Periodic Reporting for period 1 - DynaCOMP (Assessing compounds targeting DNA replication licensing complexes as anti-tumor agents)
Okres sprawozdawczy: 2017-07-01 do 2018-12-31
Cancer is a major clinical, societal and economic burden worldwide and development of novel anti-cancer therapies constitutes a major investment of public and private funds. Despite intense research over decades however, which has led to a much improved understanding of cancer biology, cancer treatment remains a challenge. This is to a large extent due to the genetic heterogeneity of cancer and the ability of cancer cells to escape treatment by constantly undergoing further genetic alterations. During our ERC funded work, we have shown that aberrations in the DNA replication licensing pathway may contribute to the genome plasticity of cancer cells, and appear a common feature of cancer cells. They may however also constitute an Achilles foot, as cancer cells seem to be more dependent on negative regulators of the licensing system for survival. Cancer cells may therefore be more sensitive than normal cells to compounds targeting this control (inhibition of untimely licensing). We have identified compounds which target the DNA replication licensing inhibitor Geminin. During the DYNACOMP PoC study we completed the following goals:
- We assessed the efficacy and specificity of the identified compounds and studied their mechanism of action. To that end, a number of hit compounds were analysed first in vitro, for specificity and favourable chemical properties, and then in cells. We showed that two of our hit compounds initiated specific cellular pathways which led to DNA replication stress, DNA damage and cell cycle arrest in a dose-specific and target-specific manner. These findings offer strong support for further development of the hit compounds towards clinical translation.
- We investigated the potential use of these compounds for studying cell cycle processes. We showed that our two top hit compounds led to a DNA replication stress phenotype. DNA replication stress has attracted significant attention in recent years as an early hallmark of cancer cells which drives tumorigenesis. Therefore these compounds, in addition to their potential clinical applications, may be a highly useful research tool for the cancer biology community, for studying the cellular responses which are initiated following DNA replication stress, as well as the pathways which may counter-balance DNA replication stress in normal cells.
- We assessed whether the functional imaging approaches developed under the mother ERC project, which quantify protein-protein interactions within living cells, may be of more general use for in-cell analysis of novel lead compounds. We further developed these assays towards high-content, high-throughput functional imaging. In parallel, we developed cellular systems in both lower and higher eukaryotes which can be used for the assessment of novel lead compounds.
- We set-out a strategy for the steps required to bring compounds to the clinic, secured IPR and entered into strategic collaborations.
The DYNACOMP PoC study has paved the way for the preclinical drug development of promising novel anti-cancer compounds and for the exploitation of tools, cellular systems and assays developed through ERC funded research.
- We assessed the efficacy and specificity of the identified compounds and studied their mechanism of action. To that end, a number of hit compounds were analysed first in vitro, for specificity and favourable chemical properties, and then in cells. We showed that two of our hit compounds initiated specific cellular pathways which led to DNA replication stress, DNA damage and cell cycle arrest in a dose-specific and target-specific manner. These findings offer strong support for further development of the hit compounds towards clinical translation.
- We investigated the potential use of these compounds for studying cell cycle processes. We showed that our two top hit compounds led to a DNA replication stress phenotype. DNA replication stress has attracted significant attention in recent years as an early hallmark of cancer cells which drives tumorigenesis. Therefore these compounds, in addition to their potential clinical applications, may be a highly useful research tool for the cancer biology community, for studying the cellular responses which are initiated following DNA replication stress, as well as the pathways which may counter-balance DNA replication stress in normal cells.
- We assessed whether the functional imaging approaches developed under the mother ERC project, which quantify protein-protein interactions within living cells, may be of more general use for in-cell analysis of novel lead compounds. We further developed these assays towards high-content, high-throughput functional imaging. In parallel, we developed cellular systems in both lower and higher eukaryotes which can be used for the assessment of novel lead compounds.
- We set-out a strategy for the steps required to bring compounds to the clinic, secured IPR and entered into strategic collaborations.
The DYNACOMP PoC study has paved the way for the preclinical drug development of promising novel anti-cancer compounds and for the exploitation of tools, cellular systems and assays developed through ERC funded research.