ERC FUNDED PROJECTS

"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects. The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."

2 497 520 €

Start date: 2016-09-01, End date: 2021-08-31

Important methods and results in discrete mathematics arise from the interaction between discrete mathematics and ``continuous'' areas like analysis or geometry. Classical examples of this include topological methods, linear and semidefinite optimization generating functions and more. More recent areas stressing this connection are the theory of limit objects of growing sequences of finite structures (graphs, hypergraphs, sequences), differential equations on networks, geometric representations of graphs. Perhaps most promising is the study of limits of growing graph and hypergraph sequences. In resent work by the Proposer and his collaborators, this area has found highly nontrivial connections with extremal graph theory, the theory of property testing in computer science, to additive number theory, the theory of random graphs, and measure theory as well as geometric representations of graphs. This proposal's goal is to explore these interactions, with the participation of a number of researchers from different areas of mathematics.

739 671 €

Start date: 2009-01-01, End date: 2014-06-30

Mirror symmetry arose originally in physics, as a duality between $N = 2$ superconformal field theories. Witten formulated a more mathematically accessible version, in terms of topological field theories. Both conformal and topological field theories can be defined axiomatically, but more interestingly, there are several geometric ways of constructing them. A priori, the mirror correspondence is not unique, and it does not necessarily remain within a single class of geometric models. The classical case relates $\sigma$-models, but in a more modern formulation, one has mirror dualities between different Landau-Ginzburg models, as well as between such models and $\sigma$-models; orbifolds should also be included in this. The simplest example would be the function $W: \C \rightarrow \C$, $W(x) = x^{n+1}$, which is self-mirror (up to dividing by the $\bZ/n+1$ symmetry group, in an orbifold sense). While the mathematics of the $\sigma$-model mirror correspondence is familiar by now, generalizations to Landau-Ginzburg theories are only beginning to be understood. Today it is clear that Homologcal Mirror Symmetry (HMS) as a categorical correspondence works and it is time for developing direct geometric applications to classical problems - rationality of algebraic varieties and Hodge conjecture. This the main goal of the proposal. But in order to attack the above problems we need to generalize HMS and explore its connection to new developments in modern Hodge theory. In order to carry the above program we plan to further already working team Vienna, Paris, Moscow, MIT.

1 060 800 €

Start date: 2009-01-01, End date: 2013-12-31

"Because of its biological complexity, cancer is still poorly understood. Chronic inflammation has been shown, both experimentally and epidemiologically, to be a predisposition to, and also an inseparable aspect of clinically prevalent cancer entities. Therefore, a detailed understanding of both tumour and immune cell functions in cancer progression is a prerequisite for more successful therapeutic startegies. My team was the first to reveal the lymphocyte-intrinsic PKC/NR2F6 axis as an essential signalling node at the crossroads between inflammation and cancer. It is the mission of this project to identify molecular signatures that influence the risk of developing tumours employing established research tools and state-of-the-art genetic, biochemical, proteomic and transcriptomic as well as large scale CRISPR/Cas9 perturbation screening-based functional genomic technologies. Defining this as yet poorly elucidated effector pathway with its profoundly relevant role would enable development of preventive and immune-therapeutic strategies against NSCLC lung cancer and potentially also against other entities. Our three-pronged approach to achieve this goal is to: (i) delineate biological and clinical properties of the immunological PKC/NR2F6 network, (ii) validate NR2F6 as an immune-oncology combination target needed to overcome limitations to ""first generation anti-PD-1 checkpoint inhibitors"" rendering T cells capable of rejecting tumours and their metastases at distal organs and (iii) exploit human combinatorial T cell therapy concepts for prevention of immune-related adverse events as well as of tumour recurrence by reducing opportunities for the tumour to develop resistance in the clinic. Insight into the functions of NR2F6 pathway and involved mechanisms is a prerequisite for understanding how the microenvironment at the tumour site either supports tumour growth and spread or prevents tumour initiation and progression, the latter by host-protective cancer immunity."

2 484 325 €

Start date: 2018-10-01, End date: 2023-09-30