tbuckley/cabot-search huggingface dataset:
Abstract 5093: Fibulin-5 supports pancreatic tumor growth through inhibition of integrin-induced ROS
Authors: Mary Topalovski, Miao Wang, Zachary Moore, David Boothman, Rolf Brekken
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a highly recalcitrant disease. One factor contributing to chemoresistance is thought to be the desmoplastic response seen in these tumors. Fibronectin (FN) is a major constituent of the desmoplastic reaction of PDA. It has been shown that integrin activation by fibronectin can induce reactive oxygen species (ROS) production by stromal cells. Increased ROS has been observed in many cancers, including PDA. Therefore, we propose that oxidation therapy is an attractive approach to increase chemoresponse in PDA as this strategy takes advantage of the sensitivity of these tumors to further ROS insults. We discovered that the matricellular protein Fibulin5 (Fbln5) is upregulated in PDA and reduces FN-mediated integrin-induced ROS production by competing with FN for binding to α5β1 integrin and blocking integrin-induced ROS production. Mutation of the RGD-integrin binding domain in Fbln5 to RGE abolishes the binding of Fbln5 to the integrin and increases integrin-induced ROS production. Fbln5RGE/RGE (RGE) mice, display reduced tumor growth in implant and genetic models of PDA (KIC and KPC) as a direct consequence of elevated ROS levels in the tumor microenvironment. Furthermore, ROS induction correlates with reduced angiogenesis in tumors from RGE animals and had an additive therapeutic effect when combined with standard therapy. We have identified multiple oxidative stress-responsive genes that are elevated in stromal fibroblasts isolated from tumors from RGE animals. One of the most promising targets is NAD(P)H dehydrogenase (quinone 1) (Nqo1). In support of this observation we found that the level of Nqo1 is significantly higher in RGE fibroblasts compared with WT fibroblasts when plated on FN but not collagen or plastic. Furthermore we have demonstrated that FN-mediated induction of ROS and Nqo1 is dependent on β1 integrin and 5-lipooxygenase (5-LOX). Our studies reveal a unique integrin-based mechanism to enhance ROS production to a level that is specifically toxic to the tumor by exploiting the tumor-specific expression of Fbln5. Current studies are focused on understanding the mechanism by which Fbln5 is induced in PDA. Citation Format: Mary Topalovski, Miao Wang, Zachary Moore, David Boothman, Rolf Brekken. Fibulin-5 supports pancreatic tumor growth through inhibition of integrin-induced ROS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5093.
Abstract 101: Identification of pancreatobilliary cancer specific fusion genes in patient tissues
Authors: Kahee Kim, Dawoon E. Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song
Journal: Cancer Research (2016)

Abstract Gene fusion occurs when a part of one gene fuses with or attaches to a part of another gene by genome rearrangement and the result in gene fusion may possess oncogenic properties; fused gene may be translated into a unique protein that may promotes cancer properties. Pancreatic cancer and bile duct cancer are one of the most lethal cancer types with low 5-year survival rates, but lack of proper diagnostic or prognostic markers. Our aim was to investigate pancreatobilliary- specific fusion genes found in patient's specimens. We used TRIzol to extract total RNA from seven pancreatic cancer tissues and normal tissues from the same patients, and five bile duct cancer tissues and normal tissues from the same patients. Total RNA was assessed for RNA sequencing and the result data was analyzed using ChimeraScan to detect gene fusion. To identify the cancer somatic fusion gene, the fusion occurred in normal tissues and previously reported fusion genes found in normal tissues were excluded and the fusion occurred in coding region was included. As a result, we found 87 pancreatic cancer tissue specific- and 52 bile duct cancer tissue specific- fusion genes. We then selected fusion genes that either one of the gene has been reported to express in cancer tissues. We confirmed the expression of selected fusion genes by RT-PCR in cancer and normal tissues as well as in cancer cell lines. As a result we observed novel pancreatobilliary cancer specific fusion genes. These findings indicate the presence of novel fusion genes as well as its possible application for the early diagnosis or prognosis of pancreatic and bile duct cancer. Citation Format: Kahee Kim, Dawoon E. Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song. Identification of pancreatobilliary cancer specific fusion genes in patient tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 101.
Abstract 2369: Molecular profile of a GM-CSF overexpressing breast cancer whole-cell vaccine with systemic anti-tumor activity
Authors: Markus Daniel Lacher, Charles L. Wiseman, Joseph Wagner
Journal: Cancer Research (2016)

Abstract BACKGROUND AND PURPOSE OF STUDY: The allogeneic whole-cell cancer vaccine BriaVax(TM) (formerly SV-BR-1-GM) is an ER/PR negative, HER2/neu positive breast cancer cell line (SV-BR-1) we engineered to stably overexpress GM-CSF. BriaVax, rendered proliferation incompetent by irradiation, has thus far been applied to 4 advanced stage cancer patients (3 subjects with breast cancer, 1 subject with ovarian cancer). One breast cancer subject responded to BriaVax with complete remission of a measurable lung lesion and near complete remission of multiple breast lesions after only 3 inoculations. Nevertheless, she relapsed 3 months after completing the protocol, with brain metastases as well as multiple breast lesions. We obtained FDA permission to resume vaccinations, and, upon doing so, all metastatic sites responded with a prompt tumor regression after only 3 inoculations. To prospectively identify patients with a high likelihood of benefiting from BriaVax therapy we began a program to identify molecular factors of diagnostic potential. Here, we describe a gene expression signature that might both be informative about BriaVax’ mechanism of action and helpful for developing diagnostic or monitoring biomarkers. METHODS: To prospectively identify patients with tumors responsive to BriaVax we began a molecular analysis of both the BriaVax cell line and cells obtained from the special clinical responder's blood. BriaVax gene expression profiles were obtained through Illumina BeadArray and NanoString nCounter technologies and compared to gene expression data sets publically available through the Gene Expression Omnibus (GEO; National Center for Biotechnology Information) portal. RESULTS: BriaVax expresses a gene signature consistent with a mechanism of action involving not only the activation of cytotoxic T cells but also the induction of a humoral response. In addition, BriaVax expresses known cancer antigens. Notably, blood-derived cells of the special clinical responder expressed genes complementing BriaVax’ gene expression signature, thus possibly explaining the unusually prompt and robust clinical response to BriaVax. CONCLUSIONS: Our findings suggest that BriaVax exerts its therapeutic effects via multiple modes. We identified both candidate immunogens overexpressed in BriaVax compared to normal breast cells and unraveled a potential mechanism of action explaining the encouraging clinical response observed. Citation Format: Markus Daniel Lacher, Charles L. Wiseman, Joseph Wagner. Molecular profile of a GM-CSF overexpressing breast cancer whole-cell vaccine with systemic anti-tumor activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2369.
Abstract 3369: Tumor-microenvironment-dependent imprinting of endothelial cells in human colorectal carcinoma
Authors: Michael Stürzl, Andrea Liebl, Vera S. Schellerer, Manuela Schütz, Patrick Kölbel, Ute Schaal, Lisa Haep, Ludger Klein-Hitpass, Timan T. Rau, Barbara Dietel, Valerie Meniel, Alan R. Clarke, Susanne Merkel, Roland S. Croner, Werner Hohenberger, Elisabeth Naschberger
Journal: Cancer Research (2016)

Abstract The tumor microenvironment (TME) and tumor cell heterogeneity contribute significantly to tumor pathogenesis. In contrast, potential stromal cell heterogeneity induced by the TME and its impact on human tumorigenesis has not been conclusively investigated. Therefore, pure tumor endothelial cells (TECs) from human colorectal carcinomas (CRCs) with differential TMEs (favorable Th1-TME and worse control-TME) were isolated and significantly different gene clusters reflecting the tumorigenic and angiogenic impact attributed to the respective TMEs were identified by transcriptome analysis. SPARCL1 - the most strongly upregulated gene in Th1-TME-derived TECs - was analyzed to prove this concept. SPARCL1 was expressed by endothelial cells (EC) in colon tissues, most prominently in mature normal vessels, similarly in CRC with Th1-TME and lost towards more aggressive and angiogenic control tumors. SPARCL1 was induced in confluent, quiescent EC in culture but absent or resolved in angiogenically active EC. SPARCL1 inhibited proliferation, migration and sprouting of cultivated EC in vitro. In human CRC tissues SPARCL1 expressing vessels were highly covered by mural cells and of larger vessel size (perimeter and area), indicting more progressed maturation. Similarly the vessels in the colon of wild type mice as compared to SPARCL1/Sc1 knockout mice exhibited a more mature vessel structure. In conclusion, exploiting cellular memory processes we demonstrated TME-dependent intratumoral TEC heterogeneity in CRC and identified SPARCL1 as novel EC-derived protein regulating vessel maturation and homeostasis. Citation Format: Michael Stürzl, Andrea Liebl, Vera S. Schellerer, Manuela Schütz, Patrick Kölbel, Ute Schaal, Lisa Haep, Ludger Klein-Hitpass, Timan T. Rau, Barbara Dietel, Valerie Meniel, Alan R. Clarke, Susanne Merkel, Roland S. Croner, Werner Hohenberger, Elisabeth Naschberger. Tumor-microenvironment-dependent imprinting of endothelial cells in human colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3369.
An individualized dose/schedule strategy for sunitinib in metastatic renal cell cancer (mRCC) on progression-free survival (PFS): Correlation with dynamic microbubble ultrasound (DCE-US) data.
Authors: B. Khalil, J. M. Hudson, R. Williams, B. Lloyd, L. M. Milot, M. Atri, A. Kiss, P. Burns, G. A. Bjarnason
Journal: Journal of Clinical Oncology (2011)

e15149 Background: Sunitinib area under the curve (AUC) correlates with response and PFS (Houk et al). Current recommendations for dose modification do not take this into account. Methods: A single center retrospective review identified mRCC patients (pts) where individualized (individ) sunitinib dose/schedule modifications (DSM) were used to maximize dose and minimize time off therapy (Rx). Pts were started on 50mg 28 days (d) on/14d off. DSM were done to keep toxicity (fatigue, skin, GI) at ≤ grade-2. DSM-1 was 50mg 14d/7d with individ increases in d on Rx based on toxicity. DSM-2 was 50mg 7d/7d with individ increases in d on Rx. DSM-3 was 37.5mg continuously with individ 7d breaks. DSM-4 was 25mg continuously with individ 7d breaks. Results: In 172 pts; median age was 60y; 20% good, 60% intermediate, 20% poor prognosis by Heng criteria; 80% had nephrectomy; 79% clear cell histology; 60% were previously untreated. At a median follow-up of 12.9 months (mo), overall median PFS was 8.9 mo. All 20 pts still on therapy are on a DSM Rx. Pts were allocated to three groups based on the dose/schedule used for the longest time. The PFS/response% (PR+SD) for each group was 4.9 mo/64.1% (standard 50mg 28d/14d; 39 pts), 10.4 mo/77.5% (DSM-1/DSM-2; 71pts) and 11.9 mo/82.3% (DSM-3/DSM-4; 62 pts) with improved PFS (p=0.0002) in both DSM groups vs. the standard schedule but no difference in response. In 20 responding pts studied by DCE-US at baseline, and after 7d and 14d on Rx or after 14d and 28d on Rx, tumor blood volume decreased at d7 and again at d14 vs. baseline but was stable or increased at d28 vs. d14. A rebound was seen after 14d off Rx. Conclusions: Based on the US data, previous pharmacokinetic data (steady state at 10-14d) and this clinical data, starting pts on 50mg 14d/7d followed by individ DSM may be safe and active. This DSM strategy was associated with a favorable toxicity profile, apparent improvement in PFS and a good PR+SD rate in a group of unselected mRCC pts, warranting confirmation in a prospective trial. Pts that tolerate 50mg 28d/14d with minimum toxicity may need dose escalation and/or less time off therapy to optimize PFS.
Abstract 4882: Megabase-scale phased haplotypes of genetic aberrations from whole cancer genome sequencing of primary colorectal tumors
Authors: Billy Lau, John M. Bell, Michael Schnall-Levin, Mirna Jarosz, Erik Hopmans, Christina M. Wood, Grace X. Zheng, Kristina Giorda, Hanlee P. Ji
Journal: Cancer Research (2015)

Abstract Cancer genomes contain multiple types of genetic aberrations that include mutations, deletions, copy number variants and chromosomal rearrangements. Despite advances in next generation sequencing, it remains a major challenge to delineate many of these somatic genomic alterations because of intrinsic complexity of cancer genomes. Haplotyping involves the assignment of genetic variants such as mutations and structural variants to specific segment of homologous chromosomes. Experimentally determined phasing of cancer genomes offers an opportunity to resolve complex genomic structures such as somatic rearrangements, aneuploidy composition and ongoing evolutionary changes. However, contiguous phasing of cancer genomes on a megabase (Mb) scale remains difficult to achieve with sequencing-based approaches. In this proof-of-concept study, we experimentally determined Mb-scale haplotypes of primary tumor samples via whole genome sequencing. To generate haplotypes, we employed an automated instrument that partitions long DNA fragments into hundreds of thousands of reactions, each of which incorporates a unique, nonrandom barcode into indexed sequencing libraries. Given need to amplify from sparse numbers of molecules and the high efficiency of the automated sequencing library construction process, the DNA requirements for each sample are less than 5 ng. We sequenced the genomes of primary colorectal cancer samples and their matched normal diploid DNA with an Illumina sequencer. We used the single nucleotide variants to generate Mb-scale haplotype blocks (N50 of 1.2 Mb) with phased haplotype block size of up to 11.3 Mb. We were able to delineate cancer genome haplotypes that cover allelic imbalances, copy number variations such as deletions and other genomic instability events. Structural variants were identified in the context of their position in specific chromosome homologues. Thus, we improved the characterization of somatic genetic aberrations using contiguity mapping and cancer genome haplotypes in the context of whole cancer genome sequencing. Overall, we demonstrated the feasibility and potential utility of conducting contiguous phased haplotypes in whole cancer genome sequencing from primary tumor samples. Citation Format: Billy Lau, John M. Bell, Michael Schnall-Levin, Mirna Jarosz, Erik Hopmans, Christina M. Wood, Grace X. Zheng, Kristina Giorda, Hanlee P. Ji. Megabase-scale phased haplotypes of genetic aberrations from whole cancer genome sequencing of primary colorectal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4882. doi:10.1158/1538-7445.AM2015-4882
Overcoming mTOR resistance: Results of a phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat.
Authors: Elizabeth R. Plimack, Yu-Ning Wong, Lois Malizzia, Alycia Corrigan, Anthony J. Olszanski, Crystal Shereen Denlinger, Susan Roethke, Colleen H. Tetzlaff, Gary R. Hudes
Journal: Journal of Clinical Oncology (2014)

501 Background: Elevation of pAKT levels has been shown to result from mTOR inhibition. We hypothesized that the HDAC inhibitor Vorinostat (Vori) would abrogate Ridaforolimus (Rida) resistance due to downregulation pAKT when used in combination in renal cell carcinoma (RCC). Methods: The primary objective was to determine the MTD most applicable to RCC patients (pts), thus while all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. There was no limit to the number of prior targeted or immunotherapies. ECOG PS 0-1 and adequate organ and marrow function were required. A modified 3+3 dose escalation design tested 2 dose levels concurrently by escalating each drug in separate cohorts. Rida was dosed days 1-5 weekly, Vori days 1-3 weekly. Results: 15 pts (10 clear cell RCC, 3 papillary RCC, 1 esophageal, 1 carcinoid) were treated at one of 3 dose levels: 1) Rida 20mg QD + Vori 100mg BID, 2) Rida 20 mg QD + Vori 200 mg BID, 3) Rida 40 mg QD + Vori 100 mg BID. Inability to complete 80% of doses during cycle 1 due to thrombocytopenia resulted in DLTs in 2/6 pts in dose level 2. There were no other DLTs and no grade 4-5 toxicities. Related grade 3 toxicities were: hyperglycemia (1), anemia (2), fatigue (1), and mucositis (1). Grade 2 pneumonitis was seen in 2 pts. The MTD was Rida 20mg QD + Vori 100mg BID, however all 7 pts who received &gt;2 cycles ultimately required dose reduction to Rida 10-20 mg QD + Vori 100 mg QD, for thrombocytopenia in 6/7 cases. Thus the recommended phase II dose to allow for chronic dosing is Rida 20mg QD + Vori 100mg QD. Four pts, all with RCC, maintained stable disease for 19, 21, 31+ and 59+ weeks. Of these, 3 had progressed on prior temsirolimus or everolimus including the 2 pts with ongoing disease control at the time of data cutoff (31+ and 59+ weeks), both of whom have papillary RCC. Conclusions: Rida 20mg QD + Vori 100 mg QD is the recommended phase II dose for this combination. Prolonged disease control was seen in 4/13 RCC pts, 3 of whom progressed on prior a prior mTOR inhibitor. Further study of combined mTOR and HDAC inhibition in RCC with tumor sampling to assess for pharmacodynamics and proof of concept is warranted to further define the toxicity, efficacy and mechanism of this combination. Clinical trial information: NCT01169532.
Pharmacokinetics (PK) and pharmacodynamics (PD) of midostaurin (PKC412) in patients with acute myeloid leukemia (AML)
Authors: O. Yin, Y. Wang, C. Lanza, T. Schimansky, S. Balez, H. F. Schran, R. M. Stone
Journal: Journal of Clinical Oncology (2008)

7064 Background: Midostaurin (N-benzoylstaurosporin) is a novel potent inhibitor of class III receptor tyrosine kinases, including FLT3 and c-KIT. We evaluated the PK and PD of midostaurin in a phase I/II clinical trial in patients with AML. Methods: Midostaurin was administered at 75 mg tid to 20 patients with FLT3-mutated (FLT3mut) AML. A second cohort of 95 patients with either wild-type (FLT3WT) (n=60) or FLT3mut (n=35) AML was randomized to receive midostaurin at 50 mg bid or 100 mg bid. Plasma concentrations of midostaurin and its two active metabolites (CGP62221 and CGP52421) were determined by an LC-MS-MS method, and peripheral blood blasts were measured to determine PD responses. Patients were classified into PD groups based on their blast responses: (1) stable responders who had at least a ≥50% decrease in blood blasts and did not relapse during the entire treatment period; (2) partial responders who initially showed a ≥50% decrease in blood blasts but later relapsed; (3) non-responders who failed to show a ≥50% decrease in blood blasts. Results: Midostaurin showed biological activity in both FLT3mut and FLT3WT patients, with 80% of patients responding (stable or partial blast responders) in the FLT3mut cohort receiving 75 mg tid, and 38% of FLT3WT and 66% of FLT3mut patients responding in the second cohort. Trough plasma concentrations of midostaurin and its metabolites reached stable levels after one cycle (28 days) of treatment in all dosing regimens. Midostaurin exposure was dose proportional between 50 mg bid and 75 mg tid, but less than proportional comparing 50 mg bid and 100 mg bid doses. The mean trough plasma concentrations of CGP62221 and CGP52421 were approximately 1.2–2.3 times and 5.2–13.9 times that of midostaurin. The trough plasma concentrations of midostaurin, CGP62221 and CGP52421 were higher in stable blast responders (3.8, 3.7 and 21.2 μM) than partial blast responders (1.7, 2.6 and 14.6 μM) or non-responders (0.8, 1.5 and 14.4 μM). Conclusions: PK-PD analysis suggests a correlation between plasma concentrations of midostaurin/metabolites and blood blast response, indicating an appropriate plasma exposure of midostaurin is needed to achieve and maintain biological response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharma SAS, Novartis Pharmaceuticals Corporation Novartis Pharma SAS, Novartis Pharmaceuticals Corporation Novartis Pharma SAS, Novartis Pharmaceuticals Corporation
Abstract 360: Detecting intracellular bRAF/cRAF dimerization using a novel luminescent complementation system
Authors: Richard L. Somberg, Marie K. Schwinn, Michael R. Slater, Thomas Machleidt, Mei Cong, Keith V. Wood
Journal: Cancer Research (2016)

Abstract BRAF mutations can promote constitutive activation of MEK/ERK signaling, leading to unregulated cell proliferation and tumorigenesis. Although inhibitors targeting oncogenic BRAF have shown promise in preventing cell growth, these same inhibitors can paradoxically activate signaling by inducing BRAF interaction with CRAF. Methods for monitoring this undesired outcome are typically low throughput or use kinase binding domains modified with a membrane targeting sequence. We sought to develop a cell-based assay that could reliably detect dimerization of full-length BRAF/CRAF and could potentially be used to rapidly screen inhibitors for modulation of this interaction. To achieve this objective, we utilized a NanoLuc luciferase-based complementation reporter consisting of 1.3 kD (SmBiT) and 18 kD (LgBiT) fusion tags that reconstitute an active luciferase when brought into proximity. In this optimally configured BRAF/CRAF assay, BRAF-LgBiT and CRAF-SmBiT fusions are stably expressed in mammalian cells, and luminescence, indicative of protein interaction, is monitored using a live cell detection reagent. With this assay, we were able to observe rapid and dose-dependent induction of BRAF/CRAF dimerization in response to a panel of kinase inhibitors. The sensitivity and robustness of the assay permitted reliable screening in both 96- and 384-well formats (Z’ factors &amp;gt; 0.9 and 0.6, respectively). Furthermore, the brightness of the reporter allowed the assay to be monitored in individual cells using bioluminescence imaging. These results suggest this BRAF/CRAF complementation assay can enable rapid, high-throughput profiling of kinase inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway. Citation Format: Richard L. Somberg, Marie K. Schwinn, Michael R. Slater, Thomas Machleidt, Mei Cong, Keith V. Wood. Detecting intracellular bRAF/cRAF dimerization using a novel luminescent complementation system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 360.