Molecular biomarkers
Introduction
Molecular biomarkers can be used to individualize the treatment of cancer so that each patient gets the best treatments with the lowest risk of unwanted side effects (also known as precision medicine). Molecular biomarkers include specific changes in biological material (DNA, RNA, or proteins), and can be studied in for instance samples of tumor and normal tissues, and blood and urine samples.
The aim of the project is to identify the most promising biomarkers for different purposes, depending on the specific kind of cancer. For some cancers, the aim would be to identify which patients do not need radiotherapy. In other cases, the aim would be to identify patients that can benefit from radiosensitizers (drugs that can enhance the benefit of radiotherapy for certain patients). Finally, the project will also investigate biomarkers that can predict the individual risk of unwanted side effects after radiotherapy.
Aim
To develop and implement molecular biomarkers that can improve the field of precision (personalized) radiation oncology for both tumor control and risk of normal tissue toxicity.
Background
Overall, molecular biomarkers are genome-based, or ‘omics’-based, markers that can include information on DNA (genetic and epigenetic), RNA (incl. miRNA), and protein levels. Analysis can be performed in tumor biopsies, normal tissue, and circulating markers in both patients and in pre-clinical in vitro and in vivo systems.
Molecular biomarkers are entering the field of precision medicine in medical oncology, with some drugs being linked to a specific molecular alteration, that has to be identified in the tumor before the drug can be used. In radiation therapy, no such biomarkers are routinely used in the clinic. Numerous markers have been proposed, but very few are being tested prospectively. One example of an ongoing prospective, randomized trial is DAHANCA 30 (see IP4).
Projects
i) Validation of gene profiles. A 15-gene hypoxia profile, currently being tested prospectively for predictive value of the benefit of hypoxic modification, a 7-gene signature for prediction of benefit of radiotherapy (RT) in breast cancer, and gene signatures related to immune response, will be tested in head and neck, in prostate, sarcoma, breast, anal and cervix cancer. When relevant, samples will simultaneously be evaluated for e.g. HPV status, tumor-infiltrating lymphocytes, and PD-L1. These studies are currently ongoing in the head and neck, breast, and cervix.
ii) NGS and gene expression data. In the coming years, data are expected to be available on a number of patients treated with RT as part of upcoming local and national initiatives on personalized medicine. The possibilities of using these data for prognostic and predictive purposes will be explored. First initiatives: a) head and neck (HPV vs smoking, ongoing) and b) glioblastoma (Hans Skougaard Poulsen).
iii) Identification of common and rare sequence alterations in genes related to the radiation response in patients with severe toxicity after radiotherapy. Studies are ongoing in breast and head and neck (Line H Schack, Jan Alsner and Nicolaj Andreassen).
iv) Development and validation of a clinically feasible predictive test for normal tissue radiosensitivity based on radiation-induced lymphocyte apoptosis (RILA) assay or gene expression pattern in lymphocytes irradiated in vitro (Nicolaj Andreassen).
Impact/Relevance/Ethics
The relevance and impact are expected in mainly three areas, identification and implementation of markers that can provide information on i) indication of radiotherapy, ii) use of radiosensitizers, and iii) predicting risk of normal tissue morbidity. The use of the markers will be tested in ethically approved prospective trials.
