bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1909: Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma
Authors: Malkova Natalia , Theilhaber Joachim , Levit Mikhail , Tolstykh Tatiana , Hebert Andrew , Atchison Kevin , Maisonet Adalis , Sinicropi-Yao Sara Sara , Protopopov Alexei , Pollard Jack , Sidhu Sukhvinder , Lin Tun Tun , Pao Lily , Wiederschain Dmitri , Sharma Sharad K. 
Published: July 2021

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, accounting for more than 700,000 deaths per year. Although transforming growth factor beta (TGF-β) can function as a tumor-suppressor in premalignant cells, patient data suggest that it plays a role in the progression of HCC. Recently, immunotherapy targeting PD-1 has been approved for HCC, however, success is limited to only ~17% objective response rate in the treated HCC patients. Analysis of genomic data from two HCC patient cohorts revealed that TGF-β pathway is highly activated in patients with advanced HCC. Collectively, these findings indicate that targeting TGF-β in combination with PD-1 blockade may be a compelling therapeutic strategy. Therefore, using two syngeneic mouse models of HCC (Hepa1-6 and H22), we examined the effect of a pan-TGF-β neutralizing antibody (1D11) in combination with PD-1 blockade. Results from our study show that co-inhibiting TGF-β with PD-1 resulted in significant tumor growth inhibition in both HCC models. Flow cytometry analysis of the tumor revealed the combination treatment group exhibited a reduction in potentially suppressive tumor-associated-macrophages relative to either single agent groups. In addition, we show that combination therapy was associated with increase in the intra-tumoral levels of proinflammatory cytokines - IFNγ, IL-1β, TNF-α as well as enhanced expression of anti-tumor immune related genes. Based on these data, clinical testing of SAR439459 (TGF-β antibody) and Cemiplimab (anti-PD1) combination has recently been initiated in HCC patients (NCT03192345).
Citation Format: Natalia Malkova, Joachim Theilhaber, Mikhail Levit, Tatiana Tolstykh, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Sara Sara Sinicropi-Yao, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Tun Tun Lin, Lily Pao, Dmitri Wiederschain, Sharad K. Sharma. Pan-TGF-β inhibition with PD-1 blockade as a combination treatment strategy to augment anti-tumor immune response in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1909.
Abstract 1915: Novel synthetic DNA vaccines in prostate cancer immunotherapy
Authors: Bordoloi Devivasha , Xiao Peng , Choi Hyeree , Ho Michelle , Perales-Puchalt Alfredo , Khoshnejad Makan , Kim J.Joseph , Humeau Laurent , Srinivasan Alagarsamy , Weiner David B. , Muthumani Kar 
Published: July 2021

Abstract
Prostate cancer (PCa) represents the most predominant cancer type among males with an estimated 191,930 cases diagnosed in 2020 with 33,330 deaths globally. Notably, different treatment modalities such as surgery, chemo, radiation and hormone therapy exhibited improved outcomes in early stage PCa patients; however, there exist high recurrence rate in the treated patients and leads to castration resistant prostate cancer, the treatment choices for which are highly restricted. This scenario has pressed us to consider synthetic DNA vaccine-based immunotherapy approach, with ability to induce antigen-specific tumor-killing immune cells. Considering the high heterogeneity of prostate cancer cells, we hypothesized that synthetic DNA vaccines targeting multiple prostate specific antigens would elicit improved immune responses in those who are at high risk as well as advanced stages of prostate cancer. Therefore, we generated synthetic enhanced DNA immunogens as DNA constructs (SEV) targeting STEAP1, PAP, PARM1, PSCA, PCTA and PSP94 through utilization of bioinformatics approaches. The SEVs for prostate cancer antigens elicited potent cellular immunity as well as polyfunctionality of antigen-specific T cells in mice. Further, they were capable of generating robust humoral immune responses to each antigen. The anti-tumor activities of the SEVs were studied in prostate tumor which showed that the induced immune responses delayed tumor progression and enhanced infiltration of anti-tumor CD8+ T cells in the tumor microenvironment in a mouse model challenge system. These data highlight further study of these novel immunogens as synthetic DNA immunogens for immunotherapy of PCa, and perhaps other human cancers.
Citation Format: Devivasha Bordoloi, Peng Xiao, Hyeree Choi, Michelle Ho, Alfredo Perales-Puchalt, Makan Khoshnejad, J.Joseph Kim, Laurent Humeau, Alagarsamy Srinivasan, David B. Weiner, Kar Muthumani. Novel synthetic DNA vaccines in prostate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1915.
Abstract 1922: Protective tumor neo-epitopes are processed from conformationally stable neo-antigen segments
Authors: Landry Samuel J. 
Published: July 2021

Abstract
Immunogenic tumor neo-epitopes are the basis of successful checkpoint immunotherapy for cancer, and they potentially offer a target for personalized cancer vaccines. However, the frequency of immunologically protective neo-epitopes appears to be very low in comparison to the frequency of tumor mutations. Vaccine designers typically select neo-epitopes by demonstrable gene expression and elevated MHC class I binding, anticipating that corresponding CD8+ T cells will be protective; but CD4+ T-cells are more often correlated with therapeutic effects. CD4+ T cells are most well known for helping B cells make antibodies, and B cells also have recently been implicated in protection from tumors. Antigen-presenting cells, including dendritic cells, B cells, and macrophages present epitope peptides in complexes with class II MHC molecules (MHCII) to CD4+ T cells, and CD4+ T cells signal responding cells to eliminate tumor cells. Studies on immunodominant CD4+ T-cell epitopes from foreign antigens suggest that immunogenicity depends on antigen conformational stability. Likewise, the immunogenic CD4+ neo-epitopes of tumors could be associated with mutations affecting residues in conformationally stable protein segments. In order to test this hypothesis, we surveyed existing tumor neo-epitope data to analyze the conformational context of neo-epitopes that are associated with protection from tumors. First, protective neo-epitopes are three-fold more likely to occur in a crystal structure (67%) than other potential neo-epitopes (22%). Second, the protective neo-epitopes are enriched within or adjacent to conformationally stable segments of the neo-antigens, as reported by the Antigen Processing Likelihood algorithm. Third, the distribution of mutations between functionally similar hotspots encoding R248 and R273 in the gene for the p53 tumor suppressor is consistent with increased immunologic selection in tumors subjected to increased immune response. These results suggest that neo-epitope evaluation for cancer prognosis and vaccines should include the analysis of conformational stability in the neo-antigen.
Citation Format: Samuel J. Landry. Protective tumor neo-epitopes are processed from conformationally stable neo-antigen segments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1922.
Abstract 1928: Erdafitinib in combination with BCLXL/BCL2 inhibitor induce apoptosis in urothelial carcinoma cells without FGFR mutation
Authors: ohtsu Akira , Arai Seiji , Sawada Tatsuhiro , Suzuki Kazuhiro 
Published: July 2021

Abstract
Although Erdafitinib has recently emerged as a treatment for metastatic urothelial carcinoma, it has been shown to be effective against FGFR mutations, but the target patient population is small, and a new treatment for urothelial carcinoma without FGFR mutations is needed. We found that Erdafitinib degrades MCL1 in urothelial carcinoma cells. Furthermore, we found that in combination with Navitoclax, a BCLXL/BCL2 inhibitor, it induced potent apoptosis in urothelial carcinoma cell lines without FGFR mutation. This combination therapy may represent a new treatment for urothelial carcinoma without FGFR mutations.
Citation Format: Akira ohtsu, Seiji Arai, Tatsuhiro Sawada, Kazuhiro Suzuki. Erdafitinib in combination with BCLXL/BCL2 inhibitor induce apoptosis in urothelial carcinoma cells without FGFR mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1928.
Abstract 1931: Evaluation of cholecystokinin receptor expression and function in non-small cell lung cancer
Authors: Miller Alexander C. , Subry Shelby J. , Assar Manijeh M. , Pearman Krista , Norris Jeffrey William 
Published: July 2021

Abstract
Introduction: Lung cancer is the leading cause of cancer-related death in the United States, with nearly 85% of cases histologically classified as non-small cell lung cancer (NSCLC). A recent epidemiological study provides evidence of an increased risk ratio for NSCLC in association with adherence to a Western dietary pattern, which has a higher dietary fat content, compared to vegetarian or Tex-Mex dietary patterns. Our laboratory and others have measured increased tumor burden in murine models of NSCLC when feeding diets are high in fat compared to a standard rodent cereal diet. In our laboratory, increased tumor burden is associated with increased tumor multiplicity, but no change in proliferative markers (Ki-67 and pS6) were observed. Dietary fat increases both tumorigenesis in mouse models of pancreatic cancer and circulating levels of the gastrointestinal hormone cholecystokinin (CCK). Inhibition of CCK receptors antagonizes progression of precursor lesions in murine models of pancreatic cancer. Although CCK receptor expression has not been detected in normal human pulmonary tissue, the CCK-B receptor has been identified immunohistologically in human lung tumors. Further, the CCK-A receptor is expressed in normal murine pulmonary epithelium.
Hypothesis: At concentrations approximating circulating levels in mice fed a high fat diet, CCK reduces apoptosis of NSCLC cells in vitro.
Materials and Methods: The murine NSCLC cell line IO33 was grown in serum-replete RPMI 1640 or serum-deprived RPM 1640 with 0 to 1000 pM exogenous CCK-8 peptide added. Expression of CCK-A and CCK-B receptors were measured in IO33 and human NSCLC cell lines by qPCR. Apoptosis was assessed using a Caspase-3/7 peptide cleavage assay.
Results: Expression of CCK-A and CCK-B receptors are reported in IO33 cells and 11 human lung cancer cell lines. Apoptosis of IO33 cells was significantly decreased by greater than 30% at CCK concentrations greater than 100pM (P &lt; 0.03), which is the circulating concentration of CCK in mice fed a high fat diet.
Conclusions: CCK receptors are expressed in human and murine NSCLC cells and circulating CCK may reduce NSCLC cell apoptosis.
Citation Format: Alexander C. Miller, Shelby J. Subry, Manijeh M. Assar, Krista Pearman, Jeffrey William Norris. Evaluation of cholecystokinin receptor expression and function in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1931.
Abstract 1934: Modulation of protein homeostasis networks upon Hsp70 inhibition in cancer cells
Authors: Sannino Sara , Brodsky Jeffrey L. 
Published: July 2021

Abstract
Cellular protein homeostasis is tightly regulated by balancing protein synthesis, folding, and degradation. Cancer cells constantly modulate protein folding and degradation efficiency to survive and proliferate without accumulating toxic misfolded proteins under acute stress conditions, such as low oxygen and energy, and exposure to chemotherapeutic agents. Many cancers rely on the unfolded protein response (UPR) to cope with stress, which increases the expression of molecular chaperones and mitigates the accumulation of misfolded proteins. Thus, it is unsurprising that the Hsp70 molecular chaperone, which serves as a master regulator of proteostasis, is upregulated in many cancers. Increased Hsp70 correlates with metastasis formation and poor patient prognosis in different cancers, like breast cancer. To define the role of Hsp70 in cancer survival and identify how cancer cells compensate for chaperone-mediated proteotoxicity, we investigated the response to a specific Hsp70 inhibitor, MAL3-101, in breast cancer cells. We discovered that breast cancer cells bin into distinct groups when subjected to Hsp70 inhibition based on their sensitivity to the compound. Moreover, we demonstrate that resistant cells have higher autophagy levels compared to more sensitive lines. Autophagy was further induced by MAL3-101 in resistant breast cancer cells, as evidenced by the accumulation of both autophagy related genes and proteins, as well as by autophagic-like structures detected by confocal microscopy. These data suggest that resistance to Hsp70 inhibition arises from autophagy induction. We then discovered that Hsp70 inhibition induces the UPR pathway, triggering apoptosis in sensitive cells. In particular, the activation of the UPR transducer, PERK, is required to induce apoptosis in sensitive cells when Hsp70 was inhibited. Overall, our work positions autophagy as a critical compensatory mechanism when molecular chaperone function is overwhelmed and misfolded proteins accumulate. Furthermore, our findings delineate a distinct role of PERK in apoptosis induction upon Hsp70 inhibition, highlighting the interplay between the PERK, Hsp70, and autophagy.
Citation Format: Sara Sannino, Jeffrey L. Brodsky. Modulation of protein homeostasis networks upon Hsp70 inhibition in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1934.
Abstract 1935: Antitumor effect mechanism of statin in PCa cells focusing on autophagy
Authors: Miyazawa Yoshiyuki , Oka Daisuke , Nakayama Hiroshi , Sekine Yoshitaka , Arai Seiji , Suzuki Kazuhiro 
Published: July 2021

Abstract
Antitumor effect mechanism of statin in prostate cancer cells focusing on autophagy Background:Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. We have studied the novel castration resistant prostate cancer (CRPC) treatment with statins. Using microarrays, we discovered up-regulation of ATG4B (Autophagy related 4 homolog B) in PC-3 cells after simvastatin treatment. In this study, we evaluated the effects of simvastatin focusing on androgen-independent prostate cancer cells. Methods:PC-3, LNCaP-LA, 22RV-1-LA (taht were derived from LNCaP and 22RV1 cells and cultured in 10% charcoal-stripped fetal bovine serum for 3 months), and DU145 human prostate cancer cell lines were used. Microarrays were performed using PC-3 untreated or administered with simvastatin (0 uM versus 5 uM). Proliferation, migration, and invasion were evaluated using MTS assay, Migration assay, and Invasion assay, respectively. The increases of autophagy were detected by western blot using microtubule associated protein 1 light chain 3 (LC-3) antibody and confirmed by a fluorescence microscope with staining autophagosomes by autophagy detection kit (abcam, Cambridge, UK). Results:Using microarrays, we discovered up-regulation of ATG4B in PC-3 cells after simvastatin treatment. Simvastatin inhibited the proliferation, migration, and invasion of PC-3, LNCaP-LA, 22RV1-LA and DU145 cells. The expression level of LC-3 was up-regulated by simvastatin in PC-3, LNCaP-LA, 22RV1-LA and DU145 cells. In PC-3 cells treated with statin, a significant increase in autophagosomes was confirmed by fluorescence microscopy. The expression of LC-3 and autophagosomes were increased in a concentration-dependent manner. Conclusions:It was found that statin administration enhances autophagy induction in a prostate cell line. We plan to study the combined effect with other drugs that induce autophagy. We would like to develop CRPC treatment by inducing autophagy cell death.
Citation Format: Yoshiyuki Miyazawa, Daisuke Oka, Hiroshi Nakayama, Yoshitaka Sekine, Seiji Arai, Kazuhiro Suzuki. Antitumor effect mechanism of statin in PCa cells focusing on autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1935.
Abstract 1942: Quantitative D2O proteomics reveals ATG9A-dependent autophagy substrates that are degraded independently of the LC3-lipidation machinery
Authors: McEwan Colten M. , Broadbent David G. , Kannangara Ashari R. , Poole Daniel M. , Naylor Bradley C. , Price John C. , Schmidt Jens C. , Andersen Josh L. 
Published: July 2021

Abstract
Autophagy is an essential catabolic process that cancer cells use to survive metabolic stress and maintain basal cellular homeostasis via degradation of dysfunctional organelles and protein aggregates. One protein with an unclear, yet essential, role in autophagy is the multi-pass transmembrane protein ATG9A. ATG9A is an apical autophagy regulator that is hypothesized to help seed the formation of nascent autophagosomes by providing membrane through its own unique ATG9A vesicles. To understand the role ATG9A plays in autophagic protein turnover, we performed whole proteome deuterium exchange and quantitative mass spectrometry to measure protein degradation rates in Wild-Type (WT) and ATG9A Knock-Out (KO) cells. This experiment revealed that ATG9A KO cells display significantly decreased degradation rates of aggregation prone proteins and autophagy adapters, such as p62/SQSTM1. In an effort to understand the relationship between ATG9A and p62/SQSTM1, we found that ATG9A associates directly with p62/SQSTM1 and mediates the basal degradation of p62/SQSTM1-associated protein aggregates. This ATG9A-mediated degradation occurs in a non-canonical way, involving a subset of ATG proteins (e.g., ATG13, ATG101), but independent of the LC3-lipidation machinery ATG5 and ATG7. Taken together, our data suggests that ATG9A controls the degradation of p62 in an ATG5/ATG7-independent manner.
Citation Format: Colten M. McEwan, David G. Broadbent, Ashari R. Kannangara, Daniel M. Poole, Bradley C. Naylor, John C. Price, Jens C. Schmidt, Josh L. Andersen. Quantitative D2O proteomics reveals ATG9A-dependent autophagy substrates that are degraded independently of the LC3-lipidation machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1942.
Abstract 1948: Investigation of the effect of LLLT on glioblastoma multiforme
Authors: Atluri Rohini , Afkhami Parsa , Choi Tae-Youl , Simmons Denise P. 
Published: July 2021

Abstract
Low-level Laser Treatment (LLLT) has a potential to alter tumor behavior such as proliferation in addition to therapeutic effects such as wound healing, inflammation reduction. Studies indicate that, different tumor cells respond distinctly to LLLT based on laser dose (J/sq. cm). GBM is an aggressive and invasive primary brain tumor which is heterogenic in nature and any treatment that could have a potential to kill or change tumor behavior or tumor microenvironment by making GBM sensitive to available treatments can help improve the survival rate. In this study, we investigated the effect of LLLT on human malignant glioma (U251) cells using He-Ne Laser (632.8 nm). The He-Ne laser parameters used for the treatment are power (14.87±0.3 mW), beam diameter (0.68 cm), and varying laser exposure times of 5 mins and 10 mins leading to variable doses of 12.28 J/sq.cm and 24.56 J/sq. cm respectively. The dose response of LLLT on U251 cells revealed that the dose 12.28 J/sq. cm lead to cell death of 17%, 24 hrs post treatment while the dose 24.56 J/sq. cm achieved cell death of 30%, 6 hrs post treatment along with some morphological changes such as vacuole formation in the heterogenic malignant glioma. Also, a biphasic response was observed post treatment with the dose of 24.56 J/sq. cm, as we observed increase in cell viability 18hrs post treatment along with neurite formation. Western analysis suggests the involvement of PARP and caspase 9 in killing LLL treated U251 cells. Thus, upon further study, LLLT could have a potential to be used as an adjunctive treatment when used with conventional treatments for malignant glioma.
Citation Format: Rohini Atluri, Parsa Afkhami, Tae-Youl Choi, Denise P. Simmons. Investigation of the effect of LLLT on glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1948.
Abstract 196: Redefining cancer subtypes using multi-omics and deep learning
Authors: Akalin Altuna , Uyar Bora , Ronen Jonathan , Franke Vedran 
Published: July 2021

Abstract
Cancer is a heterogeneous collection of diseases traditionally classified by the tissue of origin. The diversity of the molecular profiles of cancers has a big impact on the way patients are diagnosed and treated, how they respond to their prescribed treatments, the duration of survival after diagnosis, and factors such as remission, recurrence, or spread (metastasis) of the disease. While such diagnostic and prognostic outcomes are potentially predictable by taking a closer look into the changes of the genome, epigenome, transcriptome, proteome, and various other omics platforms, the contemporary cancer treatments still predominantly don't make the best use of such multi-omics profiling of patient samples. Therefore, multi-omics profiling of cancers holds great potential to define a molecularly coherent subtype definition of cancers in order to achieve the eventual goal of matching the best possible treatment to the subgroup of patients.
However, the current subtypes from consortiums such as TCGA have been defined by heterogeneous methods and molecular markers by different teams. A subset of these studies have not attempted to characterize molecular subtypes, but rather taken histopathologically defined subtypes as the gold standard and tried to characterize molecular features of these subtypes. Here we evaluate TCGA cancer subtypes based on the molecular profile coherence score. This novel metric combines survival statistics, pathways information, tumor purity estimates, and mutational signatures. We expect that subtypes that are patient subgroups should display molecular signature homogeneity. We evaluate TCGA subtypes from 21 cancers using these criteria and compare the subtypes with our own definition using multi-omics data in a deep learning framework. We have refined the several subtypes from multiple cancers towards more molecularly coherent patient subgroups.
Citation Format: Altuna Akalin, Bora Uyar, Jonathan Ronen, Vedran Franke. Redefining cancer subtypes using multi-omics and deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 196.