Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
Over the past decade, The Cancer Genome Atlas (TCGA) has profiled more than 11,000 tumors spanning 33 distinct cancer types. The TCGA PanCanAtlas is a collaborative project by the TCGA Research Network that aims to address relevant overarching questions in oncology based on a cross-cancer analysis of the full, uniformly reprocessed TCGA data set. Here, we present results from our analysis of genetic alterations in mitogenic signaling pathways across cancer. Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations and copy-number changes in 9,125 tumor samples profiled by TCGA, we analyzed the mechanisms and patterns of alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, beta-catenin / WNT, PI-3-Kinase / Akt, receptor-tyrosine kinase / RAS / MAP-kinase signaling, TP53, and TGF-beta signaling, as well as oxidative stress response. For each of these pathways, we propose an expert-curated description (or “template”) that includes the relevant (altered) genes and the connections between them, as well as a detailed catalogue of the driver mutations and copy number changes with known oncogenic relevance. We provide a high-level map of pathway alteration frequencies across tissues and relevant cancer subtypes as well as detailed frequencies of alteration at the gene level for each individual pathway. We also investigate relationships of co-occurrence and mutual exclusivity across pathways and evaluate therapeutic implications, including drug combinations. Forty-nine percent of tumors had at least one potentially targetable alteration in the evaluated pathways, and 31% of tumors had multiple targetable alterations, making them candidates for combination therapy. Our work delineates the full landscape of oncogenic alterations in mitogenic signaling pathways across cancer, and the pathway templates as well as the richly annotated data set that we provide will constitute an invaluable public resource for future use by the cancer genomics and precision oncology communities. Citation Format: Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K. Chatila, Augustin Luna, Konnor La, Sofia Dimitriadoy, David L. Liu, Havish S. Kantheti, Zachary Heins, Angelica Ochoa, Benjamin Gross, Jianjiong Gao, Hongxin Zhang, Ritika Kundra, Cyriac Kandoth, Istemi Bahceci, Leonard Dervishi, Ugur Dogrusoz, Wanding Zhou, Hui Shen, Peter W. Laird, Alice H. Berger, Trever G. Bivona, Alexander J. Lazar, Gary Hammer, Thomas Giordano, Lawrence Kwong, Grant McArthur, Chenfei Huang, Mitchell J. Frederick, Frank McCormick, Matthew Meyerson, The Cancer Genome Atlas Research Network, Eliezer Van Allen, Andrew D. Cherniack, Giovanni Ciriello, Chris Sander, Nikolaus Schultz. The molecular landscape of oncogenic signaling pathways in The Cancer Genome Atlas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3302.
We measured the optical properties on samples of rat liver tissue before and after laser-induced thermotherapy performed in vivo with Nd:YAG laser irradiation. This made it possible to monitor not only the influence of coagulation on the scattering properties but also the influence of damages to vessels and heat-induced damage to blood on the absorption properties. An experimental integrating-sphere arrangement was modified to allow the determination of the g factor and the absorption and scattering coefficients versus the wavelength in the 600 -1050-nm spectral region, with the use of a spectrometer and a CCD camera. The results show a relative decrease in the g factor of on average 21 Ϯ 7% over the entire spectral range following thermotherapy, and a corresponding relative increase in the scattering and absorption coefficients of 23 Ϯ 8% and 200 Ϯ 100%, respectively. An increase of on average 200 Ϯ 80% was consequently found for the reduced scattering coefficient. The cause of these changes in terms of the Mie-equivalent average radius of tissue scatterers as well as of the distribution and biochemistry of tissue absorbers was analyzed, utilizing the information yielded by the g factor and the spectral shapes of the reduced scattering and absorption coefficients. These results were correlated with the alterations in the ultrastructure found in the histological evaluation. The average radius of tissue scattering centers, determined by using either the g factors calculated on the basis of Mie theory or the spectral shape of reduced scattering coefficients calculated on the Mie theory, was estimated to be 21-32% lower in treated than in untreated liver samples. The Mie-equivalent average radii of scattering centers in untreated liver tissue deduced by the two methods corresponded well and were found to be 0.31 and 0.29 m, respectively, yielding particle sizes in the same range as the size of a mitochondrion.
Multiple-system organ failure resulting from ischemia-reperfusion injury and obstacle of portal hemodynamics in a subject subjected to an extended continuous hepatic inflow interruption is an unrecognized new disorder that may cause a high mortality rate. Our preliminary results indicated that animals subjected to continuous hepatic inflow interruption for 90 or 120 minutes developed various injuries to the liver, lung, heart, and gut. Therefore, we believe that continuous hepatic inflow interruption exceeding 90 minutes could also be hazardous in human beings.
Purpose: This report describes the development and preclinical qualification tests of secondgeneration anti-carcinoembryonic (CEA) designerTcells for use in human trials. Experimental Design: The progenitor first-generation immunoglobulin-T-cell receptor (IgTCR) that transmits Signal 1-only effectively mediated chimeric immune receptor (CIR)^directed cytotoxicity, but expressor T cells succumbed to activation-induced cell death (AICD). The second-generation CIR (termed ''Tandem'' for two signals) was designed to transmit TCR Signal 1 and CD28 Signal 2 to render T cells resistant to AICD and provide prolonged antitumor effect in vivo. Results: A CIR was created that combines portions of CD28,TCR~, and a single chain antibody domain (sFv) specific for CEA into a single molecule (IgCD28TCR). As designed, the genemodified Tandem T cells exhibit the new property of being resistant to AICD, showing instead an accelerated proliferation on tumor contact. Tandem T cells are more potent than first generation in targeting and lysing CEA + tumor. Tandem T cells secrete high levels of interleukin-2 and IFNg on tumor contact that first-generationTcells lacked, but secretion was exhaustible, suggesting a need for interleukin-2 supplementation in therapy even for these second-generation agents. Finally, second-generationTcells were more effective in suppressing tumor in animal models. Conclusion: An advanced generation of anti-CEA designer T cells is described with features that promise a more potent and enduring antitumor immune response in vivo. These preclinical data qualify the human use of this agent that is currently undergoing trial in patients with CEA + cancers.
Purpose: The aims of this study are to compare antitumor activities of two generations of GD3-specific chimeric antigen receptors (CAR) in human primary T lymphocytes in vitro and to evaluate the antitumor efficacy of using a combination of systemic infusion of interleukin-2 (IL2) and designer T cells to eradicate subcutaneous established GD3 + melanoma in nude mice. Experimental Design: Antitumor activities were compared for two generations of designer T cells, the progenitor first-generation with immunoglobulin T-cell receptor (TCR) with Signal 1 and the secondgeneration designer T cells with Signal 1+2. Osmotic IL2 pumps were used to deliver the maximum tolerated dose of IL2 to enhance the antitumor effects of designer T cells on subcutaneous established melanoma in nude mice.Results: Melanoma is associated with high expression of ganglioside GD3, which has been targeted with modest effect in antibody therapies. We previously showed that an anti-GD3 CAR (sFv-TCRζ) will recruit T cells to target this non-T-dependent antigen, with potent killing of melanoma cells. Here, we report the addition of a CD28 costimulation domain to create a second-generation CAR, called Tandem for two signals. We show that this Tandem sFv-CD28/TCRζ receptor on T cells confers advantages of improved cytokine secretion, cytotoxicity, proliferation, and clonal expansion on tumor contact versus the same CAR without costimulation. In an adoptive transfer model using established melanoma tumors, designer T cells with CD28 showed a 50% rate of complete remissions but only where IL2 was supplemented.Conclusions: As a reagent for clinical development, the second-generation product is shown to have superior properties to warrant its preference for clinical designer T-cell immunotherapy for melanoma and other tumors. Systemic IL2 was required for optimal activity in an established tumor model. Clin Cancer Res; 16(10); 2769-80. ©2010 AACR.
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