Drug resistance in patients with chronic lymphocytic leukemia
In Denmark, there are around 400 new cases of chronic lymphocytic leukaemia each year. In recent years, new treatments have arisen including the use of the drug, ibrutinib. This drug targets specifically the type of blood cells with cancer and has therefore improved the survival. Although promising results have been obtained with this drug, some patients still experience poor treatment response, develop resistance or a more aggressive cancer. In most cases, poor treatment will contribute to reduced quality of life for the patient - physically and mentally. In this PhD project, I will investigate the molecular background of the cancer and why some patients do not benefit from the otherwise promising drug, ibrutinib, in chronic lymphocytic leukaemia.
The PhD study will be divided into three work packages:
Work package 1
The purpose of work package 1 is to provide new and valuable information on the biology behind why some patients do not benefit from treatment with ibrutinib. Previous research has shown that resistance can be explained by changes in two specific genes, meaning that the DNA of the cancer cells has been altered. However, not all resistant patients have changes in these genes, and I will therefore explore the whole coding part of the DNA for alterations in novel genes, not previously associated with drug resistance.
It is known from other types of blood cancers that the speed of the death of the cancer cells after treatment is associated to survival. I will thus investigate the presence of the cancer cells after ibrutinib treatment using an extremely sensitive method that allows examination of very small amounts of remaining cancer.
Finally, the project may be the first to establish a tool to predict resistance towards clinically used drugs in chronic lymphocytic leukemia, based on a mathematical model. The main hypotheses of work package 1 are i) drug resistance can be explained by mutations in novel genes not previously described as being associated with chronic lymphocytic leukemia, ii) the speed of the death of the cancer cells is associated with clinical outcome, iii) we can establish a predictor based on the molecular data that can predict drug resistance early during the disease.
Work package 2
The purpose of work package 2 is to explore if changes in the DNA that are known to cause drug resistance, can be identified already at diagnosis. No previous studies have shown this in chronic lymphocytic leukemia. However, we know that this can be the case in other types of blood cancers. To explore this, I will establish a highly sensitive method. If I can show successfully that the mutations are present prior to treatment, it will have great impact on the treatment strategy for the patients. The hypothesis of work package 2 is that it is possible to detect the mutation that causes drug resistance already before starting treatment.
Work package 3
The purpose of work package 3 is to explore some of the changes in the DNA that we find in work package 1 in cell cultures. Here, I will knock down the genes, with other words suppress the genes, and then investigate the impact on cells with and without ibrutinib. These cells will be examined with respect to growth and survival of the cancer cells. The hypothesis of work package 3 is that we can show that the changes in the DNA in ibrutinib resistant patients have an impact on the growth of cancer cells when exposed to ibrutinib.
I have previously worked on a related project about chronic lymphocytic leukemia and ibrutinib treatment and have here gained an in-depth insight into most of the techniques that we plan to use in the PhD project. I have expertise in the methods for identification of novel mutations, and in our research group, the methods for measuring the speed of the death of the cancer cells and very small amounts of remaining cancer and cell culture analysis are already being used in other projects. Finally, our group includes a bioinformatician with high-level expertise in mathematical modeling, who will help to establish a predictor for identifying patients who do not benefit from the treatment.
The relevance of the project is motivated by the unsuccessful treatment response and survival of chronic lymphocytic leukemia, which may cause unnecessary suffering for the patient. As treatments with ibrutinib are already used in the clinic, we believe this to be a timely project that should be started as soon as possible. Furthermore, the use of ineffective medicine does put an obvious financial strain on the healthcare system. We are not aware of published studies, nationally or internationally that have evaluated these specific questions, relying on the strategy outlined in this project.