tbuckley/cabot-search huggingface dataset:
Toxicity and outcome of anti-GD<sub>2</sub> antibody ch14.18/CHO in front-line, high-risk patients with neuroblastoma: Final results of the phase III immunotherapy randomisation (HR-NBL1/SIOPEN trial).
Authors: Ruth Ladenstein, Ulrike Poetschger, Juliet Gray, Dominique Valteau-Couanet, Roberto Luksch, Victoria Castel, Isaac Yaniv, Genevieve Laureys, Martin Elliott, Jean Marie Michon, Cormac Owens, Toby Trahair, Godfrey Chi Fung Chan, Ellen Ruud, Henrik Schroeder, Maja Beck Popovic, Evgenia Glogova, Guenter Schreier, Hans Loibner, Holger N. Lode
Journal: Journal of Clinical Oncology (2016)

10500 Background: Dinutuximab (ch14.18/SP2/0) in combination with cytokines (IL2 and GM-CSF) resulted in a survival benefit in high risk neuroblastoma (NB) patients (2y EFS 66%±5%, A.Yu, NEJM, 2010). The role of cytokines in this context remains unclear. We investigated the role of scIL2 for immunotherapy with ch14.18/CHO in a prospective randomized Phase III clinical trial. Methods: 406 high risk NB patient (pts) (stage 4 ≥ 1y; stage 4 < 1y with MYCN amplification (MNA); stage 2,3 0-21y with MNA) were randomized (R2 of HR-NBL1/SIOPEN; APN311-302; EudraCT:2006-001489-17). Pretreatment consisted of high intensity induction followed by autologous stem cell transplantation as well as local therapy. Pts were randomized to receive immunotherapy (IT) of either 100mg/m² ch14.18/CHO (d8-12) as 5 daily 8-hour short term infusions (STI) alone (STI-A) or combined with 6x106IU/m2 scIL2 (d1-5;8-12) (STI-B) for a total of 5 cycles. All patients received 6 cycles of oral 13-cis-RA (160mg/m2,d19-32). Results: We observed 3y EFS and OS rates for 206 pts treated by STI-A of 60±4% and 66±4%. 200 pts treated by STI-B showed 3y EFS and OS rates of 57±4% and 65±4%. The difference between both arms was statistically not significant (NS). A subgroup analysis according to response to induction revealed 3y EFS rates of 68±5% and 65±5% in patients treated in CR with regimen STI-A and STI-B, respectively (NS). The 3y EFS rates in pts with VGPR or PR at the time of randomization were expectedly lower at 46±6% and 53±6% for STI-A and STI-B, respectively (NS). Toxicity analysis indicated a higher rate of early termination in STI-B (44%) compared to STI-A (18%). Lansky performance status of ≤ 30% was found in 17% of STI-A- and 39% STI-B-pts (p < 0.001). CTC-grade 3&4 allergic reactions in STI-A- and STI-B-cohorts were 9% and 20% ( < 0.001). Incidence of capillary leak and CTC-grade 3&4 fever is significantly lower in the STI-A (1% and 14%) compared to the STI-B cohort (9% and 40%). Conclusions: Outcome data of frontline patients treated with ch14.18/CHO are highly encouraging. However, survival and toxicity analysis indicated no benefit of co-treatment with scIL2 in this setting. Clinical trial information: NCT01704716.
Abstract 4908: Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells
Authors: Alfonso R. Sánchez-Paulete, Francisco J. Cueto, María Martínez-López, Sara Labiano, Aizea Morales-Kastresana, Maria E. Rodríguez-Ruiz, Maria Jure-Kunkel, Arantza Azpilikueta, José I. Quetglas, David Sancho, Ignacio Melero
Journal: Cancer Research (2016)

Abstract Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory monoclonal antibodies (mAbs) targeting PD-1 or CD137. Using Batf3-/- mice, which are defective for cross-presentation of cell-associated antigens, we show that Batf3-dependent dendritic cells (DCs) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3-/- mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFlt3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-OVA-derived melanomas, whereas this function was lost in Batf3-/- mice. These experiments show that cross-priming of tumor antigens by Flt3L- and Batf3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. Citation Format: Alfonso R. Sánchez-Paulete, Francisco J. Cueto, María Martínez-López, Sara Labiano, Aizea Morales-Kastresana, Maria E. Rodríguez-Ruiz, Maria Jure-Kunkel, Arantza Azpilikueta, José I. Quetglas, David Sancho, Ignacio Melero. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells. [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 4908.
Imatinib Induced Molecular Response in CD34+ Hematopoietic Stem and Progenitor Cells of Patients with Chronic Myeloid Leukemia Following the First Week of Therapy
Authors: Daniela Bruennert, Akos Czibere, Ingmar Bruns, Sabrina Pechtel, Norbert Gattermann, Ralf Kronenwett, Rainer Haas, Neumann Frank
Journal: Blood (2008)
Abstract 3731: TSC deficiency unmasks a novel protective role of RIP1/RIP3 signaling against mitochondrial and oxidative stress-induced cell death
Authors: Piotr T. Filipczak, Cindy Thomas, Wenshu Chen, Andrew Salzman, Jacob D. McDonald, Yong Lin, Steven A. Belinsky
Journal: Cancer Research (2016)

Abstract Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The presented study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using L-Buthionine-sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage and necrotic cell death in TSC2 deficient cells in a highly synergistic and cell context-specific manner. Furthermore, blocking RIP1/RIP3-dependent signaling using chemical inhibitors necrostatin-1 and necrosulfonamide (NSA), reported by others to protect from some cytotoxic stimuli, synergizes with BSO and auranofin in killing TSC2 deficient cells. Expression analysis demonstrated that RIP1 and RIP3 protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction. Finally, supplementation with the mitochondrial metabolite alpha-ketoglutarate, whose synthesis is regulated by RIP1/RIP3, rescues cells from the sensitizing effect of necrostatin-1 and NSA. Together, this study identifies a novel TSC context-dependent role of RIP1/RIP3 signaling in regulating mitochondrial and oxidative homeostasis, and substantiates glutathione, thioredoxin and RIP1/RIP3 pathways targeting as a promising therapeutic approach against TSC-associated tumors. Citation Format: Piotr T. Filipczak, Cindy Thomas, Wenshu Chen, Andrew Salzman, Jacob D. McDonald, Yong Lin, Steven A. Belinsky. TSC deficiency unmasks a novel protective role of RIP1/RIP3 signaling against mitochondrial and oxidative stress-induced cell death. [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 3731.
Abstract 4274: Porcine ovarian matrix supports maintenance of human intestinal organoid cultures
Authors: Jay George, Sol De Gese, Gabriel Benton
Journal: Cancer Research (2016)

Abstract Currently, extracellular matrix hydrogels derived from the Engelbreth-Holmes-Swarm murine tumor (Cultrex BME, Matrigel) are used for stem cell maintenance and differentiation of both normal and tumor organoid culture models. While this matrix is suitable for many in vitro applications, there is increasing demand for a 3D organoid culture platform that is more suitable for clinical applications. Here, we have developed a soluble extracellular matrix derived from normal porcine ovaries that forms a hydrogel polymer at physiological temperature and that supports maintenance of human small intestine organoids in culture. This matrix supports expansion of LGR5+ human stem cell populations using Wnt, EGF, Noggin, and R-Spondin 1 cell culture medium. The matrix also supports differentiation of stem cells into mini organs by removing Wnt which is characterized by the formation of intestinal crypts which exhibit immunostaining for lineage specific markers. This new extracellular matrix hydrogel represents a non-tumor sourced, normal extracellular matrix for evaluating both development and cancer progression. Citation Format: Jay George, Sol De Gese, Gabriel Benton. Porcine ovarian matrix supports maintenance of human intestinal organoid cultures. [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 4274.
Cell Proliferation (Ki-67) As Prognostic Marker in Mantle Cell Lymphoma.
Authors: Eva Hoster, Wolfram Klapper, Andreas Rosenwald, Heinz-Wolfram Bernd, Sylvia Hartmann, Christoph Loddenkemper, Thomas F.E. Barth, Wolfgang Hiddemann, Michael Unterhalt, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling
Journal: Blood (2012)
Abstract 4322: Maternal obesity increases tamoxifen resistance in female rat offspring
Authors: Xiyuan Zhang, Idalia Cruz, Hansheng Zhang, Leena Hilakivi-Clarke
Journal: Cancer Research (2016)

Abstract More than 50% of pregnant women in the USA are overweight or obese, and over 40% gain more weight than recommended by the Institute of Medicine. We investigated if maternal obesity before and during pregnancy affects mammary cancer risk in the offspring, or alters response of the mammary tumors to antiestrogen therapy in a preclinical rat model of estrogen receptor positive (ER+) breast cancer. Female Sprague-Dawley rats were fed an obesity-inducing high fat (OIHF) or control diet before and during pregnancy. Their offspring were all switched to a control AIN93G diet upon birth. Female offspring of control (n = 35) or OIHF (n = 40) diet fed dams were treated with a carcinogen DMBA on postnatal day 50 to induce ER+ mammary tumors. When mammary tumors reached a size of 13 mm in diameter, 337 ppm TAM citrate was added to the offspring's diet, resulting a daily intake of 15 mg/kg TAM. Responses of the tumors were categorized as de novo resistant (tumor kept growing), partial (size decreased but did not disappear), and complete (tumor disappeared). The animals with complete response were taken off from TAM and monitored for an additional 20 weeks to determine the risk of local recurrence. The risk of developing mammary tumors was non-significantly increased in the OIHF group. Further, the OIHF exposed offspring had significantly more de novo resistant tumors than the control offspring. Although the percentage of completely responding tumors was similar in the two groups, local recurrence in the OIHF offspring was significantly higher than in the control offspring (90% vs 29%, respectively). To investigate the possible mechanisms of increased recurrence, we measured the protein levels of the members of unfolded protein response (UPR), inflammation and tumor immune pathways. We found that de novo TAM resistant and recurring tumors in the OIHF offspring exhibited significantly increased levels of Perk and Beclin-1, indicating activation of UPR. However, Nbr1 and p62 were also significantly increased in the OIHF offspring, suggestive of inhibition of autophagy in their mammary tumors. The levels of CD8a, a marker of cytotoxic T cells, were significantly reduced, whilst ERα, erBb2/Her2 and Vegfr2 were increased. Changes in the expression of these receptors could indicate increased inflammation. We conclude that maternal obesity increased TAM resistance and the risk of mammary cancer recurrence in the female offspring. In addition, it induced changes in the UPR, autophagy and tumor immune responses in the offspring's mammary tumors. Citation Format: Xiyuan Zhang, Idalia Cruz, Hansheng Zhang, Leena Hilakivi-Clarke. Maternal obesity increases tamoxifen resistance in female rat offspring. [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 4322.
Abstract LB-232: Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy
Authors: Avik Som, Ramesh Raliya, Walter Akers, Joseph Ippolito, Srikanth Singamaneni, Pratim Biswas, Samuel Achilefu
Journal: Cancer Research (2016)

Abstract Introduction: The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors and restricts it growth. Methods: We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Biochemical simulations were used to simulate pH changes in vivo using the particle. In vitro and in vivo assays were used to determine pH changes. IV injections of the nanoparticles were implemented in a xenograft model of fibrosarcoma to determine growth changes. Results: Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) dissolution in vivo increases pH asymptotically to 7.4. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pHe over time. The persistent neutralization of tumor pHe from nano-CaCO3 induces tumor growth stasis. Conclusions: We have been able to create a novel nanoparticle based on widely existing in vivo components (Calcium and CO3) that safely equilibrates acidic pH of tumors up to normal physiological pH. As expected, this modulation restricts growth of implanted tumors in vivo. Future studies will study the effect of these particles on metastasis, and synergy with other therapeutic modalities. Citation Format: Avik Som, Ramesh Raliya, Walter Akers, Joseph Ippolito, Srikanth Singamaneni, Pratim Biswas, Samuel Achilefu. Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy. [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 LB-232.
Abstract 963: Epigenetic silencing of miR-199a-3p is associated with increased cell survival, enhanced cell motility, and sensitivity to tivantinib through regulation of c-Met expression in hepatocellular carcinoma
Authors: Kohichiroh Yasui, Akira Tomie, Naoto Iwai, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, we performed a genome-wide miRNA gene expression analysis using the human miRNA microarray (Agilent) in paired tumor and non-tumor tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis (the Illumina HumanMethylation27 BeadChip) in primary HCCs. We found that miR-214-3p, miR-199a-5p, and miR-199a-3p were significantly down-regulated by aberrant promoter hypermethylation in HCC tumors. The c-Met gene was identified as the direct target of miR-199a-3p. Our study showed that reduced expression of miR-199a-3p was associated with increased cell survival through the c-Met/Akt pathway and enhanced cell motility through phosphorylation of FAK. The transfection of miR-199a-3p mimic reduced the expression of c-Met and enhanced the sensitivity to the c-Met inhibitor tivantinib in HCC cells. In conclusion, our results suggest that epigenetic silencing of tumor suppressor miR-199a-3p may be involved in hepatocarcinogenesis through regulation of c-Met expressionand and be associated with the sensitivity to tivantinib. Citation Format: Kohichiroh Yasui, Akira Tomie, Naoto Iwai, Tomoko Kitaichi, Osamu Dohi, Yasuyuki Gen, Yoshito Itoh. Epigenetic silencing of miR-199a-3p is associated with increased cell survival, enhanced cell motility, and sensitivity to tivantinib through regulation of c-Met expression in hepatocellular 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 963.
Mutation in Retinoic X Receptor-γ Is a Possible Mechanism of All-Trans Retinoic Acid Resistance in Acute Promyelocytic Leukemia(APL): Identifying Genetic Changes Related to Drug Resistance in APL Using Whole Exome Sequencing
Authors: Jeonghwan Youk, Youngil Koh, Hyunkyung Park, Dae-Yoon Kim, Chan-Soo Lee, Junglim Lee, Hyo Jung Kim, Hwi-Joong Yoon, Kwang-Sung Ahn, Jong-Sun Jung, Inho Kim, Seonyang Park, Sung-Soo Yoon
Journal: Blood (2014)
Inhibition of Histone Deacetylase 6 (HDAC6) Disrupts the Tolerogenic STAT3 Signaling Pathway and Augments Antitumor Immune Responses in Mantle Cell Lymphoma (MCL)
Authors: Hongwei Wang, Fengdong Cheng, Zi Wang, Maritza Lienlaf, Patricio Perez-Villarroel, Tessa Knox, Eva Sahakian, Javier Pinilla-Ibarz, Pedro Horna, Selina Chen-Kiang, Peter Martin, Joel Bergman, Alan Kozikowski, Alejandro Villagra, Jianguo Tao, Bijal D. Shah, Eduardo M. Sotomayor
Journal: Blood (2012)
Abstract 2752: Characterization of the ATM-SPOP pathway in prostate cancer tumorigenesis
Authors: Joshua Fried, Rebecca Boohaker, Qinghua Zeng, Wei Zhang, Bo Xu
Journal: Cancer Research (2016)

Abstract The Speckle type Poz Protein (SPOP), an E3 ubiquitin ligase adaptor, has recently been identified as the gene that has the most common somatic point mutations in prostate cancer. SPOP mutations are associated with genomic alterations, indicating a role for SPOP in the maintenance of genome stability. We, and others, have recently demonstrated a critical role of SPOP in the DNA damage response (DDR), suggesting SPOP mutants may represent a subgroup of patients that have hyper sensitivity to DNA damaging therapies. However, how SPOP mutations might impact its function and their roles in the progress of prostate tumorigenesis remain to be extensively studied. Genomic studies have found that SPOP mutations are clustered within its substrate binding pocket. Of a particular interest, Serine119 is found to be frequently mutated to Asparagine (S119N). Using computational modeling, we found that Ser119 resides in the SBC-MATH binding interface and is in close contact with the non-polar residue of the SPOP-binding consensus motif. Therefore we hypothesized that phosphorylation of Serine 119 might directly affect substrate binding. First we characterized prostate cancer cells expressing this mutation and we found that they displayed a suboptimal DNA damage response with prolonged DNA repair. Using an in situ proximity ligation assay, we demonstrate that Serine 119 is essential for SPOP ionizing irradiation induced interaction with the Ataxia Telangiectasia Mutated kinase (ATM), a major hub protein in the DDR. With the evidence of SPOP being a phospho-protein, we further provide in vitro evidence that ATM phosphorylates SPOP on Serine 119 in response to DNA damage. Characterization of the functional significance of ATM-mediated SPOP phosphorylation indicates a wide range of downstream targets regulating cell cycle progression and DNA repair. Taken together, our data reveal a critical pathway linking ATM and SPOP in regulation of prostate cancer initiation and therapeutic responses to DNA damage. This also provides the first evidence of a pathophysiological relevant mutation linked to ATM phosphorylation in the DDR. Citation Format: Joshua Fried, Rebecca Boohaker, Qinghua Zeng, Wei Zhang, Bo Xu. Characterization of the ATM-SPOP pathway in prostate cancer tumorigenesis. [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 2752.
Abstract 1196: Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN
Authors: Gwenda F. Ligon, Jay S. Lillquist, Scott B. Seibel, Jerry Wallweber, Veronique Neumeister, David L. Rimm, Theresa M. LaVallee, Diego Alvarado
Journal: Cancer Research (2016)

Abstract ErbB3, the kinase-dead member of the EGFR/ErbB family, has been implicated as an oncogenic driver in a number of solid tumor types, including squamous cell carcinoma of the head and neck (SCCHN). However, clinical trials have demonstrated limited responses with certain single agent anti-ErbB3-directed therapies, suggesting that multiple ErbB inhibition and/or biomarker-directed patient selection may be beneficial. The anti-EGFR antibody cetuximab has demonstrated improved overall survival in SCCHN, but the overall response rate is relatively low. Several preclinical studies have suggested that pan-ErbB inhibition may result in improved clinical benefit and additionally, may overcome cetuximab resistance. Here we show that ErbB3 and its ligand neuregulin (NRG) are widely expressed in SCCHN, and that ErbB2, but not EGFR, drives ErbB3 activation in the presence of NRG. Although NRG is required for ErbB3 activation, it is not sufficient to fully predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN models. Metadata analysis of human SCCHN tumors revealed that NRG expression is significantly associated with expression of EGFR ligands amphiregulin (AREG) (P&amp;lt;0.0001; R2 = 0.33) and transforming growth factor α (TGFα) (P&amp;lt;0.0001; R2 = 0.25) but not other EGFR ligands. We demonstrate using NRG-positive cell lines that KTN3379 antitumor activity correlates with the level of secreted AREG and TGFα. Using a proximity-based assay for EGFR homodimerization as a surrogate assay for ligand (AREG or TGFα)-induced EGFR activation, we show that high EGFR homodimer levels correlate with KTN3379 antitumor activity in NRG-positive SCCHN cell lines and primary tumor models in vitro and in vivo. These preclinical studies provide the molecular rationale for combination treatment with KTN3379 and cetuximab in SCCHN patients. We propose that an enrichment strategy for NRG expression and EGFR activation signature may result in better clinical activity in response to treatment with KTN3379 and cetuximab in SCCHN patients. Citation Format: Gwenda F. Ligon, Jay S. Lillquist, Scott B. Seibel, Jerry Wallweber, Veronique Neumeister, David L. Rimm, Theresa M. LaVallee, Diego Alvarado. Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN. [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 1196.