PD Dr. Thies Schröder

Research Projects

Improving the efficacy of chemoradiation therapy in solid tumors by controlling tumor blood flow

Lack of sufficient oxygen, or hypoxia, is a hallmark of solid primary and metastatic tumors and arises from the combination of uncontrolled cancer cell growth, poorly organized vasculature and inefficient blood flow that is characteristic for the microcirculation of most tumors. Although lack of oxygen decreases the viability of cancer cells, it has also a protective effect on them: Radiation therapy requires a certain amount of free oxygen, because oxygen-derived free radicals are required for the stabilization of radiation-induced DNA double strand breaks in the treated cancer cells. Thus, hypoxic tumors are relatively resistant to radiation treatment. At the same time, areas of the tumor that are chronically hypoxic are also difficult to reach by intravenous therapeutics, because they reside distant from active blood flow. We hypothesize that tumor blood flow can be temporarily improved in human cancer patients during chemoradiation therapy, using combinatorial vascular targeting strategies. If successful, such an approach could help improve therapeutic efficacy and increase the chance of survival of patients that suffer from tumors that are difficult to treat, such as unresectable liver metastases of colorectal and pancreatic carcinoma.

Specialized models of intravital microscopy

The ability to visualize microscopic processes in tissues of anesthetized research animals, termed intravital microscopy, has already produced invaluable information about mechanisms of diseases and disease response to treatment that could not be derived from histological analyses, or in vitro. For example, processes and stages in tumor angiogenesis (ingrowth of blood vessels into the tumor), and extravasation dynamics of anticancer drugs, have been studied extensively using the dorsal window chamber model in mice and rats. Over the past decades, multiple organs have been made accessible to intravital microscopy, such as the liver, brain, mammary fat pad, and the intestine of mice and rats. We have introduced a novel technique to visualize and measure microvascular blood flow and blood oxygenation in the live rat lung (Hanna 2013, Fontanella 2013). This model has already been employed to measure the response of the pulmonary circulation to therapy under hypoxia, and to quantify microvascular blood flow in pulmonary cancer metastases (Radiloff 2014, Blueschke 2014). However, many current intravital microscopy techniques suffer from characteristic problems, such as poor accessibility of the tissue of interest, artifacts associated with the fenestration technique, and limited longevity of the respective tissue window. We strive to develop technical solutions to common technical problems associated with intravital microscopy, but also to resolve known issues of the wellbeing of research animals that can be associated with some of these these methods.

Novel treatments of hypoxemia

Normally, human blood is fully oxygenated when it leaves the lung. However, diseases such as asthma, pneumonia, pulmonary fibrosis and pulmonary arterial hypertension, as well as environmental conditions such as thin mountain air, can decrease the oxygen content in the arterial blood, a condition termed hypoxemia. Mild hypoxemia causes a loss of exercise performance capacity whereas severe hypoxemia can be lethal. Although hypoxemia eventually leads to a lack of oxygen in downstream tissues, tissue hypoxia interestingly does not directly correspond to the oxygen level in the blood. Instead, tissue hypoxia is the consequence of physiological maladaptations that are ultimately triggered by systemic hypoxemia, such as hypoxic pulmonary vasoconstriction, global vasodilation of resistance arteries in the body, and occlusion of capillary beds. Indeed, we have identified several pharmacological strategies that reverse hypoxemia-induced maladaptations and restore exercise performance capacity in hypoxemic research animals, and humans (Radiloff 2012, Radiloff 2014, Scalzo 2015, Strand 2017, Schroeder 2017). As part of a longstanding collaboration between the University of Colorado in Denver, USA, our team is currently developing suitable routes of application for human-applicable anti-hypoxemic treatments, such as via inhalation.

Co-Workers

Dipl. Chem. Cornelia Seidel

Active off-Campus Collaborations

Prof. Dr. Timo ten Hagen, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, Rotterdam, NL

Prof. Dr. David C. Irwin, Cardiovascular Research Labs, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Publications

Blueschke G, Boico A, Negussie AH, Yarmolenko P, Wood BJ, Spasojevic, Fan P, Erdmann D, SCHROEDER T, Sauerbier M, Klitzman B. Enhanced Drug Delivery To The Skin Using Liposomes. Plastic and Reconstructive Surgery Global Open, 2018, July 9

SCHROEDER T, Piantadosi CA, Natoli M, Autmizguine J, Cohen-Wolkowiez M, Hamilton KL, Bell C, Klawitter J, Christians U, Irwin DC, Noveck RJ. Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia. Clin Pharmacol Ther. 2017 Aug 31. doi: 10.1002/cpt.860

Strand TE, Khiabani HZ, Boico A, Radiloff DR, Zhao Y,Hamilton KL, Christians U, Klawitter J, Noveck RJ, Piantadosi CA, Bell C, Irwin DC, SCHROEDER T. Safety of combined bambuterol and theophylline as a potential treatment of high altitude-induced fatigue in humans. Can J Physiol Pharmacol. 2017 May 3. doi: 10.1139/cjpp-2016-0635

Blatt S, Voelxen N, Sagheb K, Pabst AM, Walenta S, SCHROEDER T, Mueller-Klieser W, Ziebart T. Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: a prospective study over 15 years. Clin Oral Invest. 2016 Jan 4

Register JK, Fales AM, Wang HN, Norton SJ, Cho EH, Boico A, Pradhan S, Kim J, SCHROEDER T, Wisniewski NA, Klitzman B, Vo-Dinh T. In vivo detection of SERS-encoded plasmonic nanostars in human skin grafts and live animal models. Anal Bioanal Chem. 2015 Nov;407(27):8215-24

Khademi S, Frye MA, Jeckel KM, SCHROEDER T, Monnet E, Irwin DC, Cole PA, Bell C, Miller BF, Hamilton KL. Hypoxia mediated pulmonary edema: potential influence of oxidative stress, sympathetic activation and cerebral blood flow. BMC Physiol. 2015 Oct 9;15:4

Scalzo RL, Binns SE, Klochak AL, Giordano GR, Paris HL, Sevits KJ, Beals JW, Biela LM, Larson DG, Luckasen GJ, Irwin D, SCHROEDER T, Hamilton KL, Bell C. Methazolamide Plus Aminophylline Abrogates Hypoxia-Mediated Endurance Exercise Impairment. High Alt Med Biol. 2015 Dec;16(4):331-42

Fontanella EN, Boss MK, Hadsell M, Zhang J, SCHROEDER T, Berman KG, Dewhirst MW, Chang S, Palmer GM. Effects of High-Dose Microbeam Irradiation on Tumor Microvascular Function and Angiogenesis. Radiat Res. 2015 Feb;183(2):147-58

Scalzo RL, Binns SE, Klochak AL, Giordano GL, Paris HLR, Sevits KJ, Beals JW, Biela LA, Larson DG, Luckasen GJ, Irwin DC, SCHROEDER T, Hamilton KL, Bell C. The Effects of Sympathetic Inhibition on Metabolic and Cardiopulmonary Responses to Exercise in Hypoxic Conditions. Wilderness Environ Med. 2015 Dec;26(4):520-4

Eigenberger P, Faino A, Maltzahn J, Lisk C, Frank E, Frank A, Loomis Z, SCHROEDER T, Strand M, Irwin DC. Retrospective Study of Acute Mountain Sickness on Mt. Kilimanjaro using Trekking Company Data. Aviat Space Environ Med. 2014 Nov;85(11):1125-9

Blueschke G, Hanna G, Fontanella AN, Palmer GM, Boico A, Min H, Dewhirst MW, SCHROEDER T. Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats. J Vis Exp. 2014 Nov 30;(93)

Radiloff DR, Boico A, Zhao Y, Blueschke G, Irwin D, Hamilton K, Noveck R, SCHROEDER T. Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PLOS One. 2014 Jun 24;9(6):e99309

Kennedy KM, Scarbrough PM, Ribeiro A, Richardson R, Yuan H, Sonveaux P, Landon CD, Chi JT, Pizzo S, SCHROEDER T (co-Senior Author), Dewhirst MW. Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLOS One. 2013 Sep 12;8(9)

Fontanella A, SCHROEDER T, Palmer G, Hanna G, Secomb T, Dewhirst MW. Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm. Microcirculation. 2013 Jun 19

Hanna G, Fontanella A, Palmer G, Shan S, Zhao Y, Irwin D, Hamilton K, Boico A, Blueschke G, Piantadosi C, Dewhirst M, McMahon T, SCHROEDER T. Automated measurement of blood flow velocity and direction, and hemoglobin oxygen saturation in the rat lung using intravital microscopy. Am J Physiol Lung Cell Mol Physiol. 2013 Jan; 304(2):L86-91

Radiloff DR, Shan S, Zhao Y, Hanna G, Hamilton K, Irwin DR, Piantadosi CA, SCHROEDER T. Evidence for synergism between theophylline and endothelin receptor antagonists to improve exercise performance of rats under simulated high altitude. J Appl Physiol 2012, Oct 15, 113:1243-1252

Peltonen GL, Scalzo RL, Schweder MM, Larson DG, Luckasen GJ, Irwin D, Hamilton KL, SCHROEDER T, Bell C. Sympathetic inhibition attenuates hypoxia induced insulin resistance in healthy adult humans. J Physiol. 2012 Jun 1;590(Pt 11):2801-9.

Prichard HL, SCHROEDER T, Reichert WM, Klitzman B. Bioluminescence imaging of glucose in tissue surrounding polyurethane and glucose sensor implants. J Diabetes Sci Technol. 2010 Sep 1;4(5):1055-62

Moon E, Sonveaux P, Porporato PE, Danhier P, Gallez B, Batinic-Haberle I, Nien YC, SCHROEDER T, Dewhirst MW. NADPH oxidase-mediated ROS production activates HIF-1 via the ERK pathway after hyperthermia treatment. Proc Natl Acad Sci. 2010, Nov 8

Dewhirst MW, Thrall DE, Palmer G, SCHROEDER T, Vujaskovic Z, Cecil Charles H, Macfall J, Wong T. Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy. Int J Hyperthermia. 2010;26(3):283-93.

Jones LW, Viglianti BL, Tashjian JA, Kothadia SM, Keir ST, Freedland SJ, Potter MQ, Moon EJ, SCHROEDER T, Herndon JE 2nd, Dewhirst MW Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol. 2010 Feb;108(2):343-8

Vishwanath K, Klein D, Chang K, SCHROEDER T, Dewhirst MW, Ramanujam N. Quantitative optical spectroscopy can identify long-term local tumor control in irradiated murine head and neck xenografts. J Biomed Opt. 2009 Sep-Oct;14(5):054051

Palmer GM, Viola RJ, SCHROEDER T, Yarmolenko PS, Dewhirst MW, Ramanujam N. Quantitative diffuse reflectance and fluorescence spectroscopy: tool to monitor tumor physiology in vivo. J Biomed Opt. 2009 Mar-Apr;14(2):024010.

Chen JL, Lucas JE, SCHROEDER T, Mori S, Wu J, Nevins J, Dewhirst M, West M, Chi JT. The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet. 2008 Dec;4(12):e1000293. Epub 2008 Dec 5

Sonveaux P, Végran F, SCHROEDER T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008 Dec;118(12):3930-42

Stein RA, Chang CY, Kazmin DA, Way J, SCHROEDER T, Wergin M, Dewhirst MW, McDonnell DP. Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer. Cancer Res. 2008 Nov 1;68(21):8805-12

SCHROEDER T, Viglianti BL, Dewhirst MW. Low-intensity alternating electric fields: a potentially safe and effective treatment of cancer? Onkologie. 2008 Jul;31(7):357-8

Manzoor AA, SCHROEDER T, Dewhirst MW. One-stop-shop tumor imaging: buy hypoxia, get lactate free. J Clin Invest. 2008 May;118(5):1616-9

Davis BH, SCHROEDER T, Yarmolenko PS, Guilak F, Dewhirst MW, Taylor DA. An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy. Ann Biomed Eng. 2007 Aug;35(8):1414-24

Viglianti BL, Ponce AM, Michelich CR, Yu D, Abraham SA, Sanders L, Yarmolenko PS, SCHROEDER T, MacFall JR, Barboriak DP, Colvin OM, Bally MB, Dewhirst MW. Chemodosimetry of in vivo tumor liposomal drug concentration using MRI. Magn Reson Med. 2006 Nov;56(5):1011-8

Yuan H, SCHROEDER T, Bowsher JE, Hedlund LW, Wong T, Dewhirst MW. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2006 Jun;47(6):989-98

Peltz C, SCHROEDER T, Dewhirst MW. Monitoring metabolite gradients in the blood, liver, and tumor after induced hyperglycemia in rats with R3230 flank tumors using microdialysis and bioluminescence imaging. Adv Exp Med Biol. 2005;566:343-8

Moeller BJ, Dreher MR, Rabbani ZN, SCHROEDER T, Cao Y, Li CY, Dewhirst MW. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005, Aug;8(2):99-110

SCHROEDER T, Yuan H, Viglianti BJ, Peltz C, Asopa S, Vujaskovic Z, Dewhirst MW. Spatial heterogeneity and oxygen dependence of glucose consumption in R3230AC and fibrosarcomas (FSA) of the Fischer 344 rat. Cancer Research 2005, 65 (12), 1-9

Walenta S, SCHROEDER T, Mueller-Klieser W. Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Current Medicinal Chemistry 2004, Aug;11(16):2195-204

Walenta S, Chau TV, SCHROEDER T, Lehr HA, Kunz-Schughart L, Fuerst A, Mueller-Klieser W: Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? Journal of Cancer Research and Clinical Oncology 2003, 129, 321-6

Walenta S, SCHROEDER T, Mueller-Klieser W. In regard to Tarnawski et al., IJROBP 2002;52:1271-1276. Int J Radiat Oncol Biol Phys. 2002, Dec 1;54(5):1576

Weinmann M, Thews O, SCHROEDER T, Vaupel P: Expression pattern of the urokinase-plasminogen activator system in rat DS-sarcoma: role of oxygenation status and tumour size. British Journal of Cancer 2002, 86 (8), 1355-61

Walenta S, SCHROEDER T, Mueller-Klieser W: Metabolic mapping with bioluminescence: basic and clinical relevance. Biomolecular Engineering 2002, 18 (6), 249-62

Brizel DM, SCHROEDER T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. International Journal of Radiation Oncology BiologyPhysics 2001, 51 (2), 349-53