma (B16) and an orthotopic model of pancreatic cancer (KPC). Measuring 3p-hpRNA by RT-PCR, there was a 1000X fold difference in RNA uptake in KPC tumor cells relative to CD45+ cells isolated from tumors. In addition, synergy between our GMAB/RNA complexes and anti-PD-1 was additionally observed in mouse models of breast (EMT6) and colon (MC38) cancer. Given the expression of ENT2 along the blood brain barrier (BBB), we demonstrate single agent activity of our GMAB/RNA complexes in an orthotopic mouse model of medulloblastoma, resulting in suppression of tumor growth and spinal metastases. Together, these studies demonstrate that the GMAB antibody can 1) localize to orthotopic and flank tumor models, 2) cross the BBB, and 3) deliver RNA payloads to tumors, providing a novel platform for delivery of immunogenic RNAs, as well as mRNAs and siRNAs, directly to tumors with high specificity following systemic administration.
Citation Format: Elias Quijano, Diana Martinez Saucedo, Minsoo Khang, Yanfeng Liu, Dale Ludwig, Bruce C. Turner, Stephen Squinto, Ranjit Bindra, W. Mark Saltzman, Luisa Escobar-Hoyos, Peter M. Glazer. Systemic targeting of therapeutic RNA to cancer via a novel, cell-penetrating and nucleic acid binding, monoclonal antibody [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 663.
Abstract 71: Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance
Authors: Kwon Eun-Ji , Lee Haeseung , Cha Hyuk-Jin 
Published: June 2022

Abstract
Limited eligibility remains one of major drawbacks of target therapeutics as the oncogenic dependency is only determined by mutation status of a target. In order to extend the eligibility of target therapeutics, transcriptome profiles of patients have been examined to better delineate sensitivity of target therapeutics. In this study, we took advantage of multiple large datasets such as cancer cell line transcriptome data (CCLE), drug response data (CTRP), and gene dependency data (Achilles Project) to determine the sensitivity markers of tyrosine kinase inhibitors currently approved by FDA. In particular, EGFR inhibitors (iEGFR: lapatinib, gefitinib and erlotinib) revealed clear sensitivity cluster of cell line regardless of EGFR mutation status. Comparative analysis between sensitive (iEGFR-S) and resistant (iEGFR-R) cell groups revealed that integrated gene signatures such as chemokine, GPCR, and PI3K-Akt signaling pathway, were predicted as putative determinants of iEGFR susceptibility. Through integrated analysis of gene dependency data, among several Achilles’ targets (of which depletion increases vulnerability), predicted in iEGFR-R cells group, druggable Achilles’ targets (available to accompanied drugs) such as CCR6, AURKA and mTOR were identified as putative targets for sensitizing iEGFR-R group to iEGFR. Following biochemical studies validated the clear sensitizing effect of the pharmacological inhibitor for each predicted target, in the isogenic cell models with acquired iEGFR resistance. In addition, prediction and following biochemical validation, we demonstrated that the CCR6 inhibition significantly attenuated resistance of iEGFR by repressing mitochondrial ROS (mt-ROS), of which induction by iEGFR rescued cell death. These data suggest that integrated-omics analysis would be a useful approach to extend eligibility and improve the efficacy of target therapeutics.
Citation Format: Eun-Ji Kwon, Haeseung Lee, Hyuk-Jin Cha. Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance [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 71.
Abstract 73: A ubiquitination cascade regulating the integrated stress response and survival in carcinomas
Authors: Cervia Lisa D. , Shibue Tsukasa , Gaeta Benjamin , Borah Ashir A. , Leung Lisa , Li Naomi , Dumont Nancy , Gonzalez Alfredo , Bick Nolan , Kazachkova Mariya , Dempster Joshua M. , Krill-Burger John M. , Piccioni Federica , Udeshi Namrata D. , Olive Meagan E. , Carr Steven A. , Root David E. , McFarland James M. , Vazquez Francisca , Hahn William C. 
Published: June 2022

Abstract
Targeting of mutated oncogenes has led to the identification of new targeted therapies. However, druggable oncogenes do not occur in most cancers. Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 793 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitination ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, is required for the survival of a subset of epithelial tumors. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization and upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
Citation Format: Lisa D. Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir A. Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua M. Dempster, John M. Krill-Burger, Federica Piccioni, Namrata D. Udeshi, Meagan E. Olive, Steven A. Carr, David E. Root, James M. McFarland, Francisca Vazquez, William C. Hahn. A ubiquitination cascade regulating the integrated stress response and survival in carcinomas [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 73.
Abstract 802: Development of replication protein A (RPA) targeted PROTACs for the treatment of lung and ovarian cancers
Authors: Kelm Jeremy M. , Gaddameedi Jitender Dev , VanderVere-Carozza Pamela S. , Samarbakhsh Amirreza , Vakeesan Nivisa , Kansou Hussein W. , Serafimovski Sara , Pawelczak Katherine S. , Turchi John J. , Gavande Navnath S. 
Published: June 2022

Abstract
Despite remarkable advances within the field of molecular cancer therapeutics over the preceding decades, DNA-damaging agents retain a central role in the pharmacotherapy of neoplastic diseases. The clinical response to DNA-damaging therapies is varied within and across cancer subtypes where a robust DNA damage response (DDR) predicts recalcitrance. Replication protein A (RPA) is the predominant human single-stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and the DNA-damage response (DDR). Inhibition of the RPA−DNA interaction is an approach to cancer drug discovery that holds potential to provide single-agent activity and/or synergy with existing therapeutics. Proteolysis targeting chimera (PROTAC) based drug design presages a paradigm shift within drug discovery as PROTACs begin to carve out a space in the clinical landscape. The PROTAC platform is particularly suited for drugging overexpressed proteins such as RPA because iterative target degradation improves drug:target stoichiometry and precludes RPA’s role in protein scaffolding. Herein, we describe the synthesis and biological evaluation of an RPA targeted PROTAC library conceived by conjugation of the diaryl pyrazole RPA inhibitor TDRL-551 and an E3-ligand via a linker of variable length and composition. Residing within the beyond rule of five (bRo5) chemical space, careful consideration was given to minimize the liability to cell permeability imposed by the high molecular weight of PROTACs. Excitingly, cellular uptake across the compound library was broadly improved relative to the unconjugated warhead TDRL-551. Similarly, RPA engagement by the PROTAC series was widely unhindered and, in many cases, improved relative to the warhead TDRL-551. A subset of the compound library unified by flexible linkers and alkyne attachment of the E3-ligand (typified by GL-3311) display low single-digit micromolar IC50 values in viability assays across H460, A549, and A2780 cell lines.
Citation Format: Jeremy M. Kelm, Jitender Dev Gaddameedi, Pamela S. VanderVere-Carozza, Amirreza Samarbakhsh, Nivisa Vakeesan, Hussein W. Kansou, Sara Serafimovski, Katherine S. Pawelczak, John J. Turchi, Navnath S. Gavande. Development of replication protein A (RPA) targeted PROTACs for the treatment of lung and ovarian 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 802.
Abstract 861: Nuclear translocation of Axl during early breast cancer progression
Authors: Graham Darby R. , Hebert Kelly D. , Newton Emma E. , Gomes Angelica M. , Behbod Fariba , Machado Heather L. 
Published: June 2022

Abstract
Axl is a receptor tyrosine kinase (RTK) that is activated by its ligand Gas6 and regulates proliferation, cell survival, and clearance of apoptotic cells in both normal physiology and a number of disease states. In breast cancer, Axl is overexpressed in Her2+ and triple-negative breast cancers and is associated with resistance to RTK targeted therapies. Recent studies have shown that upon kinase inhibition, the Axl intracellular domain (ICD) can translocate to the nucleus, however, the biological significance and functions for nuclear Axl are poorly understood. Furthermore, a functional role for Axl during ductal carcinoma in situ (DCIS) progression, a requisite step for invasive breast cancer, has not been established. To address whether Axl mediates localized invasion during DCIS progression, Axl was deleted in a DCIS cell line (MCF10A-DCIS.com) using a CRISPR-Cas9 approach. Deletion of Axl shows a significant decrease in progression to invasive cancer in vivo, which is accompanied by decreased proliferation, however microinvasion is unchanged as compared to wildtype. Analysis of patient samples of pure DCIS, DCIS with microinvasion, and DCIS with invasive cancer shows a significant increase in Axl expression in patients with evidence of invasion. Interestingly, there is a significant increase in nuclear Axl in all patient samples with evidence of invasion as compared to normal breast or pure DCIS, suggesting an important role for Axl-ICD in progression to invasive cancer. Soft agar assays using normal cells (MCF10A) shows that while full length Axl (Axl-FL) is sufficient to induce colonies, Axl-ICD-transduced cells do not form colonies, suggesting that Axl-ICD alone does not have oncogenic activity. However, Axl-ICD significantly increases colonies in DCIS cells, suggesting that the ICD is important in the progression of transformed cells. Ongoing studies are aimed at identifying transcriptional targets of Axl-ICD in DCIS cells. These studies will advance our understanding of how Axl mediates breast cancer progression and will have critical implications for ongoing therapeutic strategies aimed at targeting Axl. This work is supported by NIH R01CA212518 (H.L.M.) and Susan G. Komen CCR1637765 (H.L.M.).
Citation Format: Darby R. Graham, Kelly D. Hebert, Emma E. Newton, Angelica M. Gomes, Fariba Behbod, Heather L. Machado. Nuclear translocation of Axl during early breast cancer progression [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 861.
Abstract 904: Neural stem cells of the subventricular zone evolve into tumors around the resection cavity after surgical resection of glioblastoma via the CXCL12/CXCR4 axis
Authors: Li Xue , Kim Hyun Jung , Lee Jeong Ho , Wu Hong-Gyun , Lee Joo Ho 
Published: June 2022

Abstract
Glioblastoma multiforme (GBM) is the most common lethal primary brain tumor. Neural stem cells (NSCs) harboring cancer-driving mutations in the subventricular zone (SVZ) have recently been reported as the cells of origin for human glioblastoma (GBM) through migration. However, the pathological role of residual tumor-initiating NSCs (tNSCs) in the SVZ is undetermined for local recurrent tumor after surgical removal of the primary tumor. After the primary resection of GBM, most recurrences still appear as local tumors around the resection cavity (RC). Accordingly, we hypothesized that, after complete removal of the primary tumor, the tNSCs in SVZ might be the source for tumor construction at RC. Here, we examined the role of tNSCs in the development of local tumors around RC using a mouse model and genetic analysis of human tissues. First, cancer-driving mutations, including Trp53, Pten, and Egfr mutations, were introduced to NSCs in SVZ through in vivo electroporation, and the RC was generated in the remote cortex through stereotaxic resection. We found that the NSCs harboring driver mutations migrated specifically to the RC through the aberrant growth of oligodendrocyte-precursor cells (OPCs). Furthermore, the SVZ-originated cells constituted the GBM around the RC at four weeks post-resection in 64% of mouse models. Second, we performed deep sequencing of longitudinal matched tissues consisting of (i) normal SVZ away from the tumor, (ii) primary tumor, (iii) recurrent tumor, and (iv) blood in the patients with GBM, IDH wildtype. We found that the dominant clones of recurrent tumors genetically arose from the SVZ, not directly from the primary tumor. Third, the CXCR4/CXCL12 axis was upregulated through migration from the SVZ and tumor formation at the RC compared with primary tumors without the RC in mouse models. Blockage of the CXCR4/CXCL12 axis decreased the number of immigrating OPC lineage cells specifically and improved tumor control and survival rates. Taken together, our results reveal that the residual tNCSs harboring cancer-driving mutations in the SVZ can re-construct tumors after surgical resection of GBM. Blocking CXCL12/CXCR4 might be a potential treatment strategy for preventing the main local failures after resection.
Citation Format: Xue Li, Hyun Jung Kim, Jeong Ho Lee, Hong-Gyun Wu, Joo Ho Lee. Neural stem cells of the subventricular zone evolve into tumors around the resection cavity after surgical resection of glioblastoma via the CXCL12/CXCR4 axis [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 904.
Abstract 922: Knockout of Sod2 accelerates formation of pancreatic atypical flat lesions which are a direct precursor to pancreatic ductal adenocarcinoma (PDA)
Authors: Martinez Alicia K. Fleming , Edenfield Brandy H. , Esposito Irene , Storz Peter 
Published: June 2022

Abstract
Manganese superoxide dismutase (MnSOD) is an important reactive oxygen species (ROS) scavenger which has largely been studied in pancreatic cancer cell lines, where it contributes to invasion but also decreases proliferation. In pancreatic cancer, it is unknown whether MnSOD contributes to or prevents lesion development. Therefore, we utilize a transgenic mouse model to study precancerous lesion development and progression. We here show that knockout of Sod2 in a p48Cre;LSL-KrasG12D (KC) mouse model accelerates formation of abnormal tissue area, increases abundance of DCLK1+ cancer stem cells (CSCs) and oxidative damage, and promotes formation of atypical flat lesions (AFLs) which are a direct precursor to pancreatic ductal adenocarcinoma (PDA). We further characterize AFLs as having fewer senescent cells and less oxidative damage than low grade PanIN lesions. Thus, MnSOD has a protective effect in early pancreatic lesion development and its deletion drives tumor development.
Citation Format: Alicia K. Fleming Martinez, Brandy H. Edenfield, Irene Esposito, Peter Storz. Knockout of Sod2 accelerates formation of pancreatic atypical flat lesions which are a direct precursor to pancreatic ductal adenocarcinoma (PDA) [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 922.
Abstract 925: A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B
Authors: Durfee Cameron C. , Argyris Prokopios P. , Jarvis Matthew C. , Levin-Klein Rena , Law Emily K. , Harris Reuben S. 
Published: June 2022

Abstract
Introduction: Advanced DNA sequencing technologies have revealed a substantial endogenous source of mutations in cancers, the human DNA-mutating enzyme APOBEC3B (A3B). This protein changes DNA cytosines into uracils (C-to-U), which can become “immortalized” in the genome as C-to-T or C-to-G mutations depending on how each uracil lesion is processed. However, mice lack analogous carcinogenic A3 enzymes, which makes a definitive cause-and-effect model of A3-induced carcinogenesis difficult to establish.
Results: Using C57BL/6 mice, we have generated a novel genetically engineered mouse model (GEMM) expressing the human protein A3B, where it is driven constitutively from the Rosa26 locus in combination with the strong synthetic CAG promoter. Importantly, tumor-free survival data suggest that CAG A3B mice develop tumors at an increased rate compared to wild-type mice. These CAG A3B mice develop predominantly lymphoid neoplasms including B- and T-cell lymphomas and marked splenomegaly, and less frequently lung and liver cancers. Using immunohistochemical and whole-genome sequencing techniques, we have further characterized the tumors arising in these novel GEMMs. The above analyses thus far have revealed that A3B is actively driving tumor formation, as seen by an enrichment of canonical APOBEC-related mutations in these cancers.
Conclusion: Overall, the CAG A3B mice are the first GEMMs demonstrating the potential for A3B to drive tumor formation in vivo, with a predilection towards blood malignancies. They will be an invaluable tool for characterizing A3B-driven mutational processes in an organism and testing novel therapeutic strategies against APOBEC-induced cancer initiation and progression.
Citation Format: Cameron C. Durfee, Prokopios P. Argyris, Matthew C. Jarvis, Rena Levin-Klein, Emily K. Law, Reuben S. Harris. A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B [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 925.
Abstract 930: Novel orthotopic pancreatic cancer cell lines derived from B6-KPC mice
Authors: Zhu Fang , Ju Cunxiang , Sun Hongyan , Yu Weiwei , Ju Chao , Li Shuai , Jiang Yunlong , Jia Dongjing , Smith Steve , Li Zhiying , Zhao Jing , Gao Xiang 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. B6-KPC mice ( LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre) generate spontaneous PDAC which could recapitulate the pathogenesis and genomic features of human PDAC. Although B6-KPC model is a wildly used for the exploration of the mechanisms of PDAC, some drawbacks of the model, such as long time for tumorigenesis, individual variation and difficulties in tumor observation, limit its application in cancer therapy. It is necessary to develop the pancreatic tumor cell lines from these models. In this study, we successfully established and well-characterized the luciferase-labled cell line mPAKPC-Luciferase. This cells carried the KrasG12D and Trp53R172H mutation. The orthotopic mPAKPC-Luciferase tumor model was well established by implanting tumor cell line into pancreas of B6 wild type mice and the tumor growth was traced by in vivo imaging. Moreover, Gemcitabine or combined with CD40 agonist presented significant tumor growth inhibition in B6 bearing mPAKPC-Luciferase orthotopic mouse models. While anti-PD1 or anti-OX40 had no anti-tumor effects in this model accordance with the low T cell infiltration of mPAKPC modle as a “cold” tumor. In addition, the immune profiling of this cell line showed highly expressed of potential therapeutic targets, including Claudin 18.2, CD47, CD73. Thus, mPAKPC-Luciferase cell lines are valuable models for the PDAC preclinical therapies.
Citation Format: Fang Zhu, Cunxiang Ju, Hongyan Sun, Weiwei Yu, Chao Ju, Shuai Li, Yunlong Jiang, Dongjing Jia, Steve Smith, Zhiying Li, Jing Zhao, Xiang Gao. Novel orthotopic pancreatic cancer cell lines derived from B6-KPC mice [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 930.