ERC FUNDED PROJECTS

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations: - First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37); - Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells (Turk et al.,Cancer Res, 2009. 69(21)); - Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15); - Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204). I propose a comprehensive series of studies that will address thefollowing critical questions: - First, what is the scope of MDR-selective compounds? - Second, what is their mechanism of action? - Third, what is the optimal therapeutic modality? Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

1 499 640 €

Start date: 2012-01-01, End date: 2016-12-31

Carbon dioxide capture and storage is a technology to mitigate climate change by removing CO2 from flue gas streams or the atmosphere and storing it in geological formations. While CO2 removal from natural gas by amine scrubbing is implemented on the large scale, the cost of such process is currently prohibitively expensive. Inexpensive alkali earth metal oxides (MgO and CaO) feature high theoretical CO2 uptakes, but suffer from poor cyclic stability and slow kinetics. Yet, the key objective of recent research on alkali earth metal oxide based CO2 sorbents has been the processing of inexpensive, naturally occurring CO2 sorbents, notably limestone and dolomite, to stabilize their modest CO2 uptake and to establish re-activation methods through engineering approaches. While this research demonstrated a landmark Megawatt (MW) scale viability of the process, our fundamental understanding of the underlying CO2 capture, regeneration and deactivation pathways did not improve. The latter knowledge is, however, vital for the rational design of improved, yet practical CaO and MgO sorbents. Hence this proposal is concerned with obtaining an understanding of the underlying mechanisms that control the ability of an alkali metal oxide to capture a large quantity of CO2 with a high rate, to regenerate and to operate with high cyclic stability. Achieving these aims relies on the ability to fabricate model structures and to characterize in great detail their surface chemistry, morphology, chemical composition and changes therein under reactive conditions. This makes the development of operando and in situ characterization tools an essential prerequisite. Advances in these areas shall allow achieving the overall goal of this project, viz. to formulate a roadmap to fabricate improved CO2 sorbents through their precisely engineered structure, composition and morphology.

1 994 900 €

Start date: 2019-06-01, End date: 2024-05-31

Calcium-activated chloride channels (CaCCs) play key roles in a range of physiological processes such as the control of membrane excitability, photoreception and epithelial secretion. Although the importance of these channels has been recognized for more than 30 years their molecular identity remained obscure. The recent discovery of two protein families encoding for CaCCs, Anoctamins and Bestrophins, was a scientific breakthrough that has provided first insight into two novel ion channel architectures. Within this proposal we aim to determine the first high resolution structures of members of both families and study their functional behavior by an interdisciplinary approach combining biochemistry, X-ray crystallography and electrophysiology. The structural investigation of eukaryotic membrane proteins is extremely challenging and will require us to investigate large numbers of candidates to single out family members with superior biochemical properties. During the last year we have made large progress in this direction. By screening numerous eukaryotic Anoctamins and prokaryotic Bestrophins we have identified well-behaved proteins for both families, which were successfully scaled-up and purified. Additional family members will be identified within the course of the project. For these stable proteins we plan to grow crystals diffracting to high resolution and to proceed with structure determination. With first structural information in hand we will perform detailed functional studies using electrophysiology and complementary biophysical techniques to gain mechanistic insight into ion permeation and gating. As the pharmacology of both families is still in its infancy we will in later stages also engage in the identification and characterization of inhibitors and activators of Anoctamins and Bestrophins to open up a field that may ultimately lead to the discovery of novel therapeutic strategies targeting calcium-activated chloride channels.

2 176 000 €

Start date: 2014-02-01, End date: 2020-01-31

T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory. I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.

2 500 000 €

Start date: 2013-08-01, End date: 2018-07-31