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Hamburg, Germany

Bettegowda C.,Howard Hughes Medical Institute | Sausen M.,Howard Hughes Medical Institute | Sausen M.,Personal Genome Diagnostics (PGD) | Leary R.J.,Howard Hughes Medical Institute | And 69 more authors.
Science Translational Medicine | Year: 2014

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer. Source

Madhavan S.,Georgetown University | Gusev Y.,Georgetown University | Natarajan T.G.,Georgetown University | Song L.,Georgetown University | And 11 more authors.
Frontiers in Genetics | Year: 2013

The use and benefit of adjuvant chemotherapy to treat stage II colorectal cancer (CRC) patients is not well understood since the majority of these patients are cured by surgery alone. Identification of biological markers of relapse is a critical challenge to effectively target treatments to the ~20% of patients destined to relapse. We have integrated molecular profiling results of several "omics" data types to determine the most reliable prognostic biomarkers for relapse in CRC using data from 40 stage I and II CRC patients. We identified 31 multi-omics features that highly correlate with relapse. The data types were integrated using multi-step analytical approach with consecutive elimination of redundant molecular features. For each data type a systems biology analysis was performed to identify pathways biological processes and disease categories most affected in relapse. The biomarkers detected in tumors urine and blood of patients indicated a strong association with immune processes including aberrant regulation of T-cell and B-cell activation that could lead to overall differences in lymphocyte recruitment for tumor infiltration and markers indicating likelihood of future relapse. The immune response was the biologically most coherent signature that emerged from our analyses among several other biological processes and corroborates other studies showing a strong immune response in patients less likely to relapse. © 2013 Madhavan, Gusev, Natarajan, Song, Bhuvaneshwar, Gauba, Pandey, Haddad, Goerlitz, Cheema, Juhl, Kallakury, Marshall, Byers and Weiner. Source

Xu L.,FDA | Ziegelbauer J.,NCI Inc | Wang R.,FDA | Wu W.W.,Facility for Biotechnology Resources | And 4 more authors.
Clinical Cancer Research | Year: 2016

Purpose: To gain insight into factors involved in tumor progression and metastasis, we examined the role of noncoding RNAs in the biologic characteristics of colorectal carcinoma, in paired samples of tumor together with normal mucosa from the same colorectal carcinoma patient. The tumor and healthy tissue samples were collected and stored under stringent conditions, thereby minimizing warm ischemic time. Experimental Design: We focused particularly on distinctions among high-stage tumors and tumors with known metastases, performing RNA-Seq analysis that quantifies transcript abundance and identifies novel transcripts. Results: In comparing 35 colorectal carcinomas, including 9 metastatic tumors (metastases to lymph nodes and lymphatic vessels), with their matched healthy control mucosa, we found a distinct signature of mitochondrial transfer RNAs (MT-TRNA) and small nucleolar RNAs (snoRNA) for metastatic and high-stage colorectal carcinoma. We also found the following: (i) MT-TF (phenylalanine) and snord12B expression correlated with a substantial number of miRNAs and mRNAs in 14 colorectal carcinomas examined; (ii) an miRNA signature of oxidative stress, hypoxia, and a shift to glycolytic metabolism in 14 colorectal carcinomas, regardless of grade and stage; and (iii) heterogeneous MT-TRNA/snoRNA fingerprints for 35 pairs. Conclusions: These findings could potentially assist in more accurate and predictive staging of colorectal carcinoma, including identification of those colorectal carcinomas likely to metastasize. © 2015 American Association for Cancer Research. Source

Ewald F.,University of Hamburg | Grabinski N.,University of Hamburg | Grottke A.,University of Hamburg | Windhorst S.,University of Hamburg | And 9 more authors.
International Journal of Cancer | Year: 2013

Cholangiocarcinoma (CCA) is a rare, but devastating disease arising from the epithelium of intrahepatic and extrahepatic bile ducts. There are neither effective systemic therapies nor satisfying treatment options for inoperable CCA. Histopathological and biochemical studies of CCA show frequent dysregulation of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Therefore, we investigated the efficacy of the mTOR inhibitor RAD001 and the impact of AKT signaling following mTOR inhibition in the treatment of CCA. RAD001 significantly inhibits proliferation of CCA cell lines, however, a concentration-dependent and isoform specific feedback activation of the three AKT isoforms (AKT1, AKT2 and AKT3) was observed after mTOR inhibition. As activation of AKT might limit the RAD001-mediated anti-tumor effect, the efficacy of combined mTOR and AKT inhibition was investigated using the allosteric AKT inhibitor MK-2206. Our results show that inhibition of AKT potentiates the efficacy of mTOR inhibition both in vitro and in a xenograft mouse model in vivo. Mechanistically, the antiproliferative effect of the pan-AKT inhibitor MK2206 in the CCA cell line TFK-1 was due to inhibition of AKT1 and AKT2, because knockdown of either AKT1 or AKT2, but not AKT3, showed a synergistic reduction of cell proliferation in combination with mTOR treatment. Finally, using an AKT isoform specific in vitro kinase assay, enzymatic activity of each of the three AKT isoforms was detected in all tissue samples from CCA patients, analyzed. In summary, our preclinical data suggest that combined targeting of mTOR and AKT using RAD001 and MK-2206 might be a new, effective strategy for the treatment of CCA. What's new? Cholangiocarcinoma (CCA) has a dismal prognosis, and currently there is no effective systemic therapy available. The PI3K/AKT/mTOR pathway is frequently activated in CCA. In this study, the authors found that dual targeting of mTOR and AKT can synergistically inhibit the proliferation of CCA cells, both in vitro and in a xenograft mouse model in vivo. Mechanistically, the anti-proliferative effect of the AKT inhibitor MK2206 was due to inhibition of AKT1 and AKT2, but not AKT3. Combined targeting of mTOR and AKT may be a promising new strategy for the treatment of CCA. Copyright © 2013 UICC. Source

Juhl H.,Indivumed GmbH
Scandinavian Journal of Clinical and Laboratory Investigation | Year: 2010

Considerable research data is available that demonstrate that tissues are under tremendous biological stress when surgically separated from the body. This stress significantly changes gene and protein expression profiles, including activation or inhibition of signalling pathways and their receptors. Many of those are possibly involved in growth regulation and might serve as targets or stratification markers for new drugs. Factors that affect tissue dependent cancer research for target discovery and drug development include drug treatment and anesthesia of patients before surgical tissue removal, intrasurgical ischemia by ligation of main arteries, "cold" ischemia, i.e. the time interval between surgical removal and fixation of tissue, location of tumor biopsy within a given tumor, processing of tissue and fixation protocols and the availability of comprehensive clinical data. Controlled and rapid tissue processing is a prerequisite for understanding biological differences of patient tumors and to utilize these findings (e.g., cancer pathway activity) for targeted molecular therapies. © 2010 Informa UK Ltd. Source

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