Objective
p73 is a transcription factor of the p53 tumor suppressor family. In approximately 50% of all cancer patients
the tumor suppressor function of p53 is irreversibly disabled by point mutations, which makes p53 one of the
most frequently mutated genes in cancer. This is entirely different for p73 and much of my previous work in
this field has been devoted to research on the role of p73 in cancer.
In sharp contrast to p53, p73 is often highly expressed in its wild-type form in solid tumors compared to
the surrounding normal tissue. This suggests the rather challenging hypothesis that p73 has oncogenic
functions in cancer cells, which promote tumor progression and therapy resistance. This concept is supported
by clinical data demonstrating p73 overexpression to be correlated with advanced tumor stage, metastasis,
therapy resistance and poor overall survival in multiple tumor entities including the ‘major killers’: breast,
lung and colorectal cancer. When p73 is depleted from cancer cell lines, tumor cell proliferation and
tumorigenicity are reduced, indicating that tumor cells with high p73 expression are p73-dependent. This
places p73 in line with oncogenes like Myc or mutant Ras, which are similarly essential for the tumorigenic
phenotype. However, tumor cells are not only addicted to a particular oncogene but in many cases codependent
on other cellular factors - a phenomenon termed ‘non-oncogene addiction’. Since p73 also has
tumor suppressive functions, p73-dependent tumor cells are likely to be critically dependent on cooperating
factors, which keep the proapoptotic and tumor suppressive functions of p73 in check. Inhibition of these
factors would be ‘synthetically lethal’ with overexpression of p73. From a clinical point-of-view it would be
extremely valuable, if we knew these factors and were able to block them in order to reactivate p73’s tumor
suppressor activity and trigger growth inhibition or cell death. This approach promises to be specifically
effective in the therapeutically challenging p73-dependent tumors with little or no side effects in normal
tissues with low p73 expression.
The goal of this project is therefore the identification and validation of such synthetic lethal interactions
with p73 using different functional genomics approaches. In the first part of the project we will characterize
the impact of p73-dependence on gene expression using genome-wide expression and global chromatin state
profiling. This will enhance our molecular understanding why cancer cells rely on high-level expression of
p73. In addition, this will pinpoint genes and pathways, which are co-expressed and activated together with
p73 and which are therefore candidate genes for therapeutic targeting of p73-dependent cancer cells. In the
second part of the project we will use RNAi screening techniques on a genome-wide scale to identify in an
unbiased manner cellular factors, which enable cancer cells to tolerate high-level expression of p73. These
genes are essential for long-term proliferation and survival in the context of p73 overexpression and could be
ideal drug targets for a tumor-selective therapy of the prognostically dismal class of p73-dependent tumors
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine oncology colorectal cancer
- natural sciences biological sciences genetics mutation
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2010-StG_20091118
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
35037 Marburg
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.