Forschung Sektion Translationale… Projekte


Next generation sequencing

The rise of next generation sequencing (NGS) has opened up new opportunities for translating high-throughput functional genomics into clinical practice. By combining forces between genomics, systems biology and translation, DKFZ has begun to form an internationally leading center for personalized genome analysis in oncology. The mid- to long-term goal of this center is to develop a program for personalized oncology that will readily translate latest research and technologies from the field of functional genomics and systems biology into clinical practice.

The Heidelberg Center for Personalized Oncology – DKFZ-HIPO – integrates the best research groups in functional genomics, systems biology and translational oncology under a unified organizational structure. We cooperate with HIPO to: i) identify drivers of early metastatic spread in aggressive pulmonary adenocarcinoma (HIPO004), ii) identify resistance mechanisms in patients with metastatic NSCLC (HIPO041), and iii) perform comparative genomics of NSCLC tumors and brain metastases (HIPO056).

The main objective of this Project is to study the role of the lipogenic pathway and Rho GTPases in lung and pancreatic cancer with the ultimate goal of improving patient survival by using a multidisciplinary approach, focused in these two pathways that are likely to be universally altered in cancer and that are mechanistically linked.

These discoveries will lead to the identification of novel therapeutic targets, novel markers of resistance to standard treatments, to the design of adequate combinatorial treatments, and to better assays to establish diagnosis and prognosis that will allow the development of novel targeted and personalized therapies.

These challenging objectives will be reached through the specialized knowledge of the Consortium of a set of genes, involved in phospholipid metabolism, including upstream regulators such as Rho GTPases and their effectors (defined as the “CANCERALIA” selected genes).

As a side effect of chemotherapy patients frequently develop anemia. For the treatment of anemia recombinant erythropoietin (Epo) can be applied that stimulates the production of red blood cells. However, Epo receptors (EpoR) have been observed both in tumor cell lines, and lung tumors and a clinical trial showed a shortened progression-free survival in the patients treated with Epo. The aim of the BMBF-funded LungSys I consortium in the MedSys call was to identify the effects of EPO treatment in lung cancer from the protein to the organ level, integrating experimental data into a multi-scale model and designing strategies to avoid anemia.

Early metastatic spread involves multiple serial steps such as separation from the primary tumor mass, invasion of the surrounding tissues, entry into the blood stream and invasion of other organs. There is an increasing list of somatic mutations in lung carcinoma. Among those are activating mutations of the epidermal growth factor receptor (EGFR) for some of which can be treated by targeted therapy. However, therapy resistance rapidly arises. Factors such as hepatocyte growth factor (HGF), transforming growth factor beta (TGFbeta), insulin-like growth factor 1 (IGF-1R) and erythropoietin receptor (EpoR) are thought to contribute to therapy resistance. The aim of the BMBF-funded LungSys II consortium in the CancerSys call is to apply a Systems Biology approach to identify parameters that critically determine early spread and to predict possibilities for improved therapeutic options.

Lung cancer is a high incidence and high mortality disease. The two main lung cancer types are small-cell-lung carcinoma (SCLC; 20-30% of cases) and non-small cell lung carcinoma (NSCLC; 70-80% of cases). Patients presenting with SCLC have a particularly poor prognosis, and almost 40 % of NSCLC-patients present with metastases at time of diagnosis.  Surgery, radiation, chemotherapy, and on a limited scale, targeted treatments - alone or in combination - are used to treat lung cancer. Limited knowledge of which individual molecular markers impact the propagation and spread of the disease impedes the development and use of targeted therapies; hence the treatment success is very variable. Our research focuses on the identification of relevant molecular markers urgently needed to advance matching of targeted treatments to patients, with the ultimate goal of developing personalized therapies to improve patient outcomes. Lung cancer research at the DZL is an interdisciplinary and integrative program exploring clinically well characterized sample sets with epidemiologic, genetic, epigenetic and systems biology approaches. Within the German Center for Lund Diseases (DZL) we are part of the Translational Research Center Heidelberg (TLRC-H). In this consortium we work interdisciplinary with other DZL sites of Heidelberg and whole Germany. Several clinical trials (Sequential Biopsy Approach, Radio-Chemotherapy cohort, etc.) will be established over all DZL sites to understand and analyze recurrence of lung cancer in advanced stages.

Biomarkers are essential for early diagnosis or as a control for patients’ response to treatment in advanced tumor stages. In our lab, our research is focused on biomarkers in blood and bronchoalveolar lavages (miRNAs, protein) as well as in tumor tissue (mRNA, protein).

Glycodelin is well characterized during menstruation cycle and for its role in pregnancy. We found glycodelin strongly upregulated in Non-Small Cell lung cancer. It was detectable in serum of NSCLC patients and correlated with clinical follow-up. We currently try to establish glycodelin as a follow-up biomarker for NSCLC.