Scientists can predict in the lab whether a drug will be effective for individual colorectal tumors.
Colorectal carcinomas arise in different forms, so all treatments do not work for all patients. OncoTrack, a public-private consortium supported by the Innovative Medicines Initiative Joint Undertaking, has conducted one of Europe's largest collaborative academic-industry research projects to develop and assess novel approaches for identification of new markers for colon cancer.
Scientists from the OncoTrack Consortium, including researchers from the Max Planck Institute for Molecular Genetics in Berlin and the company Alacris Theranostics, have analyzed tumor samples from patients with this type of cancer in a preclinical study. In particular, the scientists looked for biomarkers, i.e. molecules that are typical of the different tumor sub-groups and provide valuable information for diagnosis and potential treatment. Among other things, the research team discovered molecules that can predict the effectiveness of two drugs commonly used to treat this disease: Cetuximab, which inhibits the receptor for the epidermal growth factor (EGFR), and the chemotherapy drug 5FU.
Bowel cancer is the third most common form of cancer in the world and 95 percent of cases are colorectal carcinomas. At an advanced stage they are one of the most common causes of death, as only some patients respond to drug treatment. The experts do not know all the precise reasons for this, but it is clear that colorectal carcinomas are a very heterogeneous group of cancers. "Better understanding of this molecular heterogeneity and its impact on drug response is required", says Bodo Lange, CEO at Alacris Theranostics. To be able to predict a tumor's response to certain drugs more accurately, scientists require detailed information about the molecular profiles of the patients and their tumors.
Medical scientists working at the Charité University Hospital in Berlin and University Hospital Graz collected tumor samples from over 100 colorectal cancer patients at different stages of the disease for their study.
These tumors were then grown in tissue culture systems, as well as in special mouse strains, and subsequently treated with a range of medicaments. Through this, the scientists were able to better understand the relationships between the molecular pattern and the response of the tumor to drugs.
The scientists identified the genetic composition of the tumors and analyzed their so-called transcriptome, namely the set of all RNA molecules synthesized in a given tissue. Based on this analysis, they were able to produce a definite molecular fingerprint for all of the tumors. The scientists from the Max Planck Institute for Molecular Genetics and colleagues at EPO, Berlin, and Eli Lilly, Madrid, then tested how the tumors responded to different drugs and in this way correlated the tumor fingerprints with their response to the different clinical compounds.
If a group of tumors could be successfully treated using a drug, the scientists looked for typical biomarkers for this tumor type. Up to now, doctors have decided for and against the use of a drug directed against the EGF receptor mainly based on gene mutations. However, the mutation status alone is not specific enough. The knowledge of additional biomarkers could help to improve the individual treatment of cancers.
The consortium team identified two such biomarkers, which predict whether either the EGFR inhibitors Cetuximab or the chemotherapy 5FU could trigger a successful response in colorectal cancer. "The study has revealed a number of exciting findings that have the potential to guide treatment decisions", explains Lange. The scientists now know the molecular profile of the tumors, which are more likely to be successfully treated with these drugs.
"The extensive molecular and drug sensitivity datasets generated within this study are a highly valuable resource", says Lange. "Our findings provide major new insights into the molecular landscape of colorectal cancer, including the identification of novel alterations, which can be further exploited for advancing understanding of this lethal tumor type and for personalizing therapies."
The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115234 (OncoTrack), resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions (www.imi.europa.eu).
Article: Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors, Bodo Lange et al., Nature Communications, doi: 10.1038/ncomms14262, published online 10 February 2017.