Cancer research experiments

Unveiling drug resistance mechanism in colorectal cancer treatment

WU tags: EGFR

Description

Experiment image

Cancer is fundamentally about an uncontrolled growth and tissue invasion by mutant cells in an organism. Experts often highlight the variability between types of cancers and even between patients. This high variability is due to the unique genetic profile of each tumour, which is the result of several mutations in the DNA of cells that end up causing the uncontrolled growth and the aggressive invasion of other tissues in the body (metastasis). Unlike traditional chemotherapies or radiotherapies, newer treatments aim to specifically target malignant cells. This is done by identifying certain proteins that are differentially expressed in tumourogenic cells as compared to normal cells. One example is the depicted EGFR (Epidermal Growth Factor Receptor) with 4 of its modules (domains) colored in red, green, black and cyan. EGFR is a key intermediate in the growth signal transduction pathways in cells. When a cell triggers its growth mechanisms it is doing so by receiveing and sending signals from EGFR. EGFR is found overexpressed in some cancers such as CRC (colorectal cancer), therefore it has been used as a target to differentiate malginant from normal cells. Several drugs currently in use are already targeting EGFR. One of them is cetuximab, a fragment of which is coloured in yellow and orange in the picture. Cetuximab, works by blocking the messenger molecule 'landing' domain in EGFR (in black). Cetuximab, designed to bind more strongly than the messenger, outcompetes it avoiding signal transmission and tumour growth. However, due to the high mutation rate of cancer cells, after prolonged treatment with this drug, researchers at the Hospital del Mar here in Barcelona are finding new mutations that affect the affinity of cetuximab to EGFR. In some cases, it no longer blocks the binding of the messenger. That means that the drug, for some patients, becomes ineffective. The tumour evolves and becomes resistant to the drug.
With your help, we will provide an explanation of the specific molecular mechanisms that occur in these mutated EGFR molecules that do not bind cetuximab. The ultimate objective is to provide hints on possible solutions to overcome this resistance. This work is in collaboration with researchers and medical doctors at the Hospital del Mar.
We will send several simulations measuring binding affinities of the normal and mutant receptors with the drug. Additionally we will compare these with the affinities of 'natural' messenger molecule that outcompetes the drug in the mutant case and finally we will measure affinities for a couple of other versions of the drug to see if we can 'fix it'.


Molecular simulations of the SH2 and phosphopeptide binding process

WU tags: pYEEI, SH2, SH2MSM

Description

The SH2 is a protein domain involved in protein-protein interactions. This particular domain plays a major role in cell communication on the sigalling processes for cell growth and development. We have been using this system to develop methods for computing protein-protein binding affinities but through massive free peptide binding simulations (see video) we have also expanded the knowledge on the dynamical behaviour of the system itself.
Such methods will be very useful, for example, in the study of why certain wrong forms of proteins stop interacting with other partner proteins, as a way to give explanation to phenoma observed in diseases such as Cancer

Publications

  • T. Giorgino, I. Buch and G. De Fabritiis, Visualizing the induced binding of SH2-phosphopeptide, J. Chem. Theory Comput., in press (2012)
  • I. Buch, S. K. Sadiq and G. De Fabritiis, Optimized potential of mean force calculations of standard binding free energy, J. Chem. Theory Comput., 7, 1765–1772 (2011)
  • I. Buch, M. J. Harvey, T. Giorgino, D. P. Anderson and G. De Fabritiis, High-throughput all-atom molecular dynamics simulations using distributed computing, J. Chem. Inf. and Mod. 50, 397 (2010)