bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6255: Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs)
Authors: Nethi Susheel Kumar , Sehgal Drishti , Panyam Jayanth , Prabha Swayam 
Published: September 2020

Abstract
Targeted delivery can improve drug accumulation in tumor tissue and treatment outcomes. However, currently available options suffer from a lack of selectivity for tumor cells. Mesenchymal Stem cells (MSCs) can be engineered with chemotherapeutic-loaded polymeric nanoparticles (PNPs) for tumor-targeted delivery, owing to their characteristic tumor tropic properties. Although nano-engineered MSCs demonstrated significant anticancer activity in multiple ovarian cancer models, their non-specific accumulation in clearance organs such as lungs and liver remains a concern. Parallel to the concept of chimeric antigen receptor (CAR)-T cell therapy, we advance here a strategy of modifying MSCs with synthetic antigen receptors (SARs) that target specific antigens overexpressed on cancer cells. Our approach consists of stably incorporating recombinant protein G (PG) on the surface of MSCs, followed by binding of a full-length IgG to the PG handle. Because protein G binds to the Fc region of IgG, antigen-binding affinity of the antibody is conserved. Epidermal growth factor receptor (EGFR) has been reported to be overexpressed and implicated in the pathogenesis of several malignancies especially lung cancer. Cetuximab (Cmab) is an anti-EGFR monoclonal antibody used in the treatment of metastatic lung cancer. In the current study, SAR-MSCs were developed by coating the nano-engineered MSCs with palmitated PG, followed by incorporating Cmab on the cell surface. Flow cytometry and confocal microscopy were used to confirm the incorporation of fluorescently labeled PAPG handle on MSC surface. Similarly, the installation of fluorescently labeled antibody on PAPG-functionalized MSCs was confirmed by flow cytometry. Preliminary efficacy studies in a mouse orthotopic A549-luc human lung adenocarcinoma model demonstrated significantly (P&lt;0.05) improved survival of mice treated with Cmab-modified nano-engineered MSCs compared to isotype IgG-modified nano-engineered MSCs control group. These results suggest that the SAR technology could further improve the effectiveness of MSCs as tumor targeted drug delivery vehicles.
Citation Format: Susheel Kumar Nethi, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6255.
Abstract 6268: Use of the anti-viral drug ribavirin as a radiosensitizing agent in nasopharyngeal carcinoma
Authors: Huq Sakibul , Casaos Joshua , Serra Riccardo , Peters Michael , Xia Yuanxuan , Ding Andy , Ehresman Jeffrey , Kedda Jayanidhi , Morales Manuel , Gorelick Noah , Zhao Tianna , Ishida Wataru , Perdomo-Pantoja Alexander , Cecia Arba , Ji Chenchen , Suk Ian , Sidransky David , Brait Mariana , Brem Henry , Skuli Nicolas , Tyler Betty 
Published: September 2020

Abstract
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a propensity for metastasis, leading many patients to fail available treatments and/or present with advanced-stage disease. There is currently a scarcity of targeted therapies for NPC, despite working knowledge of several proteins with key roles in NPC cancer biology. These include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor patient prognosis. These proteins are known to be targeted by ribavirin, a well-characterized anti-viral drug that has recently been repurposed as an anti-cancer agent in several solid and hematologic malignancies. In the present study, we investigated the potential of ribavirin as a targeted therapy and radiosensitizing agent in five human NPC cell lines. We show in vitro, using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, and mTOR were observed in western blots and enzymatic activity assays in response to ribavirin treatment. In vivo, monotherapy with ribavirin reduced flank tumor growth in multiple NPC xenograft models. Given that radiation therapy is a mainstay of NPC treatment, we next investigated the effects of combining ribavirin with radiation. Using clonogenic assays and flow cytometry, we demonstrate that ribavirin enhanced the cytotoxic effects of radiation on NPC cells in vitro. Most importantly, using a flank tumor xenograft model, we show that pre-treatment with ribavirin potentiated the effects of radiation therapy in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR modulation and positions ribavirin for clinical evaluation as a targeted therapy and radiosensitizing agent in this cancer.
Citation Format: Sakibul Huq, Joshua Casaos, Riccardo Serra, Michael Peters, Yuanxuan Xia, Andy Ding, Jeffrey Ehresman, Jayanidhi Kedda, Manuel Morales, Noah Gorelick, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler. Use of the anti-viral drug ribavirin as a radiosensitizing agent in nasopharyngeal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6268.
Abstract 6343: Mitochondrial bioenergetics mediate chemo-resistance of cancer cells
Authors: Zayou Fouzia , Chheda Chintan , Pandol Stephen , Edderkaoui Mouad 
Published: September 2020

Abstract
Background: Resistance to chemotherapy is a major cause of the failure of treatments in many cancers including pancreatic cancer. Accumulated evidence indicates that mitochondrial metabolic alterations are associated with cancer cells growth and proliferation. In this project, we investigated the role of mitochondrial bioenergetics in drug resistance.
Methods: Human pancreatic cancer cell lines MIA PaCa-2 and HPAF-II and mouse pancreatic cancer cell line UN-KPC-961 were treated with increased doses of chemotherapy drug Gemcitabine for 4 months until developing resistance. Mitochondrial proteins, cancer stemness markers and metabolic enzymes were measured by Western and RT-PCR. Cell survival was measured by MTT assay. Mitochondrial bioenergetics were measured by Seahorse Assay.
Results: We found that gemcitabine resistant (GR) cells grow at a much slower rate than wild type (WT) cancer cells; however, they express a significantly higher amount of cancer stemness markers such as Nanog, Oct4 and Sox2. They also expressed higher level of pro-cancer cytokines such as IL-6 and IL-4. Seahorse analysis showed a significantly lower oxygen consumption rate (OCR) in GR cells compared to WT cells. OCR did not change much in GR cells when applying inhibitors of the mitochondrial respiratory chain complex. GR cells produced lower level of ATP and lower spare respiratory capacity. However, GR cells expressed the same amount of mitochondrial proteins such as TOM40, TOM70 and COX4 suggesting the same mass of mitochondria. Pyruvate dehydrogenase-E1 Alpha1 (PDHA1) expression level was significantly lower in GR cells compared to WT cells. PDHA1 inhibition induced WT cells to develop a partial resistance to Gemcitabine; whereas, PDH1 overexpression in GR cells made these cells less resistant to Gemcitabine.
Conclusion: We showed for the first time the difference in mitochondrial bioenergetics between WT and GR cells and showed that GR cells grow independently of the mitochondrial energy production machinery. Furthermore, we identified PDHA1 as a critical mediator of cancer drug resistance.
Citation Format: Fouzia Zayou, Chintan Chheda, Stephen Pandol, Mouad Edderkaoui. Mitochondrial bioenergetics mediate chemo-resistance of cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6343.
Abstract 6374: Novel RAS inhibitors
Authors: Clark Geoffrey Justin 
Published: September 2020

Abstract
The Ras oncoprotein may participate in driving half of human tumors and as such remains the single most significant therapeutic target in cancer. Attempts to develop targeted inhibitors of RAS have proved extremely challenging. We have developed a novel Ras binding molecule that blocks the ability of Ras to interact with its downstream effector components and thus down-regulates Ras signaling. We have also developed the first direct inhibitor of the RAS effector RALGDS. Both compounds suppresses the transforming activity of mutant forms of Ras as well as the wild type protein when it is over-active due to defects in the NF1 protein. The compounds have no detectable toxicity in animals and readily crosses the blood-brain barrier. They are potently active in xenograft models of Ras mediated transformation and can eradicate the ability of Ras addicted tumor cells to form tumors in animals. We propose the compounds may serve as the basis for the development of new treatments for oncogenic RAS driven tumors and for many Rasopathy symptoms.
Citation Format: Geoffrey Justin Clark. Novel RAS inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6374.
Abstract 6452: Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis
Authors: Kwong Mei Li M. , Vallejos Paul A. , Andrianarijaona Vola-Masoandro , Choi Audrey , Selleck Matthew J. , Liu Tiantian , Kabagwira Janviere , Wang Charles , Langridge William , Wall Nathan R. , Senthil Maheswari 
Published: September 2020

Abstract
The prognosis for patients with colorectal cancer with peritoneal carcinomatosis (PC) is dismal. Current biomarkers and imaging studies lack sensitivity and specificity to identify PC at early stages. Predictive and diagnostic serum biomarkers that help diagnose PC at early stages is necessary to improve patient outcomes. In the rapidly evolving field of liquid biopsy, exosomes show significant promise. The objective of our study is to identify exosomal biomarkers that are differentially expressed in patients with PC compared to visceral metastases (VM). Proteomic and miRNA analysis were performed using mass spectrometry and next generation sequencing on plasma exosomes from ten patients with colorectal cancer VM and nine patients with PC. Multiple members of the Let-7 family had differential levels of expression between these two patient groups. Specifically, Let-7 isoforms (Let-7a, Let-7d, Let-7e, Let-7f, Let-7g, Let-7i) were upregulated in plasma exosomes of patients with PC compared to those with VM. In addition, 33 exosomal proteins that are downstream targets of Let-7 were also found to be differentially expressed. Correlative investigation was conducted using cell lines representative of PC, VM and control to investigate the possible origins for this exosomal profile. RT-PCR was performed on cell lysates taken from normal colon (CCD-33-CO) and colorectal cancer (SK-CO-1, SNU-C1, and T84) cell lines to further identify Let-7 isoforms in these samples. Let-7 isoforms (Let 7a, Let-7b, Let-7d, Let-7e, Let-7f, Let-7i) were identified at increased levels in the colorectal cancer PC cell line in comparison to cells lines of non-PC colorectal cancer and normal colon. In-vivo and in-vitro studies demonstrate plasma exosomal Let-7 and its downstream protein targets are differentially expressed in colorectal PC compared to VM. Let-7 has been previously implicated in cancer progression and chemoresistance. While this differential expression suggests possible mechanistic differences between colorectal PC and VM, it may also offer a potential liquid biopsy for predicting peritoneal metastasis at a much earlier and treatable time.
Citation Format: Mei Li M. Kwong, Paul A. Vallejos, Vola-Masoandro Andrianarijaona, Audrey Choi, Matthew J. Selleck, Tiantian Liu, Janviere Kabagwira, Charles Wang, William Langridge, Nathan R. Wall, Maheswari Senthil. Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6452.
Abstract 6471: Variable expression of ZEB-1, Bcl-2, and E-cadherin in human hepatocholangio and renal cell carcinomas
Authors: Chahine Joeffrey J. , Ko Kyungmin , Kallakury Bhaskar VS , Tuma Pamela L. 
Published: September 2020

Abstract
Although Epithelial-Mesenchymal Transition (EMT) in cancers remains controversial, its relevance in tumor progression is a subject of investigation. The presence of cellular changes associated with EMT in bladder tumor progression have been well investigated, unlike other human carcinomas with very little data available to date. ZEB-1 which targets E-Cadherin repression is a transcriptional regulator that has been implicated in EMT, and its nuclear expression in tumor cells has been associated with aggressive malignancies in some types of cancer. Recently, it was also reported that ZEB-1 inhibits the expression of proapoptotic factor B-cell lymphoma (Bcl)-2 interacting mediator of cell death (BIM) by binding directly to the BIM promoter and repressing its transcription. We tested this hypothesis with a human cohort of 24 Cholangiocarcinoma (CC), 18 Hepatocellular (HCC) and 31 Renal Cell (RCC) human carcinomas. Formalin fixed paraffin embedded tissue sections containing benign and tumor lesions were immunostained using the Dako Autostainers Link 48 along with ZEB-1 monoclonal OT13G6 (ABCAM), Bcl-2 monoclonal 124 (Agilent, Dako), and E-Cadherin monoclonal NCH-38 (Agilent, Dako) antibodies. Nuclear, membraneous and/or cytoplasmic immunoreactivity was scored based on the intensity and percentage of positive cells in both the benign epithelium and adjacent tumor in each case. E-Cadherin was highly expressed in both the adjacent benign and malignant components with no significant variability in all three carcinomas, with ZEB-1 and Bcl-2 evaluated for the any positivity staining in both components for all cases. Results are detailed in the table below.All positive ZEB-1 cases in HCC were in high grade cases unlike the positive ZEB-1 in RCC which were in low grade cases. But more noticeably, 8/10 (80%) positive ZEB-1 were also positive for Bcl-2 in all three carcinoma types. Despite the small number of cases analyzed in this cohort a trend in the expression of ZEB-1 and its co-expression with BCL-2 may have some prognostic implications. We are currently extending this analysis to a larger number of CC, HCC, and RCC to closely examine the significance of ZEB-1, and Bcl-2 expression across differently graded lesions to further test our hypothesis.
Citation Format: Joeffrey J. Chahine, Kyungmin Ko, Bhaskar VS Kallakury, Pamela L. Tuma. Variable expression of ZEB-1, Bcl-2, and E-cadherin in human hepatocholangio and renal cell carcinomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6471.
Abstract 6539: Bioinformatics algorithm of mRNA-4157 identifies neoantigens with pre-existing TIL reactivities in colorectal tumors
Authors: Zhong Shan , Breton Ben , Zheng Wei , McFadyen Iain , Hopson Kristen , Frederick Joshua , Meehan Robert S. , Zaks Tal 
Published: September 2020

Abstract
Background: Personalized cancer vaccines (PCVs) encode mutation-derived epitopes (neoantigens) predicted from each tumor's unique set of somatic mutations, and can trigger the activation of neoantigen-specific CD4+ and/or CD8+ T cells to target cancer cells. The accurate prediction of immunogenic neoantigens from a tumor's mutanome, which may contain hundreds of somatic mutations, is crucial for designing an effective PCV. In this study, we evaluated the performance of the bioinformatics algorithm for mRNA-4157, an mRNA-based therapeutic PCV, in identifying neoantigens that are recognized by pre-existing tumor infiltrating lymphocytes (TILs) in a cohort of colorectal cancers shared by the National Cancer Institute (NCI) [1].
Methods: Whole exome and transcriptome sequencing data from 29 patients with microsatellite stable, mismatch repair (MMR)-proficient metastatic colorectal cancer were shared by NCI. All patients had received at least one previous systemic therapy, and neoantigen-reactive TIL populations had been identified from these patients by high-throughput immunologic screening [1]. The same bioinformatics algorithm as used for mRNA-4157 was run on the sequencing data, to generate a vaccine design for each patient that included up to 34 neoantigens.
Results: Overall, 41% (26/64) of the neoantigens recognized by CD8+ or CD4+ TILs according to the NCI assay were included in the vaccines designed by the mRNA-4157 bioinformatics algorithm. For 61% (18/29) of the patients, at least one neoantigen with demonstrated CD8+ or CD4+ TIL reactivity was included in the vaccines designed. For 28% (8/29) of the patients, all neoantigens associated with demonstrated CD8+ or CD4+ TIL reactivities were included in the vaccines designed.
Conclusion: The bioinformatics algorithm for mRNA-4157 is able to predict and select neoantigens with pre-existing TIL reactivities based on human ex vivo assays for vaccine designs with high accuracy.
[1] Parkhurst MR, et al. Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers. Cancer Discov. 2019 Aug;9(8):1022-1035.
Citation Format: Shan Zhong, Ben Breton, Wei Zheng, Iain McFadyen, Kristen Hopson, Joshua Frederick, Robert S. Meehan, Tal Zaks. Bioinformatics algorithm of mRNA-4157 identifies neoantigens with pre-existing TIL reactivities in colorectal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6539.
Abstract 6557: Aescin, a triterpene saponin induces apoptosis & oxidative damage in human oral & laryngeal cancer cells via notch signaling
Authors: Kathiresan Suresh , Ramadoss Hemavardhini , Gupta Sanjay 
Published: September 2020

Abstract
The incidence of Head and Neck cancer in increasing worldwide. The major risk factor for these cancers includes viral infection, smoking, alcohol and tobacco consumption. Natural agents have often exhibited medicinal properties with usefulness in treating various human ailments including cancer. Aescin is one of the most prominent constituent of Aesculus hippocastanum L. (Hippocastanaceae) seeds has been conventionally used as medicinal herb. We determined the anticancer effect of aescin on human oral carcinoma (KB) cells and human laryngeal carcinoma (HEp-2) cells. Treatment of KB cells with 25µM and HEp-2 cells with 22µM aescin for 24 hours suppressed proliferation in these cells and induced morphological changes consistent with apoptosis. Exposure of both cell lines to aescin resulted in marked increase in reactive oxygen species, loss of cell viability, and reduction of cellular glutathione levels resulting in depolarization of mitochondrial membrane potential thereby increasing oxidative DNA damage in KB and HEp-2 cells. Furthermore, aescin-mediated apoptosis in these cells progress via notch signaling as shown by downregulation of Notch1, Notch2, Jagged-1, HES1, and HEY1 expression. Taken together, our results demonstrate that aescin initiate apoptosis in KB and HEp-2 cells by increasing oxidative damage implying that aescin might be developed as a potential chemotherapeutic agent for the treatment of human oral and laryngeal cancer.
Key word: Oral carcinoma, Aescin, apoptosis, anti-proliferative, Notch signaling
Citation Format: Suresh Kathiresan, Hemavardhini Ramadoss, Sanjay Gupta. Aescin, a triterpene saponin induces apoptosis & oxidative damage in human oral & laryngeal cancer cells via notch signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6557.
Abstract 6666: Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist
Authors: Sabree Shakoora , Voigt Andrew , Rogers Laura , Blackwell Sue , Lemke-Miltner Caitlin , Weiner George J. 
Published: September 2020

Abstract
CMP-001 is a virus-like particle containing a TLR9 agonist (class A CpG ODN) encapsulated by the Qβ capsid. Preclinical studies and early phase clinical trials of intralesional injection with CMP-001, combined with anti-PD1 antibody, demonstrate promising results. Prior work by our group has demonstrated that the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qβ antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNα. While a variety of cell types including monocytes and B cells can take up CMP-001, the immune response to CMP-001 is based in large part on rapid induction of IFNα production by pDCs. The current studies were designed to assess the downstream effects of CMP-001 and anti-Qβ antibody on various arms of the immune response using normal donor human peripheral blood mononuclear cells (PBMCs) as a model.
Stimulation of PBMCs with CMP-001 and anti-Qβ antibody induced production of IFNα from pDCs as previously observed. This IFNα production occurred very rapidly (within 2 hours) and was short lived, but had long term secondary effects, including induction of CXCL10 production by monocytes. Single cell RNA sequencing done 24 hours after stimulation demonstrated additional downstream changes including the following:
Upregulation of CXCL10, MIP1-α, IL1-RA and IDO by monocytes.
Downregulation of CD14 by monocytes.
Upregulation of a broad variety of interferon response genes in various cell types including NK cells and T cells.
We conclude the primary effect of in situ immunization with CMP-001 is to induce rapid production of IFNα production by pDCs. This results in significant downstream effects on various cell populations that contribute to the anti-tumor immune response. Understanding these pathways could help identify the most promising combination immunotherapies involving CMP-001. Ongoing studies are exploring the kinetics of these responses and whether similar changes are observed in the tumor microenvironment.
Citation Format: Shakoora Sabree, Andrew Voigt, Laura Rogers, Sue Blackwell, Caitlin Lemke-Miltner, George J. Weiner. Evaluation of the complexity of the immune response to CMP-001, a TLR9 agonist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6666.