tbuckley/cabot-search huggingface dataset:
Abstract 1601: Genetic and epigenetic intratumor heterogeneity of lung adenocarcinoma
Authors: Wei Zhao, Xing Hua, Tongwu Zhang, Dario Consonni, Angela Cecilia Pesatori, Jianxin Shi, Maria Teresa Landi
Journal: Cancer Research (2019)

Abstract Genomic studies have revealed remarkable intratumoral heterogeneity (ITH) in lung adenocarcinoma (LUAD) and increasing evidence suggests its impact in cancer treatment. However, to what extent epigenomic abnormalities and somatic copy number alterations (SCNAs) are involved in shaping genetic clones in lung tumors and are associated with clinical outcome is under-appreciated. Here we applied Infinium HumanMethylation450K BeadChips, Infinium Global Screening Arrays and ultra-deep (&amp;gt;500X) targeted sequencing of 35 LUAD driver genes to 369 samples (including 77 normal tissues) from 84 LUAD patients to investigate the genetic and epigenetic architecture of subclonal diversification. SCNAs were mostly clonal events. For patients with more than three tumor regions assayed, 66% SCNAs were located on the trunk of the evolutionary trees. Similar evolutionary trajectories were inferred from SCNAs and DNA methylation. The driver genes’ sequencing depth allowed to identify subclonality even in TP53, EGFR, and BRAF mutations, which were largely reported as clonal events in previous studies. Elevated copy number ITH was associated with higher risk of death, while no significant association was found between clinical outcome and DNA methylation ITH or heterogeneous CpG island methylator phenotype (CIMP), in contrast with the observed prognostic capability of DNA methylation ITH in hematological malignancies. These findings expand our understanding of the coevolution of genetic and epigenetic aberrations in tumorigenesis, the subclonal complexity for therapeutic targets and the implication of ITH in cancer prognosis. Citation Format: Wei Zhao, Xing Hua, Tongwu Zhang, Dario Consonni, Angela Cecilia Pesatori, Jianxin Shi, Maria Teresa Landi. Genetic and epigenetic intratumor heterogeneity of lung adenocarcinoma [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 1601.
Abstract 14290: Genetic Deficiency of Anti-aging Gene Klotho Impairs Vascular Endothelial Function and Causes Arterial Stiffening
Authors: Yi Lin, Zhongjie Sun
Journal: Circulation (2013)

Objective: Klotho (KL) is a recently discovered anti-aging gene. Genetic mutation of KL expedites the aging process and shortens the lifespan while overexpression of KL slows down the aging process...
Baseline high-sensitivity C-reactive protein to predict progression-free survival in metastatic renal cell carcinoma patients treated with first-line sunitinib.
Authors: Ryuichi Mizuno, Go Kimura, Tsunenori Kondo, Takeshi Ueda, Hidehiko Hara, Takeshi Kishida, Haruki Kume, Sunao Sohji, Takashi Hatano, Jun Morita, Nozomu Kawata, Kazuhiro Matsumoto, Masaru Ishida, Shunji Takahashi, Kazunari Tanabe, Hayakazu Nakazawa, Shigeo Horie, Mototsugu Oya
Journal: Journal of Clinical Oncology (2013)

e15527 Background: Predicting the efficacy of tyrosine kinase inhibitors (TKI) would be of clinical value in patients with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that serum inflammatory markers are associated with clinical outcome in mRCC patients at favorable or intermediate prognostic risk treated with first-line sunitinib. Methods: Eighty-nine mRCC patients were prospectively monitored at baseline (day 0) during sunitinib treatment. Serum interleukin-6 and 8 levels were determined by CLEIA and ELISA, respectively. A high-sensitivity C-reactive protein (hs-CRP) levels were measured using laser nephelometry. Correlations between baseline interleukin-6, 8, hs-CRP levels and response to sunitinib, and progression-free survival (PFS) were examined. Results: Median PFS was 9.2 months. Clinical benefit rate (CBR; percent complete responses+partial responses +stable disease 24 weeks) was 57.3%. Baseline interleukin-8 (P=0.0240) and hs-CRP (P=0.0060) was associated with CBR. No association between baseline interleukin-6 and 8 with PFS was observed. However, baseline hs-CRP were associated with PFS (P=0.0016; unit risk 1.010; 95% CI 1.004 to 1.017). Conclusions: Baseline serum inflammatory markers could be of clinical interest in sunitinib-treated mRCC patiens to predict outcome. Baseline hs-CRP serum levels warrant further study. Clinical trial information: UMIN000009622.
Notch-1 Inhibition Promotes Immune Regulation in Transplantation Via Regulatory T Cell–Dependent Mechanisms
Authors: Ciara N. Magee, Naoka Murakami, Thiago J. Borges, Tetsunosuke Shimizu, Kassem Safa, Shunsuke Ohori, Songjie Cai, Audrey Uffing, Jamil Azzi, Wassim Elyaman, Louis-Marie Charbonnier, Kaifeng Liu, Demet Toprak, Gary Visner, Talal A. Chatila, Christian W. Siebel, Nader Najafian, Leonardo V. Riella
Journal: Circulation (2019)

Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell-mediated immunity.We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex-mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs.We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G-treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1-treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3EGFPCreNotch1fl/fl). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) signaling.Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.
Abstract 3445: Mechanism, physiological and therapeutic implications of LGR-independent potentiation of WNT signaling by R-spondins
Authors: Andres M. Lebensohn, Rajat Rohatgi
Journal: Cancer Research (2019)

Abstract The WNT signaling pathway encodes positional information in animals, orchestrates patterning and morphogenesis during embryonic development, and promotes tissue renewal and regeneration in adults. Dysregulation of WNT signaling has been implicated in many diseases, including developmental malformations, skeletal and dental abnormalities, cardiovascular and neurodegenerative disorders, diabetes, and many types of cancer. Members of the R-spondin family of secreted growth factors have emerged as key regulators of WNT signaling strength. The R-spondin system is a vertebrate adaptation that may be related to the appearance of sophisticated stem cell compartments, which require exquisite control of WNT signaling. The four members of the family (R-spondin 1-4) can strongly potentiate responses to WNT ligands during development and in stem cells, but the mechanisms by which they transduce signals are not fully understood and the reasons why they produce different physiological effects are largely unknown. Unexpectedly, we discovered that R-spondins 2 and 3 can uniquely potentiate WNT signaling in cells lacking LGRs 4, 5 and 6, the principal R-spondin receptors. We determined the protein domains on R-spondins necessary and sufficient for this new mode of signaling, and showed that it is mediated by an alternative interaction with cell-surface heparan sulfate proteoglycans. This finding is transformative because LGRs 4-6 were thought to be required to transduce all R-spondin signals and hence determine their site of action. Indeed, these LGRs are highly expressed in many stem cell compartments whose maintenance depends on potentiation of WNT signaling by R-spondins. Instead our work shows that there are two modes of signaling by R-spondins, an LGR-dependent and an LGR-independent mode, and that different R-spondins may use distinct molecular mechanisms to transduce signals in various biological contexts. Supporting our findings, recent work from another group demonstrated that during limb development, R-spondin 2 signals through an LGR-independent mechanism. Since components of the R-spondin signaling module are commonly mutated in cancer, therapeutic targeting of LGR-independent signaling deserves evaluation. I will present the results demonstrating our conclusions and discuss their implications in physiology and disease. Citation Format: Andres M. Lebensohn, Rajat Rohatgi. Mechanism, physiological and therapeutic implications of LGR-independent potentiation of WNT signaling by R-spondins [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 3445.
Abstract 4509: Overexpression of CADM1 enhances malignant features of small-cell lung cancer
Authors: Toko Funaki, Takeshi Ito, Yoshinori Murakami
Journal: Cancer Research (2019)

Abstract Small-cell lung cancer (SCLC) is one of the representative intractable cancers with the 5-year survival of less than 10 %. Novel approaches to the treatment of SCLC are required because recurrence arises inevitably after the initial chemotherapy. CADM1 was originally identified as a tumor suppressor of non-small cell lung cancer (NSCLC) which encodes a member of immunoglobulin superfamily cell adhesion molecules. CADM1 consists of an extracellular domain with three immunoglobulin-like loops, a trans-membrane domain and a short cytoplasmic domain containing a protein 4.1-binding motif (4.1BM) and a PDZ-II-binding motif. We have reported that CADM1 is highly expressed in 90% of human SCLC cell lines and promotes subcutaneous tumor formation of SCLC cells in nude mice. In this study, we performed clinicopathological evaluation of CADM1 in SCLC and analyzed the molecular mechanisms of malignant progression of SCLC by overexpressing CADM1. Firstly, we performed immunohistochemical analysis of CADM1 expression in high-grade neuroendocrine tumor (HGNEC) of the lung, including SCLC and large cell neuroendocrine carcinoma (LCNEC). We found that CADM1 protein was expressed in 75% (33/44) of SCLC tumors and correlated with the nodal involvement in lung HGENC. To understand pathological significance of CADM1 overexpression in SCLC, we introduced a full-length CADM1 and its mutants in the extracellular or intracellular domain into SCLC cells, SBC5, lacking endogenous CADM1 expression and assessed their malignant features in comparison with control SBC5 cells. CADM1 expression significantly enhanced colony formation in soft agar and subcutaneous tumor formation in nude mice of SBC5, whereas a mutant in 4.1BM did not. Then, we screened chemical library of 170 small molecules of known function to identify compounds which inhibit anchorage-independent growth of SCLC cells enhanced by CADM1. Inhibitors of PI3K, Akt and PKA significantly suppressed cell growth of SBC5, suggesting that CADM1 activates PI3K/Akt and PKA signaling pathways through its 4.1BM and promotes anchorage-independent growth of SCLC cells. We also found that orthotopic injection of NCI-N417 cells overexpressing CADM1 into the lung of nude mice significantly enhanced their metastasis to mediastinal lymph nodes. These results suggest that CADM1 enhances tumor growth and metastasis of SCLC cells probably by activating PI3K/Akt and PKA pathways through its binding proteins at 4.1BM. Citation Format: Toko Funaki, Takeshi Ito, Yoshinori Murakami. Overexpression of CADM1 enhances malignant features of small-cell 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 4509.
A phase III study of TAS-118 plus oxaliplatin versus S-1 plus cisplatin as first-line chemotherapy in patients with advanced gastric cancer (SOLAR study)
Authors: Y. Kang, K. Chin, H. Chung, S. Kadowaki, S. Oh, N. Nakayama, K. Lee, H. Hara, I. Chung, M. Tsuda, S. Park, H. Hosaka, S. Hironaka, Y. Miyata, M. Ryu, M. Takeuchi, H. Baba, I. Hyodo, Y. Bang, N. Boku
Journal: Annals of Oncology (2019)
Endosonography-guided alteration of upper surgical anatomy to facilitate endoscopic management of biliary cast syndrome post-liver transplantation
Authors: Majidah A. Bukhari, Olaya Brewer, Yen-I Chen, Saowanee Ngamruengphong, Omid Sanaei, Payal Saxena, Mouen A. Khashab
Journal: Endoscopy (2019)

A 41-year-old woman who had undergone orthotopic liver transplantation (OLT) with Roux-en-Y reconstruction for primary sclerosing cholangitis (PSC) presented with recurrent cholangitis due to biliary cast syndrome. She had undergone a total of seven enteroscopy-assisted endoscopic retrograde cholangiopancreatographies (ERCPs) at an outside tertiary institution without successful clinical results. She was referred to our center for further management. Magnetic resonance cholangiopancreatography (MRCP) revealed an extensive burden of large intrahepatic stones ([Fig. 1 a]).
Abstract 5257: Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways
Authors: Brady G. Strittmatter, Peter Hollenhorst
Journal: Cancer Research (2019)

Abstract The TMPRSS2-ERG re-arrangement occurs in ~50% of prostate cancers and results in androgen driven aberrant expression of the transcription factor ERG. ERG acts as an oncogene in the prostate and activates a transcriptional program which results in cell migration, epithelial to mesenchymal transition, and tumorigenesis. Activation of both the Ras/ERK and PI3K/AKT signaling pathways has been demonstrated to be necessary for transcription of ERG target genes and is required for ERG mediated phenotypes in the prostate, however, the exact mechanism of this requirement is not known. Recently, our lab demonstrated that ERK1/2 phosphorylation of ERG abrogates ERG’s interaction with the co-repressor EZH2 and the PRC2 and is necessary for ERG-mediated transcription of genes involved in cell migration. It has been demonstrated that ERG also requires activation of the PI3K/AKT pathway for ERG-mediated tumorigenesis in the prostate, however how the Ras/ERK and PI3K/AKT pathways cooperate in transcription of ERG target genes and ERG mediated phenotypes is not well understood. Here we use genomic and transcriptomic approaches to demonstrate that Ras/ERK and PI3K/AKT pathway requirements for ERG function differ between distinct ERG-mediated mediated gene expression programs which correlate with distinct phenotypic outputs. Overall, our results demonstrate how the Ras/ERK and PI3K/AKT pathways contribute to ERG mediated tumorigenesis in the prostate and point the way towards new therapeutic targets. Citation Format: Brady G. Strittmatter, Peter Hollenhorst. Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways [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 5257.
The prognosis of <i>NF1</i> mutations in newly diagnosed AML: A single-center retrospective study.
Authors: Mohammad Telfah, Haitham Abdelhakim, Nicole Balmaceda, Eyad Gharaibeh, Andrew K. Godwin, Ziyan Y. Pessetto, Joseph McGuirk, Tara L. Lin
Journal: Journal of Clinical Oncology (2019)

e18525 Background: Several recurrent genetic mutations have been described in acute myeloid leukemia (AML), which have both prognostic and therapeutic implications. Recurrent mutations in the Neurofibromin 1 ( NF1) gene are reported in 1-5 % of AML patients; however, there are limited data regarding its prognostic implications. Here, we report the outcomes for patients with newly diagnosed AML with a somatic NF1 mutation at our center. Methods: A retrospective chart review included patients with newly diagnosed AML at KUMC from 01/2016 through 09/2018. All patients had targeted next-generation sequencing (NGS) at diagnosis. Baseline characteristics were compared between patients with NF1 mutations and those who were wild-type using Fisher’s exact test for categorical variables, and the Wilcoxon rank-sum test for continuous variables. The primary outcome was overall survival (OS), which was measured from the time of diagnosis to the time of death from any cause. A stepwise Cox proportional-hazard model was used to adjust for potential confounders. Results: Data on 110 patients were included. Out of the 110 patients, 15 (13.6%) had a delectable NF1 mutation, while 95 (86.4%) patients were NF1 wild-type. The baseline characteristics of the two groups are displayed below. Median OS for patients with an NF1 mutation was 7.3 months, while it was 18.4 months for patients with NF1 wild-type, Log-rank test p-value 0.02. After adjusting for potential confounders, including age, ELN risk category, induction regimen, presence of other mutations such as TP53, the hazard of death remained significantly higher for patients with NF1 mutations, HR 2.4, CI (1.05-5.6), p-value 0.04. Conclusions: In this single-center retrospective study, the presence of a NF1 mutation was associated with worse overall survival in patients with newly diagnosis AML. [Table: see text]
Abstract 20962: Under-diagnosis of Cardiac Sarcoidosis Using the Original Japanese Ministry of Health and Welfare Criteria
Authors: Amr Mohsen, Alejandro Jimenez, Timm Dickfeld, Anastasios Saliaris, Richard Kuk, Stephen Shorofsky, Magdi M Saba
Journal: Circulation (2010)

Background: Cardiac Sarcoidosis (CS) is an under-diagnosed disease with significant morbidity and mortality and is responsible for 50% of the deaths of patients (pts) with sarcoidosis. The Japanese...
Abstract 4849: CAP-100: first-in-class anti-CCR7 antibody for CLL
Authors: Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Javier Loscertales, Fernando Terron, Wim Mol
Journal: Cancer Research (2019)

Abstract The homeostatic CC-chemokine receptor 7 (CCR7) is highly expressed in many hematological malignancies including chronic lymphocytic leukemia (CLL). CCR7 surface expression levels are much higher than those of CD20, and are correlated with poor prognosis. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of CLL cells to locations where these chemokines are expressed, such as the lymph node (LN). In this protective microenvironment CCR7 ligands contribute to CLL cell survival and proliferation. Indeed, high CCR7-mediated in vitro migration of patient CLL cells correlates with LN involvement and adverse prognostic factors. Thus, strategies targeting CCR7 could provide an additional therapeutic approach for CLL. Therefore, we have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21. The antibody effectively inhibited CLL cells migration and survival. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. The antibody showed potent cell killing activity against CLL cells while preserving normal blood cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed standard-of-care in CLL, such as rituximab. ADCC and migration inhibition were both independent of prognostic markers for high risk CLL, such as TP53 mutation including 17p deletion and relapse/refractoriness to various standard therapies, including BTK-inhibitors. Finally, when given as monotherapy in disseminated NHL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition in established tumors and provided significant survival. Collectively, our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in CLL primary cells, including those from relapsed/refractory patients. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in CLL. CAP-100’s unique propensity to block migration of CLL cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100 in CLL, either as monotherapy or in combination with novel agents such as BTK-inhibitors. Clinical trials in CLL and other CCR7-expressing NHL will be initiated soon. Citation Format: Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Javier Loscertales, Fernando Terron, Wim Mol. CAP-100: first-in-class anti-CCR7 antibody for CLL [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 4849.