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ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial.

Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community.

// Jian-Guo Sun 1,2 , Xie-Wan Chen 2 , Lu-Ping Zhang 2 , Jiang Wang 2 and Max Diehn 1 1 Cancer Institute, Stanford University School of Medicine, Stanford, California, USA 2 Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China Correspondence to: Jian-Guo Sun, email: // Max Diehn, email: // Keywords : Yap1, breast cancer, tumor initialing cells, self-renewal, Smad3 Received : June 06, 2015 Accepted : October 08, 2015 Published : December 18, 2015 Abstract Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49f high EpCAM low cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro ( p < 0.01) and self-renewal in vivo ( p < 0.01), and led to a 4-fold increase in TIC frequency ( p < 0.05).A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro ( p < 0.01) and in vivo ( p < 0.01), and it also led to an over 200-fold decrease in TIC frequency ( p < 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3).Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.

Pancreas cancer is the third most common cause of cancer-related death, owing in part to high rates of unresectable disease at time of diagnosis and poor long-term response to chemotherapy. Biomarkers are needed to sensitively identify and monitor disease burden, and to measure response to therapy. The CA19-9 tumor marker lacks sufficient positive or negative predictive value to guide treatment decisions, and digital droplet PCR (ddPCR) assessment of circulating KRAS mutations suffers poor sensitivity on account of only assessing a single DNA locus. We hypothesize that a multitargeted circulating tumor DNA assay can outperform CA19-9 and ddPCR as biomarker for the detection and monitoring of pancreas cancer. Our lab has developed the cancer personalized profiling by deep sequencing (CAPP-Seq) method, which combines high-depth sequencing with several strategies of error-suppression to identify minute amounts of tumor DNA circulating in patients’ blood. The development of our CAPP-Seq targeted sequencing panel hinged primarily on capturing regions of the genome known to be recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), based on The Cancer Genome Atlas project. These regions contain mutations in KRAS, TP53, SMAD4, and by a long-tail of mutations in many other genes for which we contributed approximately 200 kb of selector space. In addition to recurrent SNVs, we also contributed approximately 35 kb for recurrent copy number variant locations, 10 kb for recurrent noncoding variants, and 20 kb for regions with aberrant expression patterns in PDAC based on TCGA RNA-sequencing data. This purpose of this study is to employ CAPP-Seq in two pancreas cancer cohorts: patients who underwent resection at Stanford and had blood drawn before and after surgical resection (n=30), and a cohort of patients with metastatic disease who are undergoing chemotherapy with blood draws at multiple time-points (n=20). The former cohort will assess prediction of recurrence based on ctDNA level, and the latter will assess patients with early development of resistance to chemotherapy. Before assessing this ctDNA detection assay in patients with pancreas cancer, we first evaluated the CAPP-Seq approach on two healthy research subjects and achieved on average 4000x de-duplicated sequencing depth, for a theoretical limit of detection of 0.03% circulating tumor fraction. We next sequenced samples from 7 patients with resectable disease and 8 with metastatic disease, with results expected in early July. Citation Format: Dan King, Mari Olsen, George Fisher, Max Diehn, Ash Alizadeh. Development of a circulating tumor DNA assay in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C29.

Das Teilprojekt E-Mail hatte ursprunglich die Aufgabe einen zentralen Mailservice mit verteilter Administration der Mailadressen fur die TUM aufzubauen und diesen durch Anti-Spam- und Anti-Viren-Masnahmen zu schutzen. Auf diesen Mailservice sollten sowohl die am LRZ gehosteten Maildomains als auch die vielen lokal betriebenen Mailserver – soweit von deren Betreibern gewunscht – migriert werden. Neben einigen Ruckschlagen und Hindernissen kam es im Laufe des Projektes auch zu einer Anderung der Anforderungen, sodass zum Ende des Projektes statt eines reinen Mailsystems ein Doppelsystem mit „shared SMTP address space“ bestehend aus einem klassischen Message-Store mit POP/IMAP-Zugriff auf Basis von Postfix + Dovecot und einem Groupware-System auf Basis von Microsoft Exchange in Produktion ging, wobei jeder Mitarbeiter und Student der TUM wahlen kann, auf welchem der beiden Systeme sich seine Mailbox befindet.

Die E-Mail-Infrastruktur an der Technischen Universitat Munchen (TUM) ist historisch bedingt sehr heterogen und komplex. Viele Einrichtungen mussen wertvolle Arbeitskraft auf die Administration eigener Mailserver verwenden. Auf der anderen Seite wird bei einigen Einrichtungen der Ruf nach Groupware-Funktionalitaten wie z.B. gemeinsame Kalender immer lauter. Das Teilprojekt E-Mail stellt einen zentralen Mail- und Groupware-Service bereit, der den Einrichtungen ermoglichen soll, den Betrieb eigener Server und zugehoriger Systeme (etwa lokaler Benutzerverwaltungen) fur diesen Zweck aufzugeben und diese Dienste an das Teilprojekt E-Mail zu migrieren, ohne ihre Verwaltungshoheit oder ihre Maildomains aufgeben zu mussen. Dieser Service versteht sich als eine Erganzung zur bestehenden Grundversorgung der TUM mit den Maildiensten des myTUM-Mailers, ist mandantenfahig aufgebaut und kann daher kunftig neben der TUM auch weiteren Organisationen im Munchner Wissenschaftsnetz zur Verfugung gestellt werden.

Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44 + CK5 + CK20 − ). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% β-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.

Circulating tumor DNA (ctDNA) represents a promising biomarker for sensitive, specific, and dynamic detection of disease burden in cancer patients. Additionally, ctDNA analysis allows non-invasive access to cancer genomes and therefore can be used for non-invasive tumor genotyping and monitoring of resistance mutations. In this presentation I will describe technical aspects of ctDNA detection and emerging clinical results from recent studies employing ctDNA analysis. Citation Format: Max Diehn. Deep sequencing of circulating tumor DNA for personalized cancer detection and monitoring. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA25.

At central synapses, P/Q-type Ca 2+ channels normally provide a critical Ca 2+ entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking α 1A (Ca V 2.1), the pore-forming subunit of P/Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from α 1A (-/-) mice. First, the presynaptic response to an ionophore-mediated Ca 2+ elevation was 50% greater, indicating an enhanced Ca 2+ sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in α 1A (-/-) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in α 1A (-/-) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the α 1A (-/-) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca 2+ -sensing molecules were consistent with implications of the direct physiological experiments.

Stem-like “Tumor Initiating Cells” (TICs) have been isolated from a number of tumors including breast, and they are likely involved in all aspects of tumor biology including metastasis. Recent studies have established a link between epithelial stem-like properties and the epithelial-mesenchymal transition (EMT), a step that leads to invasion and metastasis. Identifying key signaling pathways that regulate both tumor initiating and metastatic events could enable more accurate prognosis and reveal important mediators of the process that could serve as novel therapeutic targets. Previous studies from our laboratory and others have shown that let-7 inhibits breast tumor initiation and metastasis. Previously, we have shown that BACH1, a transcription factor that is a direct target of let-7, promotes metastasis. Using gene expression arrays to quantify transcription in BACH1 depleted cells, we show that BACH1 regulates a number of downstream targets including Bone Metastasis Signature (BMS) genes. Utilizing an approach based on experimental and clinical validation, we identify genes implicated in both tumor initiation and metastasis. Gene set analysis confirmed that the BACH1 target genes significantly correlate to the metastatic pathway including BACH1, let-7 and BMS gene expression across a set of more than 1200 primary human tumors, and, in tumors selected for a basal phenotype, the expression levels of individual BACH1 target genes can significantly stratify metastasis free survival in patients. Using FACS to sort metastatic breast cancer cell lines, we see a significant increase in the transcription levels of BACH1 regulated genes when comparing TICs to non-tumor initiating cells. Additionally, in metastatic cell lines known to be enriched in TICs, BACH1 depletion reduces the population of cells expressing cell surface markers (CD44+CD24-/lowESA+) specific to a tumor initiating phenotype. And finally, gene set enrichment analysis indicates that BACH1 and the BACH1 target genes are enriched in human and mouse primary breast TICs relative to non-initiating tumor cells. Taken together, these results suggest that let-7 regulates a signaling cascade involving BACH1 and BACH1 target genes that promotes both tumor initiation and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3329. doi:1538-7445.AM2012-3329