Metabolic control of radioresistance in breast cancer
Host: Université catholique de Louvain
Contact person: email@example.com
Location: Louvain, Belgium
Breast cancer is the first type of cancer in women worldwide, and Europe has the highest rate of diagnosis. Chemoradiotherapy associated with surgery is part of standard breast cancer clinical care, but tumors can relapse, often because cancer cells acquire intrinsic chemoradioresistance. Our project aims to test the possibility that metabolic alterations are responsible for the acquired radioresistance of breast cancer cells to X-rays. Based on previous observations of our team in head and neck squamous cell carcinoma cells the focus will be set on mitochondria, as these organelles control DNA repair (ATP generation), cell proliferation (biosynthesis) and apoptosis (cytochrome c, superoxide and Ca2+ release). Because it is not protected by histones and has limited repair capacities, mitochondrial DNA (mtDNA) also potentially constitutes a main target of radiotherapy, which will be investigated together with mitochondrial turnover (mitophagy and mitochondrial biogenesis).
This project will identify a metabolic profile associated with radioresistance and lay the ground for antimetabolic strategies aimed to radiosensitize breast cancer cells and, potentially, other cancer types.
In vivo real-time imaging of the impact of ionizing radiation on cellular energy metabolism
Host: University of Zurich
Contact person: firstname.lastname@example.org
Location: Zurich, Switzerland
Although radiotherapy is used in more than half of cancer treatments, the effect of ionizing radiation on a differential metabolism in tumor and healthy cells is not well understood. The aim of this project is to collect quantitative data on the energy metabolism of healthy and tumor brain cells using recently developed fluorescent biosensors which allow measuring metabolic parameters in vivo and in real time. This project will be performed in collaboration with Prof. B. Weber at the University of Zurich, who is world-leading expert for in vivo real-time bioimaging. Simultaneously, we will perform millimeter-scaled tumor irradiation to understand the effect of ionizing radiation on the energy metabolism in vivo.
These data will provide fundamental insights to better target the effect of ionizing radiation on the energy metabolism of tumor cells. For the first time, we will provide a real-time readout of ionizing radiation (and anti-tumor drugs) on critical parameters of energy metabolism. This hybrid method coupling ionizing radiation and real time imaging of metabolic substrate is expected to significantly advance the knowledge of tumor biology and therefore provide a knowledge to increase radiotherapy efficiency.
Targeting tumor metabolism to improve the therapeutic window for radiotherapy
Host: University of Oxford
Contact person: email@example.com
Location: Oxford, United Kingdom
The efficacy of radiotherapy is limited by the adverse effects caused by damage to healthy tissues adjacent to the tumor. Tumor radiosensitivity is determined by intrinsic sensitivity, the inherent sensitivity of the tumor cells, and extrinsic sensitivity, resistance to killing that is imparted through the tumor environment. One key factor determining extrinsic radiosensitivity is tumor hypoxia. A possible strategy to reduce tumor hypoxia is to decrease the oxygen consumption rate in the normoxic tumor cells thereby increasing the availability of oxygen to the hypoxic areas. In order to identify compounds that can alleviate tumor hypoxia, we conducted a high throughput screen to measure oxygen consumption in cancer cells and screened library of 1,697 FDA-approved compounds. One of the potential compounds we identified was the anti-malarial drug atovaquone as a potent reducer of oxygen consumption. Atovaquone was subsequently demonstrated to reduce hypoxia in spheroids and xenograft tumors and caused significant tumor growth delay in combination with radiation in these models. The aim of this project is to further investigate the mechanism of action of atovaquone and other compounds identified in the screen or their derivatives in vitro and in vivo in combination with radiation and other anti-cancer therapeutics.
Our research will identify new drug therapies to selectively render tumors more sensitive to radiation without exacerbating effects in normal tissues.
Glioma organoids to decipher mechanisms of treatment resistance
Host: Universiteit Maastricht
Contact person: firstname.lastname@example.org
Location: Maastricht, The Netherlands
Glioblastoma (GBM) is the most aggressive adult primary brain tumor and remains incurable. At present, there is still a large knowledge gap and lack of clinically relevant models to identify the molecular and cellular mechanisms that drive intrinsic and -de novo- treatment resistance in GBM. The aim of this project is to establish GBM organoid models expressing genetically encoded fluorescent tracers (confetti) that can be temporally ‘activated’ to enable lineage tracing and cell ablation and to visualize patters of clonal evolution in response to treatment or changes in the tumor microenvironment in a spatial and temporal manner within and between patients.
This project will enable, by developing a primary human tumor cell culturing platform, the understanding the impact of tumor cell mutations on stem cell renewal and differentiation and the identification of new interventions against recurrent treatment-resistant glioblastoma.
The cancer cell adhesome for chromatin organization and DNA damage response
Host: Technische Universität Dresden
Contact person: email@example.com
Location: Dresden, Germany
The cancer cell adhesome connects the cell with both the surrounding extracellular matrix (ECM) and the cell membrane with the cytoplasmic and nuclear matrix. It is well accepted that the cancer cell adhesome fundamentally impacts on the response to anticancer therapies. Our preliminary data outlines that growth in three-dimensional ECM and ECM stiffness are key determinants for DNA repair efficacy as well as chromatin organization and flexibility. The aim of this project is identifying the underlying mechanisms how the adhesome/Chromatin/DNA repair machinery controls cancer cell resistance to (radio)therapy and facilitates the development of acquired resistance in head and neck squamous cell carcinomas.
This project will unravel how adhesome, chromatin and DNA repair are mechanistically intertwined and identify new targets for combined cancer therapy.
Impact of radiation quality (photons versus protons) on molecular and cellular responses
Host: West German Proton Therapy Centre
Contact person: firstname.lastname@example.org / email@example.com
Location: Essen, Germany
Proton beam therapy is increasingly applied in cancer treatment, as it promises to reduce normal tissue damage at critical radiosensitive structures. However, some recent reports point to a potential biological effect of the increased LET of protons at the distal edge of the spread out Bragg peak (SOBP) in tumor models and normal tissue damage models in vitro and in vivo. So far, potential differences in the biology of induced DNA damage and the resulting cellular responses between irradiation with photons or protons are not well understood. We propose to use state-of-the art radiobiology endpoints as well as innovative molecular (CRISP/cas9) and cell biology methods (e.g. 2D, 3D culture) and high resolution microscopy to compare the consequences of irradiation with photons and protons at the molecular (DNA damage and repair) and cellular level (survival, signaling) in tumor cells and normal tissue cells and to explore the consequences of genetic or pharmacologic inhibition of molecular factors involved in the regulation or execution of DNA repair.
The proposed project will define similarities and differences in DNA damage induction and repair, cell survival and cell signaling of tumor and normal tissue cells in response to irradiation with photons and protons (plateau, spread out Bragg peak, distal Bragg peak) and elucidate if cells with specific defects in the DNA damage response might be more sensitive or resistant to proton irradiation. These results are of clinical relevance as they may help to select patients that could particularly benefit from proton or photon therapy and to define rational approaches for combining proton therapy with drugs targeting components of the DNA repair machinery.