p73 dependence in cancer: from molecular mechanisms to therapeutic targeting (P73CANCER)

Framework: FP7 — Ideas
Programme: European Research Council
Theme: European research council
Destination: Starting grants
Action type: Support for frontier research (ERC)
Panel: Physiology, Pathophysiology and Endocrinology
Countries involved: Germany
Call:  (ERC-2010-StG_20091118, 2010)
Start date: 2010-10-01
End date: 2016-09-30
Duration (months): 72.0
Total project cost (EUR): 1499040.0
EU funding (EUR): 1499040.0
Participants: 1
Project status: CLOSED

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

Keywords: cancer,tumor suppressor,oncogene,p53,p73