tbuckley/cabot-search huggingface dataset:
Abstract 1719: Copper levels and the p53 protein: A delicate balance
Authors: Patricia Muller, Yannick von Grabowiecki, Callum Hall
Journal: Cancer Research (2019)

Abstract The tumor suppressor p53 is mutated in 50% of all cancers and in about 90% of small lung cancers. Mutations lead to loss of p53 expression or the expression of mutant p53 proteins. These mutants often lose WT function, but they have also been shown to acquire invasive and metastatic functions. p53 requires a zinc molecule in its core domain to fold properly and to function as a transcription factor and tumor suppressor. Loss of this zinc through competition with copper causes p53 to unfold and to lose its transcription function. Copper is an essential heavy metal required for a large variety of biological processes as it is required for the function of many enzymes. In cancer patients, increased serum levels of copper have been found and people with a predisposition for copper accumulation in the liver (Wilson’s disease, mutations in ATP7B) are prone to develop liver cancers. Our preliminary results have indicated that an unfolded WT p53 molecule does not only lose its transcription function, but also gains mutant p53-like functions in promoting invasion. Copper-induced unfolded p53 interacted with the mutant p53 specific interacting proteins Dicer, Ago, p63 and p73 and impaired p63 function. These results raise the question as to why a WT molecule would lose its function and whether it perhaps could act as a redox sensor. Experiments are ongoing to explore p53 mediated transcription in response to copper exposure. In addition, we are setting up mouse models to investigate p53 folding in vivo in response to mild increases in copper serum levels and we are developing methods to better determine p53 folding in patients and in mice. These results will help us assess p53 status in relation to serum metal levels in vivo and determine whether p53 is important in the development of cancers and metastasis. Citation Format: Patricia Muller, Yannick von Grabowiecki, Callum Hall. Copper levels and the p53 protein: A delicate balance [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 1719.
Abstract 527: High-dimensional profiling of the systemic immune response informs on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB)
Authors: Kevin L. Chua, Michael Fehlings, Pek Lim Chu, Xiao-Tian Lin, Eugenia Yeo, Kar Perng Low, Dennis Poon, Enya Ong, Wai Yee Woo, Joseph Wee, Alessandra Nardin, Gopalakrishna Iyer, Daniel S. Tan, Kee Chee Soo, Evan Newell, Melvin Chua
Journal: Cancer Research (2019)

Abstract Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB. Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N=10). All patients received ablative RT (8-50Gy/1-5fr) for oligoprogression and/ or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools. Results: Median follow-up of the overall cohort was 18mo; median duration of ICB received in the ICB-RT-ICB arm was 15mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/ effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P&amp;lt;0.01). This clinical phenomenon corresponded to an increased %Ki67high CD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P&amp;lt;0.01). Deeper immunophenotyping of the Ki67high subsets revealed associated high expression of GranzymeB and Eomes. Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB. Citation Format: Kevin L. Chua, Michael Fehlings, Pek Lim Chu, Xiao-Tian Lin, Eugenia Yeo, Kar Perng Low, Dennis Poon, Enya Ong, Wai Yee Woo, Joseph Wee, Alessandra Nardin, Gopalakrishna Iyer, Daniel S. Tan, Kee Chee Soo, Evan Newell, Melvin Chua. High-dimensional profiling of the systemic immune response informs on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB) [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 527.
Abstract 1792: Exploring new therapeutic options for chemoresistant locally advanced lung cancer
Authors: Roberto Cuttano, Elisa Dama, Valentina Melocchi, Tommaso Colangelo, Cristiano Carbonelli, Giorgia Maroni, Elena Levantini, Fabrizio Bianchi
Journal: Cancer Research (2019)

Abstract Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. About one third of NSCLC patients present at diagnosis with locally advanced disease (stage IIIA) which are characterized by lymph node metastases. For this group of patients, neoadjuvant chemotherapy (NACT) followed by surgery is the best therapeutic option. However, clinical response to NACT is heterogeneous including patients with a complete eradication of lymph node metastases (pN0), and patients with persistent disease (pN2). Of note, 'pN0' patients showed a favourable prognosis (~50-60% survival, at 5-year) when compared to 'pN2' patients (~20-30% survival, at 5-year). Methods: To identify new molecular determinants involved in NACT response, we recently performed whole-microRNA expression profiling of metastatic lung tumor cells, which were collected from mediastinal lymph nodes before NACT either by endobronchial ultrasound transbronchial aspiration (EBUS-TBNA) (n=11) or mediastinoscopy (n=41). In addition, we performed a meta-analysis of a cohort (n=84) of NSCLC (i.e. The Cancer Genome Atlas LUAD and LUSC dataset) with complete follow-up. Results: We found a set of 20 miRNAs significantly differentially expressed in pN2 vs. pN0 tumors. Hierarchical clustering analysis using this 20-miRNA set revealed a clear separation of pN0 patients from pN2 patients. However, when the 20-miRNA set was used in the primary NSCLCs from TCGA dataset, the chemoresponsive and chemoresistant tumors could not be stratified. This possibly suggests unique properties of this 20-miRNA set and their modulated target genes in metastatic cells, and in the acquisition of a chemoresistant phenotype. Furthermore, by coupling miRNA and mRNA expression profile in metastatic samples, we rewired i) cancer intrinsic gene networks with a role in chemotherapy resistance, and ii) an augmented infiltration of tumor promoting immune cell populations (TILs). Conclusions: Lung cancer metastases are intrinsically distinct and there exist molecular subtypes with different NACT response, identifiable by miRNA expression profile. Future efforts will be directed to identify the landscape of molecular mechanisms mediated by miRNAs, including the modulation of TILs possibly involved in the acquired chemoresistance. Citation Format: Roberto Cuttano, Elisa Dama, Valentina Melocchi, Tommaso Colangelo, Cristiano Carbonelli, Giorgia Maroni, Elena Levantini, Fabrizio Bianchi. Exploring new therapeutic options for chemoresistant locally advanced lung 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 1792.
Abstract 3971: MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma.
Authors: Amanda N. Ruggieri, Matthew R. Farren, Mark Yarchoan, Nilofer S. Azad, Lauren Dennison, Bassel El-Reyes, Gregory B. Lesinski
Journal: Cancer Research (2019)

Abstract Cholangiocarcinoma (CC) is a rare but aggressive cancer of the bile ducts with a five-year survival rate of only 2% in patients with metastatic disease. MAP kinase signaling is important in the pathogenesis of CC and serves as a key regulator of cell proliferation and survival. Our data indicate this pathway is constitutively active in several CC cell lines and accompanied by production of immunomodulatory cytokines including IL-6, MCP-1 and GM-CSF. Cobimetinib is a potent and selective inhibitor of MEK that has been utilized clinically in patients with advanced CC. Although MEK inhibitors (MEKi) have been studied in a variety of solid tumors, the mechanisms by which they act upon CC cells are not completely defined. These agents have modest single agent activity in CC, and their impact in combination with immunotherapy is under active investigation. We hypothesized that MEKi can modulate cytokine and chemokine expression from CC tumors, thereby complementing immunotherapy in this aggressive disease. Using a novel panel of human CC cell lines, we demonstrated a variable impact of cobimetinib on in vitro cell proliferation, with a reduction in viability no greater than 35%. However, MEKi reproducibly limited cytokine (GM-CSF and IL-1β) and chemokine (MIP-1α) production from human CC cell lines in vitro. The ability of cobimetinib to limit MAPK signal transduction in these cells was confirmed via immunoblot. These data complement prior published observations by Ebert et al.in 2016 indicating that single agent MEKi is sufficient to elicit T cell infiltration into tumors. We have completed enrollment of a Phase II clinical trial (NCT03201458) evaluating the efficacy of cobimetinib in combination with the PD-L1 inhibitor, atezolizumab. An extensive series of correlative studies are underway in peripheral blood and tumor biopsies to examine the impact of cobimetinib on modulating cytokine and chemokine signatures in the context of PD-L1 targeted therapy. These data will provide new insight into the impact of MEK inhibitors as a complement to immunotherapy in a disease that is refractory to most conventional therapies. Citation Format: Amanda N. Ruggieri, Matthew R. Farren, Mark Yarchoan, Nilofer S. Azad, Lauren Dennison, Bassel El-Reyes, Gregory B. Lesinski. MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma. [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 3971.
Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer
Authors: Christopher H. Lieu, Erica A. Golemis, Ilya G. Serebriiskii, Justin Newberg, Amanda Hemmerich, Caitlin Connelly, Wells A. Messersmith, Cathy Eng, S. Gail Eckhardt, Garrett Frampton, Matthew Cooke, Joshua E. Meyer
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer. Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established. Results: Overall genomic alteration rates in the younger (&amp;lt;40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR &amp;lt; 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR &amp;lt; 0.01), KRAS (FDR &amp;lt; 0.01), BRAF (FDR &amp;lt; 0.01), and FAM123B (FDR &amp;lt; 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR &amp;lt; 0.01), BRAF (FDR &amp;lt; 0.01), and KRAS (FDR &amp;lt; 0.01). Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.
Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Kerry Anne Rogers, Philip A. Thompson, John Nathan Allan, Morton Coleman, Jeff Porter Sharman, Bruce D. Cheson, Raquel Izumi, Melanie M. Frigault, Cheng Seok Quah, Rakesh K. Raman, Min Hui Wang, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2019)

7530 Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range &lt;1-55); common AEs that led to IBR discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%) and rash (12%). At a median follow-up of 19 mo (range 1-31), 67% of pts remain on acalabrutinib; discontinuations were mostly due to PD (13%) and AEs (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common AEs (any grade) were diarrhea (48%), headache (40%), contusion (35%) and dizziness (32%). Serious AEs (≥2 pts) were pneumonia (10%), anemia (3%) and syncope (3%). Atrial fibrillation occurred in 3 pts (5%; all Gr 1/2) and major hemorrhage in 2 (3%; Gr 3 hematuria and Gr 2 subdural hematoma). Gr 5 AEs were pneumonia (n=2), bronchopulmonary aspergillosis (n=1) and ventricular fibrillation (n=1), all considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in IBR-intolerant pts, providing a viable strategy for continuing BTK inhibitor therapy. Clinical trial information: NCT02717611. [Table: see text]
Abstract 388: Functional Role of Inositol 1,4,5-Trisphosphate Receptors in Cardiac Hypertrophy
Authors: Martha Iveth Garcia
Journal: Circulation Research (2016)

Calcium is a second messenger that is essential for the control of a variety of cellular functions. In the heart, calcium plays an integral role in many cellular processes including energy metabolism, contraction, gene expression, and cell death. The inositol 1,4,5-trisphosphate receptor (IP 3 R) is a calcium channel that is ubiquitously expressed throughout the body. There are three IP 3 R isoforms encoded by separate genes. In the heart, the IP 3 R-2 isoform is reported to being most predominant with regards to both expression levels and functional significance. Several groups have shown that perinuclear IP 3 R-2 may play a key role in the progression of hypertrophy by mediating nuclear calcium release in response to endothelin-1 (ET-1) and angiotensin II. However, the functional roles of IP 3 R-1 and IP 3 R-3 in the heart are essentially unexplored despite measureable expression levels. We hypothesize that all three IP 3 R isoforms can contribute to cytosolic calcium transients and cardiac stress induced by ET-1. As our model we used dissociated neonatal and adult rat ventricular cardiomyocytes. We found readily detectable levels of expression of all three IP 3 Rs in both neonatal and adult rat ventricular cardiomyocytes. We found that in addition to the perinuclear area, all three IP 3 R isoforms were expressed throughout the cardiomyocyte including the sarcoplasmic reticulum. Using isoform specific siRNA, we found that knocking down individual IP 3 Rs did not alter ET-1 induced calcium responses in neonatal cardiomyocytes. However, knocking down all three isoforms abolished the effects of ET-1 on calcium homeostasis. We next tested whether IP 3 Rs mediate nuclear-specific calcium elevations. Using a genetically encoded calcium indicator targeted to the nucleus we were able to specifically discriminate nuclear versus cytosolic calcium transients after ET-1 treatment. Contrary to previous reports, we found no evidence that IP 3 R-mediated calcium release is confined to the nucleus. Our findings that IP 3 R isoforms are functionally redundant in the heart have significant implications for animal models of hypertrophy and human disease.
Pre-clinical investigation of the synergy effect of interleukin-12 gene-electro-transfer during partially irreversible electropermeabilization against melanoma
Authors: Lise Pasquet, Elisabeth Bellard, Sophie Chabot, Bostjan Markelc, Marie-Pierre Rols, Justin Teissie, Muriel Golzio
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Melanoma is a very aggressive skin tumor that can be cured when diagnosed and treated in its early stages. However, at the time of identification, the tumor is frequently in a metastatic stage. Intensive research is currently ongoing to improve the efficacy of the immune system in eliminating cancer cells. One approach is to boost the activation of cytotoxic T cells by IL-12 cytokine that plays a central role in the activation of the immune system. In parallel, physical methods such as electropermeabilization-based treatments are currently under investigation and show promising results. <h3>Methods</h3> In this study, we set electrical parameters to induce a partial-irreversible electropermeabilization (pIRE) of melanoma to induce a sufficient cell death and potential release of tumor antigens able to activate immune cells. This protocol mimics the situation where irreversible electropermeabilization is not fully completed. Then, a peritumoral plasmid IL-12 electrotransfer was combined with pIRE treatment. Evaluation of the tumor growth and survival was performed in mouse strains having a different immunological background (C57Bl/6 (WT), nude and C57Bl6 (TLR9−/−)). <h3>Results</h3> pIRE treatment induced apoptotic cell death and a temporary tumor growth delay in all mouse strains. In C57Bl/6 mice, we showed that peritumoral plasmid IL-12 electrotransfer combined with tumor pIRE treatment induced tumor regression correlating with a local secretion of IL-12 and IFN-γ. This combined treatment induced a growth delay of distant tumors and prevented the emergence of a second tumor in 50% of immunocompetent mice. <h3>Conclusions</h3> The combination of pIL-12 GET and pIRE not only enhanced survival but could bring a curative effect in wild type mice. This two-step treatment, named Immune-Gene Electro-Therapy (IGET), led to a systemic activation of the adaptive immune system and the development of an anti-tumor immune memory.
Abstract 1128: Metastasis suppressor RKIP modulates gene expression variance in triple negative breast cancer
Authors: Dongbo Yang, Sebastian Pott, Marsha Rosner
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with a highly metastatic phenotype. Conventional chemotherapy and radiotherapy are generally ineffective at treating metastasis. Natural metastasis suppressors such as the Raf kinase inhibitory protein (RKIP) are not functional in many TNBC cases and associated with poorer relapse-free survival. Although tumor cell heterogeneity is strongly implicated in contributing to metastasis, it is unknown whether metastasis suppression by RKIP reduces heterogeneity. Therefore, we performed single-cell RNA sequencing of mouse TNBC tumors as well as cultured cells to study the effect of RKIP overexpression on gene expression variance in tumor cells. Elucidating RKIP’s effect on gene expression variance at the single cell level reveals gene sets that are important in tumor cell transitions from non-metastatic to metastatic states. We predict that the gene sets whose variance is decreased by RKIP are effective drug targets for metastatic breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Dongbo Yang, Sebastian Pott, Marsha Rosner. Metastasis suppressor RKIP modulates gene expression variance in triple negative breast 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 1128.
Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population
Authors: Jonathan P. Piccini, William T. Abraham, Christopher Dufton, Ian A. Carroll, Jeff S. Healey, Dirk J. van Veldhuisen, William H. Sauer, Inder S. Anand, Michel White, Stephen B. Wilton, Ryan Aleong, Michiel Rienstra, Steven K. Krueger, Felix Ayala-Paredes, Yaariv Khaykin, Bela Merkely, Vladimir Miloradović, Jerzy K. Wranicz, Leonard Ilkhanoff, Paul D. Ziegler, Gordon Davis, Laura L. Emery, Debra Marshall, David P. Kao, Michael R. Bristow, Stuart J. Connolly
Journal: JACC Heart Failure (2019)