bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-198: Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding
Authors: Feng Xiao , Sun Dawei , Qin Suofu , Jin Lei , Wang Tao , Yan Hongbo
Published: August 2019

CD47 is a widely expressed cell surface protein that functions as a checkpoint in the immune system. When overexpressed on tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. Thus, targeting CD47 is becoming a hot spot of cancer immunotherapy. However, its ubiquitous expression on circulating cells, especially RBCs and hepatocyte, poses a safety concern in CD47 targeted therapy.In this study, we discovered a novel anti-CD47 antibody, GenSci-059. GenSci-059 exhibited equivalent anticancer effects with Hu5F9-G4, a humanized anti-CD47 antibody in clinical trial, evidenced by inducing significant phagocytosis of tumor cells in vitro and prolonging the survival of xenografted mice. Especially for non-Hodgkin’s lymphoma (NHL), GenSci-059 showed almost 100% tumor growth inhibition with 100% response rate in the patient-derived xenograft (PDX) NHL models tested. Remarkably, GenSci-059 did not bind to human RBCs and induced minimal RBC phagocytosis by in vitro assay. In cynomolgus monkeys, GenSci-059 was well tolerated at doses up to 300 mg/kg, and did not produce adverse effects including anemia and hepatic dysfunction, which are common side effects of other anti-CD47 therapies. Overall, GenSci-059 is a promising candidate with great potential and safety profile for cancer immunotherapy.

Citation Format: Xiao Feng, Dawei Sun, Suofu Qin, Lei Jin, Tao Wang, Hongbo Yan. Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-198.
Abstract LB-210: An enhanced tumor evolution model for colorectal cancer evolution
Authors: Yang Lixing
Published: August 2019

The classical genetic model of colorectal cancer presents somatic APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of somatic genome alterations such as genomic rearrangements are still unclear. Here, we performed detailed analysis of somatic genetic alterations, including point mutations, copy number alterations and genomic rearrangements, in 63 whole-genome sequenced colorectal cancers from the Cancer Genome Atlas Research Network. The relative order of these alterations occurring during tumorigenesis was inferred from variant allele fractions. We found that driver point mutations, gene fusions, and arm level copy losses typically arise early. Copy-neutral loss of heterozygosity is often a two-step event: a deletion followed by a duplication. Different mechanisms act in different genomic regions to optimize the DNA dosage. Chromothripsis, clustered genomic rearrangements previously thought to occur as a single catastrophic event, is frequent and may occur multiple times independently in the same tumor through different mechanisms. In contrast to recent studies reporting neutral growth of tumors, selection is often present on subclones. Our results suggest that different evolutionary models can operate in a single tumor at different stages. Combining these results, we present a refined tumor progression model for human colorectal cancer. Our enhanced genetic model significantly expands our understanding of tumorigenesis process.

Citation Format: Lixing Yang. An enhanced tumor evolution model for colorectal cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-210.
Abstract LB-238: Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients
Authors: Liu Xiaohe , Ao Zheng , Preiss Jordan S. , Neal Joel , Zhou Lisa Ya , Sambucetti Lidia , Wakelee Heather A.
Published: August 2019

Early detection and intervention are crucial for long-term survival of either primary or recurrent lung cancer patients. Circulating tumor cells (CTCs) could be powerful biomarkers for the diagnosis, prognosis, and treatment planning of cancer. In this work we applied our FAST cytometer, a fiber-optic array scanning technology (FAST) to develop a sensitive diagnostic blood tests (“liquid biopsies”) for NSCLC. This technology is based on the ultra-rapid, sensitive and accurate detection of rare circulating cells expressing the biomarker(s) of interest. By applying the FAST cytometer with a unique NSCLC specific cocktail, we were able to detect CTC in NSCLC setting with higher sensitivity as compared with traditional cytokeratin-based detection. In a pilot cohort of 51 NSCLS patients, we have detected CTC in 74.2% using our unique panel for NSCLC CTC, this has raised our sensitivity from 48.8% using traditional cytokeratin-based detection. In addition, we have also interrogated circulating cancer associated fibroblasts (cCAF) as an additional liquid biopsy marker for NSCLC. We detected cCAF in 67% NSCLC patients. When combined with our enhanced CTC detection method, addition of cCAF further increased our sensitivity to 88.5%. Moreover, using clinically validated PD-L1 antibody (Ventana SP263) as reference, we have demonstrated our capacity to analyze PD-L1 expression on CTC at protein level, we have shown detection of PD-L1+ CTC in 80% of the patients. To summarize, we have developed an unique panel to detect CTC with higher sensitivity using combinational detection and we have demonstrated that by combining CTC detection with cCAF detection, liquid biopsy sensitivity for cancer detection can be further increased without significant increase in false positive rates. Lastly, we developed a method to analyze the PD-L1 expression on CTC using clinically validated Ventana PD-L1 (SP263) rabbit monoclonal antibody as reference which can potentially serve as a companion diagnostics tool for NSCLC immunotherapy

Citation Format: Xiaohe Liu, Zheng Ao, Jordan S. Preiss, Joel Neal, Lisa Ya Zhou, Lidia Sambucetti, Heather A. Wakelee. Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-238.
Abstract LB-259: FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition
Authors: Hao Huaixiang , Lu Hengyu , Liu Chen , LaMarche Matthew , Engelman Jeffrey A. , Hammerman Peter S. , Caponigro Giordano
Published: August 2019

Introduction: The non-receptor protein tyrosine phosphatase SHP2 mediates RAS activation downstream of various receptor tyrosine kinases (RTKs). Cancer cell lines dependent on RTK signaling are generally sensitive to SHP2 genetic knockdown but differ widely in their sensitivity to allosteric SHP2 inhibitors such as SHP099. A recent report suggested that FGFR can drive resistance to MAPK inhibitors independently of SHP2. We sought to understand the molecular basis of differential sensitivity to allosteric SHP2 inhibitors when SHP2 is activated by different RTKs, particularly FGFR versus EGFR.

Experimental procedures: We profiled a panel of cancer cell lines driven by various wild-type FGFR activation (receptor amplification or autocrine ligand mediated) for their sensitivity to SHP099 and characterized MAPK pathway inhibition at various time points and SHP099 doses, in comparison with EGFR-driven cell lines. We also compared the inhibitory effects of SHP099 on FGFR- and EGFR-mediated pathway feedback activation in response to MEK inhibitor treatment.

Results: We find FGFR-driven cell lines are often more resistant to SHP099 compared to EGFR-driven cell lines. Those SHP099-resistant FGFR-driven cell lines were sensitive to SHP2 knockdown and SHP099 inhibited p-ERK in those cells at earlier time points. However, p-ERK quickly rebounded after SHP099 treatment, which was not observed with FGFR inhibitors and can be attenuated with high concentrations of SHP099. Consistently, FGFR-driven MAPK pathway feedback activation following treatment with MEK inhibitor was also more resistant to SHP099 compared to EGFR-driven feedback activation. Additional studies are being performed in isogenic cell lines for direct comparison.

Conclusions: Our findings suggest that many FGFR-driven cell lines are dependent on SHP2 but are intrinsically resistant to allosteric SHP2 inhibition, compared to EGFR-driven cell lines. FGFR-driven cells tend to have a quick p-ERK rebound following initial pathway inhibition by SHP099, which is mediated by the feedback activation of FGFR. The feedback activated FGFR likely efficiently promotes the open conformation of SHP2 and causes resistance to allosteric SHP2 inhibitors. For certain FGFR-driven cancers, SHP2 inhibitor combinations such as with MAPK inhibitors might be needed for sustained efficacy.

Citation Format: Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro. FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-259.
Abstract LB-311: Exosomal gain-of-function p53 protein promotes cancer-associated phenotype
Authors: Ma Shaolin , McGuire Michael H. , Stur Elaine , Bayraktar Emine , Villar-Prados Alejandro , Wu Sherry Y. , Yokoi Akira , Dasari Santosh K. , Rodriguez-Aguayo Cristian , Liu Jinsong , Lopez-Berestein Gabriel , Sood Anil K.
Published: August 2019

TP53 is the most commonly mutated gene in cancer. Certain mutations can produce gain-of-function (GOF) phenotypes, resulting in pathogenic effects beyond the loss of p53 function. Recent study suggested that tumor cells could affect the p53 status of stromal cells while the mechanisms remains unclear. Exosomes have emerged as an important mode of extracellular communication and a major player in cancer pathogenesis, by promoting pro-tumor microenvironment. We hypothesized that packaging of mutated p53 protein into exosomes and dissemination via exosomes could impact a variety of stromal cell processes, producing a pro-tumorigenic microenvironment. In this study, we carried out a series of in vitro (immunoblot analysis, Q-PCR, Gene array, Co-Immunoprecipitation and lentiviral transfection) and in vivo (subcutaneous mouse models) experiments to determine the presence of mutant p53 in exosomes and its biological significance in tumor microenvironment. We demonstrated that gain-of-function (GOF) p53 protein is packaged into p53 mutant cancer cell-derived exosomes and transferred to fibroblasts. Further studies showed that this process is facilitated by the enhanced stability and consequent intracellular concentration of GOF p53. The packaging of GOF p53 into exosomes is selectively bound by HSP90 chaperone proteins. Inhibition of HSP90 blocks the packaging of GOF p53, but not wild-type into exosomes. Uptake of GOF p53-containing exosomes by fibroblasts results in conversion to a cancer-associated phenotype. In vivo study have shown that GOF p53 exosomes-induced cancer-associated fibroblasts promote tumor growth in a colon cancer cells (HT29 cells) xenograft mouse model. These findings reveal a crucial role of exosomes in modifying tumor microenvironment and hold great consequence in broadening our understanding of tumor biology.

Citation Format: Shaolin Ma, Michael H. McGuire, Elaine Stur, Emine Bayraktar, Alejandro Villar-Prados, Sherry Y. Wu, Akira Yokoi, Santosh K. Dasari, Cristian Rodriguez-Aguayo, Jinsong Liu, Gabriel Lopez-Berestein, Anil K. Sood. Exosomal gain-of-function p53 protein promotes cancer-associated phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-311.
Abstract LB-312: Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency
Authors: Werner-Klein Melanie , Grujovic Ana , Obradovic Milan , Hoffmann Martin , Lu Xin , Kirsch Stefan , Treitschke Steffi , Köstler Cäcilia , Weidele Kathrin , Irlbeck Christoph , Botteron Catherine , Werno Christian , Polzer Bernhard , Guzvic Miodrag , Buchholz Stefan , Rümmele Petra , Heine Norbert , Rose-John Stefan , Klein Christoph A.
Published: August 2019

While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous.

Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-312.
Abstract LB-314: Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1
Authors: Suh Jinyoung , Kim Do-Hee , Na Hye-Kyung , Surh Young-Joon
Published: August 2019

Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin (α-SMA) and fibroblast activating protein. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through crosstalk with them. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. We found the increased expression of α-SMA in human breast tumor tissues compared with normal adjacent tissues. In particular, α-SMA was highly expressed in the most of estrogen receptor (ER)-negative tumor tissues. When ER-negative breast cancer MDA-MB-231 cells and MDA-MB-468 cells were treated with the CAF-conditioned medium (CM), the cell viability was significantly elevated. In addition, MDA-MB-231 cells exhibited elevated expression of proliferative and invasive genes when incubated with CAFs. Notably, fibroblast growth factor-2 (FGF2) expression was correlated with the presence of CAFs. We noticed that mRNA level of FGF2 in CAFs as well as the concentration of FGF2 in CAF-CM was higher than that in normal fibroblasts. FGF2 exerts its biological effects by binding to FGF receptor 1 (FGFR1). In the breast cancer tissue microarray, 42% ER-negative patients co-expressed FGF2 and FGFR1 proteins, whereas only 19% ER-positive patients co-expressed those proteins. While the expression of FGFR1 was up-regulated in breast cancer cells, another major FGF2-corresponding receptor FGFR2 was barely expressed.This prompted us to explore FGF2-FGFR1 signaling in the context of paracrine communication. CAF-stimulated MDA-MB-231 cell migration and invasion as well as FGFR1 signaling activation were abolished when FGF2-neutralizing antibody was added to the CAF-CM. In a xenograft mouse model, co-injection of shmock-MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, which suggests that stromal-derived FGF2 enhances tumor formation through activation of FGFR1 in cancer cells. Furthermore, FGF2 promotes nuclear localization of FGFR1 which might be associated with cancer cell proliferation and migration. In conclusion, secretion of FGF2 by CAFs stimulates proliferation and migration of breast cancer cells through interaction with FGFR1 which may contribute to human breast cancer progression.

Citation Format: Jinyoung Suh, Do-Hee Kim, Hye-Kyung Na, Young-Joon Surh. Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-314.
Abstract LB-317: Use of in vivo microdialysis to evaluate biomarker levels in the tumor and tumor free flank of freely-moving PDX mice
Authors: Heins Mariette , Weichert Loreen , Gorynia Sabine , Flik Gunnar , Rassoulpour Arash
Published: August 2019

The tumor microenvironment (TME) constitutes unique surroundings where cancer cells communicate with one another and with the host immune system by releasing a multitude of factors. Information about the physiological state of the TME can help in gaining a broader understanding of cancer biology and developing novel cancer therapeutics. Previous work has demonstrated the ability to use in vivo microdialysis to monitor the release of adenosine and its metabolites from murine cancer models. To further these findings, we used in vivo microdialysis to measure biomarkers in the patient-derived xenograft (PDX) cancer model. By using human tumor tissue models, we aim to bridge the gap between rodent models and human tumors to help develop better cancer therapeutics.

The current set of studies used microdialysis in different PDX lines representing human tumor models (provided by CRL DRS Freiburg). Xenograft growth was monitored and upon a tumor volume > 400 mm3, the animals underwent surgical implantation of microdialysis probes in the tumor and the tumor-free flank. The implanted probes were perfused with dialysate fluid and samples from the both flanks were continuously collected over several hours. Levels of ATP, inosine and kynurenine metabolites were quantified by EIA or LC-MS/MS analysis.

Analysis of microdialysate samples from tumor and tumor-free flank demonstrated differences in analyte levels between the two sampling sites within one animal indicating that the levels of ATP and metabolites measured in PDX tumors is unique to the tumor microenvironment. In addition, the various PDX models showed differences in biomarker levels between the different tumor types. There is a wide range of biomarkers which are important indicators of energy consumption and provide an insight in the differences in metabolic activity between the different xenografts. Moreover, these data demonstrate that microdialysis can be used to test targeted therapies and follow relevant biomarker levels over time. Thereby, providing better insight in effects of new therapeutic treatments within the patient specific tumor tissue itself.

Citation Format: Mariette Heins, Loreen Weichert, Sabine Gorynia, Gunnar Flik, Arash Rassoulpour. Use of in vivo microdialysis to evaluate biomarker levels in the tumor and tumor free flank of freely-moving PDX mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-317.
Abstract PL04-02: HIV malignancies: From despair to gene therapy
Authors: Noy Ariela
Published: August 2019

HIV antiretroviral therapy has dramatically decreased the relative risk of HIV associated cancer. Nonetheless, the longevity of people living with HIV and the ongoing exposure to a variety of interconnected risk factors results in an increased life time risk of cancer compared with the general population. This includes AIDS defining and non-AIDS defining cancers. Risks increase during breaks in antiviral therapy and reinforce the recommendation that patients should avoid breaks in therapy. The non-HIV factors which interplay in carcinogenesis include immune dysregulation, immunosuppression, viral co-infections, and lifestyle habits that are more prevalent among people living with HIV. In this lecture we will explore these issues as they relate to non-Hodgkin lymphoma, Hodgkin lymphoma, Kaposi sarcoma, anal and cervical cancer, lung cancer and hepatocellular carcinoma. We will outline fundamental principles of therapy with an emphasis on the much-improved prognosis compared to the era before antiviral therapy. We will explore some of the current research questions including the incorporation of lentivirus vectors carrying anti-HIV genes into hematopoietic stem cells. We will also review the impact of anti-HIV bias on cancer clinical trials and the response of the American Society of Clinical Oncology to broaden eligibility in those trials. The approach to cancer in HIV infected patients has evolved dramatically since the recognition of AIDS and patients can now benefit from more definitive approaches to malignancy with far superior outcomes.

Citation Format: Ariela Noy. HIV malignancies: From despair to gene therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL04-02.
Abstract SY19-01: Metabolic consequences and liabilities of TCA cycle truncation in cancer
Authors: Gottlieb Eyal
Published: August 2019

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes while SDH is also part of the respiratory chain. Despite their key housekeeping activities, the genetic loss of FH or of any of the SDH subunits is associated with susceptibility to cancers. SDH or FH inactivation leads to the accumulation of metabolites which cause the activation of hypoxia-inducible factors and the inhibition of histone and DNA demethylases, establishing pseudohypoxic and hypermethylator phenotype. However, surviving the loss of these essential metabolic enzymes requires a significant metabolic adaptation as backup mechanisms for the dysfunctional TCA cycle and oxidative phosphorylation in these tumors. Identifying these adaptations would reveal effective and specific metabolic vulnerabilities which can serve as potential molecular targets for therapeutic intervention. We have identified in the past a few metabolic essentialities in cells deficient in FH and SDH and now performed a pharmacologic phenotypic synthetic lethal screen to identified effective drugs that specifically kill SDH- and FH-deficient cells. Utilizing metabolomics, we have delineated the molecular target of the effective compounds.

Citation Format: Eyal Gottlieb. Metabolic consequences and liabilities of TCA cycle truncation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY19-01.
Abstract SY20-01: Linking epigenetics, metabolism, and cancer: Lessons from SIRT6
Authors: Mostoslavsky Raul
Published: August 2019

In recent years, chromatin regulators have emerged as key modulators in cancer. These factors could work as both tumor suppressors and oncogenes, providing plasticity to cancer cells as they adapt to overcome the host responses. In recent years, we discovered that the mammalian histone deacetylase SIRT6 is a key chromatin factor, modulating expression of metabolic, developmental, and ribosomal protein genes. In recent studies, we identified a loss of function mutation in SIRT6 behind a human syndrome of perinatal lethality. In the context of cancer, we found SIRT6 to act as a robust tumor suppressor, by modulating glucose metabolism. As Otto Warburg described decades ago, cancer cells exhibit glycolytic metabolism, where pyruvate, instead of contributing to ATP production in the mitochondria, is converted to lactate even under normoxia conditions. We found SIRT6 as the first chromatin factor in charge of suppressing the Warburg effect in colon cancer. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic and ribosomal genes, co-repressing Hif1a and Myc, respectively, and acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase to specifically inhibit transcriptional elongation in these genes. Strikingly, we determined in new studies that such glycolytic switch provides an advantage even at the early initiating cancer stem cells stage, in what we identified as the cell-of-origin for the Warburg effect. In addition, we found SIRT6 to act as a robust tumor suppressor in the context of pancreatic cancer. However, in this case, SIRT6 did not influence metabolism, but rather silenced expression of the developmental gene Lin28b, in this way protecting against aggressive undifferentiated pancreatic adenocarcinoma. Our studies highlight the important role epigenetic factors, such as SIRT6, play in protecting against tumor progression by providing “epigenetic plasticity”, inhibiting adaptive responses in transformed cells.

References

1. Zhong, L., et al., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293.

2. Sebastian, C., et al. and Mostoslavsky, R. (2012). The Histone Deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199.

3. Kugel., et al. and Mostoslavsky, R. (2016). SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell, 165, 1401-1415. Ferrer et al.

4. Mostoslavsky, R. (2018). An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & Dev. 32, 373-388

Citation Format: Raul Mostoslavsky. Linking epigenetics, metabolism, and cancer: Lessons from SIRT6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY20-01.
Abstract SY21-01: Analyzing tumor metabolism in patients
Authors: Deberardinis Ralph J.
Published: August 2019

Metabolism is dynamic and responds to a wide range of cell-intrinsic and cell-extrinsic factors. Many human diseases involve perturbations of metabolism at the cellular level, and in many cases normalizing the metabolic state has proven to be therapeutically valuable. Cancer is one such disease, in which factors both intrinsic and extrinsic to the malignant cell impact tumor biology and disease progression. In cancer, cell-intrinsic influences on metabolism include somatically-acquired mutations in oncogenes and tumor suppressor genes, many of which regulate metabolic activity. Cell-extrinsic factors include nutrient access, which may become limiting due to inadequate vasculature and intense fuel utilization, and metabolic interactions with stromal and immune cells. A major challenge in cancer metabolism research is to understand how these various factors culminate in the metabolic phenotype of an intact tumor, and ultimately to identify which altered pathways represent potential therapeutic targets. Among the many metabolic pathways reprogrammed in cancer, nucleotide metabolism and responses to DNA damage are highly integrated with aberrant signaling and gene regulatory networks in cancer. We have taken two parallel approaches to understand metabolic complexity and identify potential therapeutic liabilities in human cancer. The first uses a combination of multi-parametric imaging and intraoperative stable isotope infusions to assess metabolic fluxes in patients with solid tumors, and to compare fluxes between tumors and adjacent tissue. Genomic, histological and metabolic analysis of tumor samples allows us to correlate various intrinsic and extrinsic factors to specific aspects of the metabolic phenotype. The second approach uses standardized culture conditions to assess cell-intrinsic heterogeneity of metabolic preferences and dependencies in large panels of human cancer cell lines. This approach has uncovered liabilities associated with specific molecular subtypes of non-small cell and small cell lung cancerm ncluding several related to nucleotide and nucleic acid metabolism. I will discuss the application of these approaches to metabolic heterogeneity in human cancer, with an emphasis on features relevant to intact tumors and therapeutic liabilities and the role of metabolic imaging in studying cancer metabolism.

Citation Format: Ralph J. Deberardinis. Analyzing tumor metabolism in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY21-01.
Abstract SY28-03: Extending the paradigm of hormonal dependency of cancer to account for effects of lifestyle on risk and prognosis
Authors: Pollak Michael N.
Published: August 2019

Cancer behavior is determined by cancer metabolism. Abnormalities in cancer cell metabolism are determined in part by intrinsic or autonomous characteristics of each cancer cell, which relate to in part to genetic alterations in oncogenes and cancer suppressor genes, and in part to host effects, which are mediated in large part by hormones and growth factors. Dietary and lifestyle factors that influence cancer risk or cancer prognosis influence levels of hormones such as insulin. We now recognize that these hormones influence the behavior of a subset of common cancers. Attempts to treat cancer by altering the hormonal milieu related to gonadal steroids have led to many widely used treatments for cancer of the breast and prostate, but it remains uncertain if this paradigm can be extended to lifestyle and nutritionally regulated hormones such as insulin, which have been found to be growth-stimulatory in certain preclinical models. We will review these concepts, including recent laboratory and clinical data related to metformin, an anti-diabetic drug under study for possible anti-neoplastic activity.

Citation Format: Michael N. Pollak. Extending the paradigm of hormonal dependency of cancer to account for effects of lifestyle on risk and prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY28-03.
Abstract SY30-01: A wrinkle in TiME: How the aging TME drives tumor progression
Authors: Weeraratna Ashani T.
Published: August 2019

Most cancers arise after the age of 50, and the molecular mechanisms that underlie this observation are not well understood. Our overarching goal is to elucidate and target the age-related changes that drive tumor progression. We have made the seminal discovery that aged fibroblasts secrete, or stop secreting, key molecules that affect multiple aspects of tumorigenesis. Our current investigations include: the loss of molecules that maintain ECM integrity, resulting in changes in mechanotransduction and increased metastasis; the secretion of molecules that increase resistance to targeted therapy; the secretion of macromolecules such as lipids that are taken up by melanoma cells in the aged microenvironment, affecting tumor cell metabolism; changes in the aged immune tumor microenvironment; the secretion of non-canonical Wnt molecules that affect cell signaling leading to angiogenesis, metastasis, and therapy resistance. Overall, our studies indicate that the age of the mouse models we study, as well as the patients we treat must be considered in order to understand tumor progression and therapy resistance.

Citation Format: Ashani T. Weeraratna. A wrinkle in TiME: How the aging TME drives tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY30-01.
Abstract SY40-02: YAP/TAZ activity as hallmark of cancer: Biologic properties, upstream regulations, and downstream targets
Authors: Piccolo Stefano
Published: August 2019

Enhanced YAP/TAZ activity is emerging as common trait of multiple solid tumors in humans. Strikingly, in mouse models, adult organs lacking YAP/TAZ are unable to develop tumors without overt side effects for normal tissue homeostasis, making YAP/TAZ prime candidates for cancer therapy. That said, YAP/TAZ have physiological functions during tissue repair, being essential for organ regeneration after injury. YAP/TAZ are typically inactive in normal tissues but potently induced by mechanical and physical cues that the cell receives from its microenvironment, such as extracellular matrix stiffness and topology, and 3D architectural features of the tissue. I will focus on new discoveries on the mechanisms by which YAP/TAZ are controlled by mechanotransduction, and on YAP/TAZ as reprogramming factors in epithelial cells. Indeed, in normal tissues YAP/TAZ activation turns more differentiated normal cells into cells endowed with stem-like properties; in tumors, YAP/TAZ convert non-stem tumor cells into cancer-stem cells, increasing tumor aggressiveness and fueling metastasis. I will also expand on these mechanisms, providing new hints for therapeutic intervention.

Citation Format: Stefano Piccolo. YAP/TAZ activity as hallmark of cancer: Biologic properties, upstream regulations, and downstream targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY40-02.
Statin Treatment and Prognosis of Elderly Patients Discharged after Non-ST Segment Elevation Acute Coronary Syndrome
Authors: Vicent Lourdes , Ariza-Solé Albert , Díez-Villanueva Pablo , Alegre Oriol , Sanchís Juan , López-Palop Ramón , Formiga Francesc , González-Salvado Violeta , Bueno Héctor , Marín Francisco , Llibre Cinta , Llaó Isaac , Vidán María T. , Abu-Assi Emad , Aboal Jaime , Martínez-Sellés Manuel
Published: August 2019

Background: Statins are recommended for secondary prevention. Our aims were to describe the proportion of very elderly patients receiving statins after non-ST segment elevation acute coronary syndrome (NST-ACS) and to determine the prognostic implications of statins use. Methods: This prospective registry was performed in 44 hospitals that included patients ≥80 years discharged after a NST-ACS from April 2016 to September 2016. Results: We included 523 patients, the mean age was 84.2 ± 4.0 years and 200 patients (38.2%) were women. Previous statin treatment was recorded in 282 patients (53.4%), and 135 (32.5%) had LDL cholesterol levels >2.6 mmol/L. Mean LDL cholesterol levels during admission were 2.3 ± 0.9 mmol/L. Statins were prescribed at discharge to 474 patients (90.6%). Compared with patients discharged on statins, those that did not receive statins were more often frail (22 [47.8%] vs. 114 [24.4%], p < 0.01) and underwent an invasive approach less frequently (30 [61.2%] vs. 374 [78.9%], p = 0.01). During a 6-month follow-up, 50 patients died (9.5%). There was a nonsignificant trend to higher mortality in patients not treated with statins (6 [15%] vs. 44 [9.6%], p = 0.30), but statins were not independently associated with lower mortality (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.30–2.11, p = 0.65), nor with a reduction in the combined endpoint mortality/hospitalizations (HR 0.89; 95% CI 0.52–1.55, p = 0.69). Conclusions: Although most octogenarians presenting a NST-ACS are already on statins before the episode, their LDL cholesterol is frequently >2.6 mmol/L. Octogenarians who do not receive statins have a high-risk profile, with significant frailty and comorbidity.
The Relationship between Age-Related Hearing Loss and Cognitive Disorder
Authors: Dong Sung Hwa , Park Jung Min , Kwon Oh Eun , Kim Sang Hoon , Yeo Seung Geun
Published: August 2019

Background: Although the rates of occurrence of age-related diseases, including presbycusis and cognitive disorders, have increased with an increase in the geriatric population, the relationship between these two conditions remains unclear. Objective: To investigate the association between presbycusis and cognitive disorder. Subjects and Methods: A retrospective review of patient medical records was conducted at a single tertiary university hospital. This study enrolled 399 patients aged ≥65 years who were prescribed hearing aids for the chief complaint of hearing loss. For main outcomes and measures we used audiograms, the Korean Mini-Mental State Examination, and the Global Deterioration Scale (GDS). Results: Of the 399 patients who were prescribed hearing aids for presbycusis, 45 (11.3%) had dementia and 354 (88.7%) did not have dementia. When the cognitive disorder group was divided into mild (1–4) and severe (5–7) subgroups based on the GDS scores, the threshold of hearing loss was significantly higher in the severe group than in the mild group (p < 0.05). The prevalence of dementia was significantly higher in patients with hearing loss for ≥10 years than in patients with hearing loss for <10 years (p < 0.05). Conclusion: Presbycusis and cognitive disorder are correlated. More severe and prolonged hearing loss is associated with a higher prevalence of cognitive disorder.
Aligning Lung Function Equipment and Reference Values in Adults
Authors: Verbanck Sylvia , Schuermans Daniel , Thompson Bruce R. , Vanderhelst Eef
Published: August 2019

Background: When introducing new equipment or reference equations into the lung function laboratory, systematic z-score deviations could arise due to local differences in population or equipment. Objective: To propose a workable method for aligning reference equations with lung function equipment. Method: Using two cases of equipment transition in our laboratory as a test case, we first performed lung function testing after the transition, on a control group of 40 normal young adults (20 male/20 female; 20–30 years old). For those indices with an average z-score in excess of ±0.5, adapted reference values were obtained by an offset or scaling factor on the M coefficient with the so-called lambda-mu-sigma (LMS) method recommended by the Global Lung Function Initiative, and the z-scores were computed again. Results: Following a transition involving instrumental dead space reduction, the lung clearance index was predictably reduced, resulting in a mean (±SD) z-score of –1.9 (±1.1) in the control group; by adapting the reference values with an offset on M, the z-score became –0.1 (±1.1). Applying the same method to a transition of standard lung function equipment, the z-scores became centered around zero in the control group, but also became properly aligned in a test group of 81 other subjects spanning a wider age range (20–80 years). Conclusions: We proposed and verified a method for aligning local equipment with reference values obtained elsewhere, or following a local change in equipment. The key is to measure a relatively small young adult group, identifying those lung function indices that need adaptation based on z-scores, in order to then obtain laboratory-specific reference values that can be applied over the entire age range.
Audiovestibular Phenotypes and Advanced Magnetic Resonance Imaging Features of Cochlin Gene Mutation Carriers
Authors: Conte Giorgio , Lo Russo Francesco , Caschera Luca , Zanetti Diego , Castorina Pierangela , Sina Clara , Triulzi Fabio , Di Berardino Federica
Published: August 2019

Objective: To describe clinical and imaging findings in a group of patients affected by nonsyndromic deafness A9 (DFNA9), using advanced magnetic resonance imaging (MRI) with 3-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) sequence. Method: A retrospective case review was conducted in a tertiary referral center in Italy. Four sequential adult DFNA9-affected patients, who had undergone MRI at our Department between January 2017 and June 2018, were enrolled (male = 2, female = 2; median age: 65.6 years; 8 diseased ears analyzed). Three patients were relatives; the fourth was unrelated. The main outcome measures – age, sex, records of audiological and vestibular testing, genetic assessment, MRI findings – were analyzed. Results: All subjects suffered from bilateral progressive sensorineural hearing loss, more severely at the high frequencies and with a typical clinical pattern of bilateral chronic degenerative cochleovestibular deficit. Aural fullness was reported at the onset of the disease. All patients revealed a pathogenic heterozygous mutation in the Limulus factor C, Coch-5b2 and Lgl1 domain of cochlin. None of the patients showed a significant vestibular and cochlear endolymphatic hydrops at MRI, while high bilateral contrast enhancement on 4-h delayed postcontrast 3D FLAIR sequence was observed in all ears. Conclusions: Increased perilymph enhancement on 4-h delayed postcontrast 3D FLAIR sequence is the common imaging feature of DFNA9 ears, suggesting that blood-labyrinthine barrier breakdown may play the main role in the pathophysiology of this disease. Significant hydrops has been excluded by MRI. This finding might be clinically useful in differentiating DFNA9 disease from other pathologies with similar clinical findings like Ménière’s disease.
Pulmonary Embolism and Gas Exchange
Authors: Fernandes Caio J. , Luppino Assad Ana Paula , Alves-Jr Jose L. , Jardim Carlos , de Souza Rogerio
Published: August 2019

Acute pulmonary embolism (PE) impairs hemodynamics, gas exchange, and lung mechanical capacity. Considering PE pathophysiology, most attention has been paid to hemodynamic impairment. However, the most prevalent symptoms in PE patients come from gas exchange alterations, which have not been in the spotlight for many years. Pulmonary physiology and consequent gas exchange impairment play a pivotal role in the high risk of death from PE. In this review, we will look at the pathophysiology of PE, from the vascular occlusion to the resultant heterogeneity in pulmonary perfusion and gas exchange impairment, discussing in detail its causes and consequences.
What Makes Soteria Work? On the Effect of a Therapeutic Milieu on Self-Disturbances in the Schizophrenia Syndrome
Authors: Nischk Daniel , Rusch Johannes
Published: August 2019

Soteria represents an alternative approach to the treatment of acute psychosis providing a community-based social milieu, personal relationships (“being-with”), and meaningful shared activities (“doing-with”) along with minimal neuroleptic medication. In this review article, we analyze Soteria’s potential to adapt to and restore self-disturbances, a central element of phenomenological conceptions of the schizophrenia syndrome. Based on typical difficulties of psychotic patients in responding adequately to situational demands, in relating to others, and in utilizing skills, we analyze how the architectural and social context, being-with, and doing-with take account of self-disturbances. The central elements of the Soteria approach all appear to carry the potential to adjust to self-disturbances and even offer opportunities for their relief. We suggest that it is precisely this property of the Soteria paradigm that induces sustained relaxation in patients, allowing for symptom relief, thereby specifying a central claim of “affect-logic” to explain the antipsychotic effect of Soteria.
Provider Attitudes toward the Use of Hepatitis C Virus-Positive Organs in Kidney Transplantation
Authors: Couri Thomas , Katz Joshua , Stoeckle Kate , Nugooru Aishwarya , Yeh Heidi , Chung Raymond , Paul Sonali
Published: August 2019

Background: Direct-acting antivirals have changed the landscape of hepatitis C virus (HCV) care. While transplantation with HCV-positive donor organs is increasing, little is known about providers’ attitudes toward this topic. The aim of this study is to determine providers’ attitudes toward HCV-positive kidney transplantation. Methods: Willing transplant and nontransplant nephrologists, transplant surgeons, and mid-level providers completed an online survey from April through May 2018. The survey asked about HCV knowledge and willingness to transplant HCV-positive antibody, nucleic acid testing-positive kidneys into HCV-negative recipients. Descriptive analyses including mean and median for continuous variables and frequencies for categorical variables were calculated. Results: Seven-hundred surveys were emailed and 99 providers (62 transplant nephrologists, 28 nontransplant nephrologists, 7 transplant surgeons, and 2 advanced practice providers) completed the survey (participation rate 14.1%). All providers knew that HCV was curable, with 60% believing that it had no effect on transplant success and 32% thinking it reduced transplant success. Providers were significantly more likely to offer a HCV-positive organ to HCV-positive recipients compared to HCV-negative recipients in all queried circumstances (p < 0.005 in all cases), especially with increasing impact on patient’s quality of life. While only 39% of providers would offer a HCV-positive organ for transplant to a patient without HCV if it reduced the waitlist time by 1 year, 92% would offer a HCV-positive organ if it reduced the waitlist time by 4 years. However, only 47% thought that the use of HCV-positive kidneys should be for routine care, while 38% believed it should be reserved for research purposes only. There were no significant differences between transplant and nontransplant nephrologists in attitudes toward HCV-positive kidney transplantation. Providers believed that donor organs from those who were obese, >50 years old, or had died from a cardiac arrest were significantly more likely to reduce the likelihood of a successful transplant 1-year posttransplant when compared with a HCV-positive organ (p < 0.005 in all cases). Eighty-six percent of providers had concerns about HCV curability posttransplant. Conclusion: Although 92% of providers were willing to offer a HCV-positive kidney for transplant as patient waitlist time increases, less than half supported offering HCV-positive transplantation for routine care rather than for research. The results underscore the need for further education and data about the efficacy and safety of HCV-positive kidney transplantation.