Major current projects


I. Molecular mechanisms of chemotherapy- and radiotherapy-induced cell death and targeted approaches to overcome intrinsic and hypoxia-mediated therapy resistance


Major mechanisms of antineoplastic action of standard chemo- and radiotherapy include the induction of lethal DNA-damage and DNA-damage-induced cell inactivation and/or cell death (apoptosis, necrosis or reproductive cell death). In turn, resistance to genotoxic therapies is related to alterations of the under­lying molecular pathways. Genetic and epigenetic alterations in the tumor cells together with the stress conditions within the tumor microenvironment force the selection of cells that survive cellular stress resulting in treatment resistance. We investigate the signaling pathways initiated by chemo- and radiotherapy with a focus on cell death and survival signaling. Moreover, we analyze resistance-associated molecular changes acquired by tumor cells during tumor initiation and progression. Finally, we explore the possibility to induce alternative cell death modes in cells with resistance to chemotherapy- and radiotherapy-induced cell death by using targeted drugs alone and in combination with standard treatment options in vitro as well as in mouse models.

Selected publications

  • Wolfsperger F, High-Binder SA, Bornes L, Psaras T, Huber SM, Jendrossek V, Rudner J. Deubiquitylating enzyme USP9x regulates radiosensitivity in glioblastoma cells by Mcl-1-dependent and -independent mechanisms. Cell Death Dis Dec 2015 accepted for publication)
  • Rudner J, Elsaesser SJ, Müller AC, Belka C, Jendrossek V. Differential effects of anti-apoptic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis. Biochem Pharmacol. 79: 10-20 (2010).
  • Handrick R, Ganswindt U, Faltin H, Goecke B, Daniel PT, Budach W, Belka C, Jendrossek V. Combined action of celecoxib and ionizing radiation in prostate cancer cells is independent of proapoptotic Bax. Radiother Oncol 90, 413-421 (2009)
  • Müller AC, Handrick R, Elsaesser SJ, Rudner J, Henke G, Ganswindt U, Belka C, Jendrossek V. Importance of Bak for celecoxib-induced apoptosis. Biochem Pharmacol 102: 371-82 (2008).
  • Belka C*, Jendrossek V*, Verheij M, Pruschy M, Budach W. Apoptosis modulating agents in combination with radiotherapy - current status and outlook. Int J. Radiat. Oncol. Biol. Phys. 58: 542-554 (2004). * shared first authorship

The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway as a target for the modulation of the therapy response

Among the signaling molecules with crucial relevance for the regulation of tumor cell resistance several direct apoptosis regulators like Bcl-2 as well as indirect apoptosis modulators like the PI3K/Akt survival pathway have been identified. The PI3K/Akt pathway constitutes a major mediator of physiologic survival signals originating from growth factor stimulation, cytokines or the extracellular matrix. Moreover, the PI3K/Akt pathway is activated by stress stimuli and has clinical relevance to radiation resistance thought to derive from contributions to the DNA damage response. Various reports implicate Akt in DNA double strand break repair and apoptosis, but prevailing models and suggested mechanisms remain poorly defined and are often contradictory. In current investigations we aim to explore the functional relevance of tumor-associated Akt mutations and of its phosphorylation state for altered sensitivity of cancer cells to radiotherapy and to identify novel target proteins integrating Akt into the DNA damage response.

Moreover, we explore the use of small molecule inhibitors of PI3K/Akt signaling to increase efficacy of ionizing radiation focusing on prostate cancer. We previously showed that up-regulated activity of Akt in patients with localized prostate cancer occurs as a consequence of phosphatase and tensin homologue deleted on chomosome ten (PTEN)-dependent and PTEN-independent mechanisms. Moreover, a substantial heterogeneity in the expression and phosphorylation levels of known Akt target proteins was detected. These findings suggest that patients with localized prostate cancer represent different molecular subgroups with assumed distinct sensitivity to radiotherapy and agents targeting the PI3K/Akt pathway. Currently we explore the value of membrane-targeted Akt inhibitors for modulating tumor cell intrinsic and stroma-mediated resistance to radiotherapy. The drugs target cellular membranes without direct interaction with the DNA. In our hands, membrane-targeted alkylphosphocholines increase sensitivity of solid tumor cells to radiation-induced cell death and overcome resistance signals from the extracellular matrix. Aim of the project is to delineate the molecular mechanisms linking alkylphosphocholine-induced membrane changes to the engagement of death pathways in solid tumor cell, and to evaluate their potential for radiosensitization of cancer cells with aberrant Akt activation or cultured in a resistance-promoting microenvironment.

Selected publications

  • Chometon G, Cappuccini F, Raducanu A, Aumailley M, Jendrossek V. The membrane-targeted alkylphosphocholine Erufosine interferes with survival signals from the extracellular matrix Anticancer Agents in Medicinal Chemistry May; 14(4):578-91(2014).
  • Henke G, Meier V, Lindner L H, Eibl H, Bamberg M, Belka C, Budach W, Jendrossek V. Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice. Radiation Oncol Oct 18;7(1):172 (2012).
  • Rudner J, Ruiner CE, Handrick R, Eibl H, Belka C, Jendrossek V. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short-term effects of ionizing radiation. Radiation Oncology 5:108 (2010).
  • Henke G, Lindner LH, Vogeser M, Eibl H, Wörner J, Müller AC, Bamberg M, Wachholz K, Belka C, Jendrossek V. Pharmacokinetics and biodistribution of Erufosine in nude mice – implications for combination with radiotherapy. Radiation Oncology 4:46 (2009)
  • Jendrossek V, Henkel M, Hennenlotter J, Vogel U, Ganswindt U, Müller I, Handrick R, Anastasiadis AG, Kuczyk M, Stenzl A, Belka C. Analysis of complex PKB/Akt signalling pathways in human prostate cancer samples. Br J Urol 102: 371-82 (2008).
  • Handrick R, Rübel A, Faltin H, Eibl H, Belka C, Jendrossek V. Increased cytotoxicity of ionizing radiation in combination with membrane-targeted apoptosis modulators involves downregulation of Proteinkinase B/Akt-mediated survival-signalling. Radiother Oncol 80: 199-206 (2006)

Molecular mechanisms of hypoxia-mediated treatment resistance

Hypoxia is a common feature of human solid tumors and is considered as one main biological factor driving malignant progression and promoting tumor cell resistance to chemotherapy and radiotherapy: The reduced availability of molecular oxygen during acute hypoxia hampers the manifestation of DNA-damage induced by radiotherapy and thus decreases its cytotoxic action. Moreover, acute hypoxia activates several survival pathways that decrease therapy-induced cell death. Finally, chronic cycling hypoxia is an important driving force in the clonal evolution of hypoxia-tolerant tumor cells with high intrinsic radiation resistance. A variety of genetic, epigentic and cellular changes allows the to survive these shighly adverse conditions and increases their resistance to ionizing radiation in parallel. Among others, tolerance of tumor cells to chronic cycling hypoxia has been associated with loss of the tumor suppressor p53, upregulation of free radical scavenging systems, and deregulated expression of antiapoptotic proteins of the Bcl-2 family. The increase in radical scavenging systems is of particular interest, because ROS are important mediators oft he toxic effects of ionizing radiation and low cellular ROS-levels can be associated with improved survival and radiation resistance, e.g. of glioma stem cells.

We aim to develop novel treatment approaches to overcome therapy resistance of hypoxic cancer cells. To this end, we search for hypoxia-active drugs that are effective in eradicating hypoxic cancer cells, increase the activity of ionizing radiation in hypoxic tumor cells, or both, preferentially by targeting survival pathways that are essential for hypoxic cancer cells (context-dependent lethality). Furthermore, we study molecular alterations induced by adaptation of tumor cells to chronic cycling hypoxia relevant to hypoxia tolerance and radiation resistance with the ultimate goal to gain a better understanding of tumor heterogeneity and to define nocel biomarkers and therapeutic targets for specific eradication of radiation resistance cell  fractions in chronically hypoxic tumors. In this context, we currently focus on cellular ROS defense and metabolic adaptation.

Selected publications

  • Ontikatze T, Rudner J, Handrick R, Belka C, Jendrossek V. Dihydroartemisinin is a hypoxia-active anticancer drug in colorectal cancer cells. Frontiers Oncol May 19; 4:116 (2014).
  • Weinmann M*, Jendrossek V*, Handrick R, Güner D, Goecke B, Belka C (2004) Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner. Oncogene, 23(21):3757-69 (2004).
  • Weinmann M, Betsch A, Jendrossek V, Marini P, Goecke B, Budach W, Belka C: Influence of Hypoxia on TRAIL-induced Apoptosis in tumor cells. Int J. Radiat. Oncol. Biol. Phys. 58: 386-396 (2004).
  • Weinmann M, Jendrossek V, Güner D, Goecke B, Belka C. Cyclic exposure to hypoxia and reoxygenation selects for tumor cells with defects in mitochondrial apoptotic pathways. FASEB J  18: 1906-1908 (2004)
  • Weinmann M, Belka C, Guner D, Goecke B, Muller I, Bamberg M, Jendrossek V.: Array-based comparative gene expression analysis of tumor cells with increased apoptosis resistance after hypoxic selection. Oncogene. 24(38):5914-22 (2005).

II. Impact of stromal cells on therapy response & therapeutic targeting

Ionizing radiation exerts its cytotoxic effects on cancer cells primarily by causing lethal DNA damage. However, the response of the tumor stroma is now increasingly recognized as critical determinant of the tumor radiation response. Critical stromal components are endothelial cells/vascular structures, immune cells and fibroblasts, particularly cancer-associated fibroblasts (CAFs). CAFs derive from different precursor cells like resident stromal fibroblasts, epithelial cells or bone marrow-derived cells. Cancer cells reprogram and activate these cells towards CAFs. CAFs secrete several signaling molecules to promote cancer cell growth, angiogenesis and metastasis as well as to induce tumor-promoting inflammation and immune suppression. They also remodel the extracellular matrix by secreting extracellular matrix components. However, their role in the outcome of radiotherapy is largely unknown. We speculate that CAFs alter the radiation response of tumor cells through cell-to-cell interactions and paracrine signaling networks. Aim of the project is to characterize the effects of CAFs on the efficacy of radiotherapy in vitro and in vivo and to define the mechanisms underlying CAF-mediated radiation response modulation. This basic knowledge shall then be used to design innovative strategies for radiationresponse modulation.

Selected publications

  • Klein D, Schmitz T, Verhelst V, Panic A, Schenck M, Reis H, Drab M, Sak A, Herskind C, Maier P and Jendrossek V. Endothelial Caveolin-1 regulates the radiation response of epithelial prostate tumors. Oncogenesis  May 18;4:e148 (2015). doi: 10.1038/oncsis.2015.9
  • Chometon G, Jendrossek V: Targeting the tumour stroma to increase efficacy of chemo- and radiotherapy. Clin Transl Oncol 11, 75-81 (2009).
  • Handrick R, Rudner J. Müller I, Eibl H, Belka C, Jendrossek V. Bcl-2-mediated inhibition of erucylphosphocholine-induced apoptosis depends on its subcellular localisation. Biochem Pharmacol. 70:837-50 (2005)

III. Molecular mechanisms of radiation-induced pneumopathy & therapeutic targeting

Radiotherapy is an integral part of standard treatment for thorax-associated neoplasms. Unfortunately, adverse late effects in the highly radiosensitive lung limit the radiation dose resulting in suboptimal local control, metastases and decreased quality of life. Lung toxicity also limits the dose of total body irradiation in conditioning regimens for hematopoietic stem cell transplantation. Although several novel disease biomarkers have been described during recent years disease pathogenesis remains poorly understood and no effective treatment is available. We aim to elucidate the connection between radiation-induced acute damage to resident cells, the resulting immune changes and the development of pneumonitis/fibrosis in vitro and murine models by genetically defined mouse strains. Ultimate goal is to use our improved understanding of the underlying mechanisms for the definition of novel biomarkers/therapeutic targets for the development of effective radioprotective treatments protecting the normal tissue without protecting the tumor. These are validated in preclinical in vivo models.

Stem cell therapy for overcoming radiation-induced damage to resident cells

In an effort to develop novel and effective radioprotective treatments we investigate the potential of therapeutically applied multipotent mesenchymal stem cells (MPSC) isolated either from the bone marrow or the vascular wall to counteract the adverse effects of ionizing radiation in highly radiosensitive tissues such as the lung. We postulate that vascular wall-derived MPSCs are particularly well suited for the radioprotection of endothelial cells within the processes of radiation-induced lung injury. In current work we aim to identify the underlying cell-dependent and/or paracrine mediators of the protective effects of MPSC therapy on vascular dysfunction and tissue inflammation.

Radiation-induced immune changes, adverse late effects and therapeutic targeting

Up to now the contribution of radiation-induced immune changes for disease pathogenesis is largely unknown and needs to be further elucidated. Currently we explore the role of ecto-5'-nucleotidase/CD73-generated adenosine, an important endogenous regulator of inflammation, in the development of lung fibrosis after thoracic irradiation. Though CD73 and adenosine are crucial for the regulation of lung homeostasis, their role during radiation-induced pneumopathy is unknown. As earlier reports showed both tissue-protective and pro-fibrotic effects of CD73 and adenosine in pulmonary fibrosis we ask whether they would be protective or harmful in radiation-induced lung disease and evaluate their potential as therapeutic targets (DFG JE 275/4-1).

Furthermore, we analyze molecular targets and signaling networks mediating radiation (hyper)sensitivity and radiation resistance in tumor and normal tissue cells by a systems biology approach in a collaborative research project funded by the BMBF. Here, we currently focus on similarities and differences in signaling networks between irradiated tumor and normal tissue cells to exploit this knowledge for a specific and effective radiation response modulation (ZiSS). Collaboration partners in thes prokect are the LMU Munic (C. Belka, K. Lauber), the BfS Muni (U. Kulka, S. Harnhardt, M. Gomolka), the Helmholtz Center Munic (H. Zitzelsberger, K. Unger, J. Hess) and the Charité Berlin (N. Blüthgen).

Selected publications

  • Klein D, Schmetter A, Imzak R, Wirsdörfer F, Unger K, Jastrow H, Stuschke M, Jendrossek V.   Therapy with multipotent mesenchymal stromal cells protects tlungs from radiation-induced injury and reduces the risk of metastasis. Antioxidant Redox Signaling Jul 16. (2015) [Epub ahead of print].
  • Wirsdörfer F, Cappuccini F, Niazman M, de Leve S, Westendorf AM, Lüdemann L, Stuschke M, Jendrossek V. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells.
  • Radiation Oncology Apr 25; 9(1):98 (2014). Eldh T, Heinzelmann F, Velalakan A, Budach W, Belka C, Jendrossek V. Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent. Strahlenther Onkol  188(3):274-81 (2012).
  • Cappuccini F, Eldh T, Bruder D, Gereke M, Jastrow H, Schulze-Osthoff, Ute Fischer, David Köhler D, Stuschke M, Jendrossek V. New insights into the molecular pathology of radiation-induced pneumopathy Radiother Oncol 101(1):86-92 (2011).
  • Heinzelmann F, Jendrossek V, Lauber K, Nowak K, Eldh T, Boras R, Handrick R, Henkel M, Martin C, Uhlig S, Köhler D, Eltzschig HK, Wehrmann M, Budach W, Belka C. Irradiation induced pneumonitis is mediated by the CD95/CD95-ligand system. J Nat Canc Inst 98: 1248-1251 (2006).

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