tbuckley/cabot-search huggingface dataset:
Abstract 5596: Dynamic monitoring of plasma DAMP proteins during multimodal anticancer treatment in advanced lung cancer patients
Authors: Hiroyuki Inoue, Hirono Tsutsumi, Yoshimasa Shiraishi, Koji Okamura, Yoichi Nakanishi, Isamu Okamoto
Journal: Cancer Research (2020)

Abstract Immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells is a potential contributor to the synergistic antitumor effects of the combination of cytotoxic chemotherapy with immune checkpoint blockade. However, little information on the kinetics of circulating DAMP levels in cancer patients has been available. We evaluated the possible effects of various anticancer treatment modalities on the kinetics of plasma DAMP proteins in lung cancer patients. In a prospective observational study, plasma concentrations of three representative DAMP proteins–high-mobility group box 1 (HMGB1), calreticulin (CRT), and histone H3–in 50 patients with advanced lung cancer were measured at five time points during the first cycle of anticancer therapy by ELISA assay. The plasma levels of HMGB1 and CRT increased during the first treatment cycle in 42 (84%) and 35 (70%) patients, respectively, with these increases being detectable as early as day 3. The maximum fold changes in HMGB1 and CRT concentrations was associated with clinical response. Among the various treatment modalities, cytotoxic chemotherapy induced the greatest increases in the concentrations of these DAMPs. There was no correlation between the maximum fold changes in the plasma levels of HMGB1 and CRT. Meanwhile, histone H3 was essentially undetectable in most patients. In conclusion, serial monitoring of plasma revealed that anticancer treatment modalities increased the circulating levels of DAMPs with their association with clinical response, suggesting that agents capable of increasing the release of DAMPs into plasma might induce immunogenic cell death in advanced lung cancer patients. Citation Format: Hiroyuki Inoue, Hirono Tsutsumi, Yoshimasa Shiraishi, Koji Okamura, Yoichi Nakanishi, Isamu Okamoto. Dynamic monitoring of plasma DAMP proteins during multimodal anticancer treatment in advanced lung cancer patients [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 5596.
Abstract 3338: Intra-tumoral microbes correlate with immune cell fractions in lung cancer biopsies not other cancers
Authors: Xiaokui Mo, Daniel Spakowicz, Rebecca Hoyd
Journal: Cancer Research (2020)

Abstract Exogenous sequences in bacteria have been found in many tumors, but their effect on outcomes remains largely unknown. We hypothesize that intratumoral microbes elicit effects through the recruitment of immune cells, such as CD8+ T-cells that are important for immunotherapy response. Through ORIEN (Oncology Research Information Exchange Network), we obtained RNA-seq data from biopsies of 480 tumors (Melanoma=16, Bladder=104, Colorectal=20 Renal Cell Carcinoma=20, Sarcoma=118, Lung=202) from patients treated at The Ohio State University Comprehensive Cancer Center. Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Human gene expression was deconvolved to relative abundances of immune cells using CIBERSORT. Across cancers, an average of 99.87% of reads were aligned to the human reference genome. The immune cell types CD8+ T-cells, activated dendritic cells and M1 macrophages were significantly enriched in lung cancer (p-values &amp;lt;0.0001), and M2 macrophages were significantly enriched in sarcoma (p-values&amp;lt;0.0001). On the other hand, exogenous reads were aligned to 1328 genomes of bacteria, archaea, viruses and fungi. The phyla with the largest average relative abundances were Proteobacteria, Firmicutes and Actinobacteria, with average relative abundances of 39.5%, 20.1%, and 5.16% respectively. In lung cancer, there was a significant positive correlation between the fraction of CD8+ T-cells and Acinetobacter junii (p-value=0.035), and between activated NK cells and Acidipropionibacterium virtanenii (p-value=0.035). This suggests a mechanism by which intratumoral microbes may affect the immune system and thereby cancer outcomes. Citation Format: Xiaokui Mo, Daniel Spakowicz, Rebecca Hoyd. Intra-tumoral microbes correlate with immune cell fractions in lung cancer biopsies not other cancers [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 3338.
Abstract 5509: Breaking the paradox breakers - RAF inhibitor mechanisms
Authors: Gaurav Mendiratta, Thomas McFall, Edward Stites
Journal: Cancer Research (2020)

Abstract A number of ATP competitive inhibitors of RAF onco-protein have been successful in tumors with RAF V600 mutations but have failed for more common cases with upstream mutations. Instead, a paradoxical activation (PA) of downstream signaling is observed in response to these inhibitors when RAF is not the driver mutation. A detailed understanding of processes that potentiate PA would help in minimizing side effects, choosing appropriate mono- or combination treatments and guide future drug development. Several mechanisms of PA have been proposed in the past, such as negative co-operativity to additional drug binding and RAF dimer stabilization. However, the evidence for these mechanisms is indirect and does not explain PA for all the different types of drugs. In our work, we created a mathematical model of RAF activation solely based on canonical RAF signal regulatory processes to show how autoinhibition provides a general mechanism of PA. We also used this model to show that 14-3-3 proteins could further potentiate PA by stabilizing autoinhibited RAF. Based on the computational work, we predicted that transfecting 14-3-3 proteins would potentiate PA even with drugs which are otherwise expected to provide minimal or no PA. Our experiments with these drugs in SKMEL2 melanoma cells and SW48 colon cancer cells validated our predictions thereby providing support for our general model of PA. Citation Format: Gaurav Mendiratta, Thomas McFall, Edward Stites. Breaking the paradox breakers - RAF inhibitor mechanisms [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 5509.
Abstract 4646: Association between dietary vitamin B intake and risk of endometrial cancer in the prospective Singapore Chinese Health Study
Authors: Ming Lei, Shalkar Adambekov, Robert Edwards, Renwei Wang, Jianmin Yuan, Samia Lopa, Faina Linkov
Journal: Cancer Research (2020)

Abstract Background: Endometrial cancer (EC) is the 6th most common cancer worldwide. However, only few studies addressed dietary factors influencing EC risk in Asia. We explored the association between dietary risk factors and endometrial cancer in the prospective Singapore Chinese Health Study. Methods: A population of 34,028 ethnically Chinese women aged 45-74 residing in Singapore were enrolled in a longitudinal prospective cohort study between 1993 and 1998, and followed up to Dec 31, 2010. Data on baseline demographics, dietary, and reproductive factors were collected via a structured questionnaire. Endometrial cancer cases were identified from the Singapore Cancer Registry. Poisson regression was used to estimate the incidence rate ratio (IRR) on established and dietary risk factors. Results: 166 EC cases were identified (age 53.6±7.2; BMI 24.1±3.3). Obesity (IRR=1.84, 95%CI 1.06-3.06) and having a higher number of live births (IRR=0.43, 95%CI 0.24-0.79, 5+ vs nulliparous) were associated with EC. Overall, compared with the lowest quartile, elevated risk of EC was observed for the highest quartile of dietary thiamine (IRR 1.74, 95%CI 1.02-2.58), riboflavin (IRR 1.58, 95%CI 1.01-2.53), vitamin B6 (IRR 1.71, 95%CI 1.07-2.80), and folate (IRR1.56, 95%CI 1.00-2.47). The highest quartiles of riboflavin (IRR 1.74, 95%CI 1.00-3.12), vitamin B6 (IRR 1.91, 95%CI 1.04-3.65), and folate (IRR 1.89, 95%CI 1.01-3.64) were associated with elevated EC risk in postmenopausal women, but not among premenopausal women. Conclusion: Obesity, parity, and higher intake of dietary vitamin B were associated with elevated EC risk in our analysis. More studies are needed to evaluate the association of supplementary vitamin B complex and EC risk. Citation Format: Ming Lei, Shalkar Adambekov, Robert Edwards, Renwei Wang, Jianmin Yuan, Samia Lopa, Faina Linkov. Association between dietary vitamin B intake and risk of endometrial cancer in the prospective Singapore Chinese Health Study [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 4646.
Abstract 1847: Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders
Authors: Sharlene Velichko, Sheryl P. Denker, Alison O'Mahony
Journal: Cancer Research (2020)

Abstract Small molecule inhibitors of Janus kinases (Jakinibs) represent a promising treatment for myeloproliferative disorders including polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). Currently multiple JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, baricitinib) are either approved or in clinical development for the treatment of MF. The primary target of Jakinibs, the JAK-STAT pathway, plays a critical role in multiple cellular processes relevant for myelofibrosis, including survival, differentiation, and proliferation. However, all approved Jakinibs are reportedly promiscuous in that they inhibit kinases beyond the JAK family. Their overall clinical impact, therefore, reflects the sum of these target activities, as well as downstream secondary pharmacology relevant to both efficacy and safety. We evaluated these four Jakinibs using phenotypic profiling with the BioMAP® Diversity PLUS Panel to identify common versus differential activities. The BioMAP platform consists of human primary cell-based assay or systems designed to recapitulate key aspects of tissue and disease states. Distinct activity profiles were generated for each of the tested Jakinibs based on their impacts on 148 different biomarkers in 12 different model systems. Comparison of these profiles at concentrations relevant for clinical exposure levels revealed common activities including inhibition of T and B cell proliferation and decreased levels of inflammation and immune activation biomarkers. Together these activities represent a phenotypic signature related to shared primary JAK targets. In contrast, multiple differentiating activities were observed between the four drug profiles: baricitinib increased TNFα levels whereas momelotinib decreased TNFα in the LPS system modeling monocyte activation; fedratinib and momelotinib, but not ruxolitinib or baricitinib, inhibited endothelial cell proliferation; only momelotinib inhibited macrophage responses and decreased PGE2 levels. These data indicate that even within the specific JAK2 inhibitor drug class, individual entities have distinct modes of action relevant for clinical outcomes. Citation Format: Sharlene Velichko, Sheryl P. Denker, Alison O'Mahony. Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders [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 1847.
Abstract 4641: Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study
Authors: Claire E. Thomas, Hung N. Luu, Renwei Wang, Jennifer Adams-Haduch, Jian-Min Yuan, Aizhen Jin, Woon-Puay Koh
Journal: Cancer Research (2020)

Abstract Background: Intake of tomato and/or lycopene have been found to be associated with reduced risk of several cancer types, but epidemiological data on risk of hepatocellular carcinoma (HCC) are sparse. Methods: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 years at enrollment in 1993-1998 with 25 years of follow-up. Tomato and lycopene consumption was evaluated using a validated semi-quantitative food frequency questionnaire. Incident HCC cases were ascertained through the linkage analysis with the nationwide Singapore cancer registry. Cox proportional hazard regression was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association among individuals negative for hepatitis B surface antigen (HBsAg). Results: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for multiple potential confounders (Ptrend&amp;lt;0.001). Compared to the lowest quartile, HRs (95% CIs) of HCC for the 2nd, 3rd, and 4th quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained (Ptrend=0.03). There was no association between lycopene intake and HCC risk (Ptrend=0.54). Conclusion: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus. Citation Format: Claire E. Thomas, Hung N. Luu, Renwei Wang, Jennifer Adams-Haduch, Jian-Min Yuan, Aizhen Jin, Woon-Puay Koh. Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study [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 4641.
Abstract 6343: Mitochondrial bioenergetics mediate chemo-resistance of cancer cells
Authors: Fouzia Zayou, Chintan Chheda, Stephen Pandol, Mouad Edderkaoui
Journal: Cancer Research (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 233: Tumor-associated carbonic anhydrase IX maintains cellular proliferation by regulating tumor metabolism: a novel link revealed by proteomics
Authors: Martin Benej, Eliska Svastova, Radivojka Banova, Juraj Kopacek, Adriana Gibadulinova, Martin Kery, Simona Arena, Andrea Scaloni, Monica Vitale, Nicola Zambrano, Ioanna Papandreou, Nicholas C. Denko, Silvia Pastorekova
Journal: Cancer Research (2020)

Abstract Tumor hypoxia is a critical microenvironmental stress occurring in virtually all types of solid tumors. Survival of cancer cells is dependent upon their ability to adapt to these limiting conditions. Hypoxia-induced carbonic anhydrase IX (CA IX) plays a crucial adaptive role in response to hypoxic and acidic microenvironments by catalytically hydrating extracellular CO2 to produce bicarbonate ions that maintain intracellular pH (pHi). In order to determine how CAIX function impacts other cellular processes, we used proteomic profiling to identify changes in response to transient CA IX knockdown in hypoxia. We discovered a significant reduction of key glycolytic enzyme levels with a most prominent decrease in lactate dehydrogenase (LDH). Our data shows that in addition to participating in cellular regulation of pHi, CA IX significantly stimulates glycolytic flux, lactate production and rate of proliferation in hypoxia. Because LDH activity contributes to pHi regulation by consuming cytoplasmic protons in the process of NADH regeneration, CA IX knockdown-mediated LDH suppression may further compromise the pHi regulating ability in hypoxia. Interestingly, addition of the alternative LDH substrate alpha-ketobutyrate compensates for reduced lactate production and restores pHi and proliferation in CA IX-deficient cells. These findings suggest that CA IX confers adaptive plasticity and supports proliferation of cancer cells both directly and indirectly - through its effect as a pHi regulator and by maintaining glycolysis-permissive intracellular environment, respectively. Because CA IX expression is limited almost exclusively to tumors, our findings highlight the role as well as provide mechanistic insight for the utility of CA IX as an anti-cancer target and suggests that highly glycolytic tumors might be particularly vulnerable to CA IX-targeted therapy. Citation Format: Martin Benej, Eliska Svastova, Radivojka Banova, Juraj Kopacek, Adriana Gibadulinova, Martin Kery, Simona Arena, Andrea Scaloni, Monica Vitale, Nicola Zambrano, Ioanna Papandreou, Nicholas C. Denko, Silvia Pastorekova. Tumor-associated carbonic anhydrase IX maintains cellular proliferation by regulating tumor metabolism: a novel link revealed by proteomics [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 233.
Abstract 1078: The nucleosomal acidic patch helps anchor of <i>de novo</i> DNA methyltransferase DNMT3A2/3B3 complex
Authors: Ting-Hai Xu, Minmin Liu, Edward Zhou, Gangning Liang, Eric H. Xu, Karsten Melcher, Peter A. Jones
Journal: Cancer Research (2020)

Abstract CpG methylation by de novo DNA methyltransferases (DNMT) 3A and 3B is essential for mammalian development and differentiation, and is frequently dysregulated in cancer. DNMT3s preferentially bind nucleosomes yet can not methylate the DNA wrapped around the nucleosome core, and favor the methylation of linker DNA at positioned nucleosomes. Here we present the cryo-EM structure of a ternary complex of catalytically active DNMT3A2, the catalytically inactive accessory subunit DNMT3B3, and a nucleosome core particle flanked with linker DNA. We find that the catalytic-like domain (CLD) of the accessory DNMT3B3 binds the acidic patch of the nucleosome core, which orients the binding of the catalyticaly active DNMT3A2 to linker DNA. The sterical constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur. Citation Format: Ting-Hai Xu, Minmin Liu, Edward Zhou, Gangning Liang, Eric H. Xu, Karsten Melcher, Peter A. Jones. The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex [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 1078.
Abstract 5029: Targeting fatty acid oxidation to promote anoikis and inhibit ovarian cancer progression
Authors: Benjamin Guy Bitler, Brandon Sawyer, Lubna Qamar, Jennifer K. Richer, Kian Behbakht, Isabel R. Schlaepfer
Journal: Cancer Research (2020)

Abstract Purpose: Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy and in the US accounts for over 14,000 deaths per year. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by the loss of attachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient-deprivation. Reports describe metabolic reprogramming that promotes fatty acid oxidation (FAO) potentially supports anoikis resistance. Experimental Design: Examination of a panel of HGSOC cell lines cultured in adherent and suspension conditions. Evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, and flow cytometry. Using the Seahorse Bioanalyzer examined mitochondria activity in suspension. Tested the role of exogenous free fatty acids in anoikis resistance and metabolism. In a patient-derived xenograft model, administered an FAO inhibitor and/or platinum-based chemotherapy. Results: HGSOC cultured in suspension upregulated the FAO rate-limiting enzyme, Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A is overexpressed in HGSOC and correlates with poor overall survival. The knockdown of CPT1A promoted anoikis. HGSOC cells in suspension culture have decreased oxygen consumption that is rescued by exogenous fatty acids. In a patient-derived xenograft of HGSOC, a CPT1A inhibitor, etomoxir, significantly inhibited tumor growth and reduced tumor distribution. Conclusions: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a potential approach to promote a more durable anti-tumor response and improve patient outcomes. Citation Format: Benjamin Guy Bitler, Brandon Sawyer, Lubna Qamar, Jennifer K. Richer, Kian Behbakht, Isabel R. Schlaepfer. Targeting fatty acid oxidation to promote anoikis and inhibit ovarian cancer progression [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 5029.