Treating cancer is often a long-term process that involves surgery, radiation therapy and/or chemotherapy, all of which can have enormous impact on the patient's quality of life. Surgical interventions can be very mutilating; in advanced stages of cancer it can be necessary to completely remove glands, organs or large tissue parts. The side-effects of radiation therapy and chemotherapy can be very severe and, during the treatment period, make it impossible for patients to lead a normal life.

To offer better treatment to cancer patients, with less impact on their overall condition, new innovative therapies are needed, as well as methods to predict a patient's response to drugs. The latter can enhance the chances of success, while at the same time minimizing overtreatment. In order to generate new leads for drug development, we need more insight in the response of the human body to the occurrence of cancer and the interactions between tumor tissue and the surrounding healthy tissues. Detailed understanding of the genetic characteristics of cancer cells in relation to body's reaction is needed to understand individual differences between patients.

We focus on the body's response to cancer, in which we will concentrate on the immunological and non-immunological response. In addition, we will examine the differences in the tumor's response to chemotherapy.

Non-immunological response
The reaction of the tissue surrounding a tumor can be classified as a non-immunological response; in this light metastasis is a form of response as is angiogenesis (formation of blood vessels). Somehow, the interaction between the tumor and the surrounding tissue enables the tumor to grow and to spread. By including the role of the surrounding tissue in our genetic studies, we hope to identify new targets for drug development, for example aimed at preventing angiogenesis and combating metastasis.

Immunological response
The problems in cancer immunology are twofold. On one hand the effective anti-cancer immune response falls short of the maximally possible response. On the other hand the tumor is too much regarded as a healthy "self" tissue and accordingly protected against rejection by immunoregulatory mechanisms. These two aspects of the anti-cancer immune response will be studied using cervical cancer as the case-study. Cervical cancer is strongly linked to infections with the Human Papilloma Virus (HPV). While the majority of women is at some point infected with HPV, only a minority develops cervical cancer. Women who are able to eliminate the virus appear to have an increased interferon-gamma production. We aim to identify the genes that are involved in the production of interferon-gamma by HPV-specific immune cells, as this will possibly provide leads for the development of preventive and therapeutic vaccines for HPV infections. Especially in developing countries, where cervical cancer is a major cause of death in young women, a therapeutic vaccine is needed.

Response to chemotherapy
We will determine whether genetic predisposition in relation to genetic defects of DNA repair proteins sensitizes normal cells to anticancer therapy. To this end, we will perform genomic analysis on patient-derived cells that are exposed to anticancer drugs. Anticancer treatment will result in wanted (i.e. anti-tumor) as well as unwanted toxicity to normal tissue. Using proteomic analysis of whole serum, we will determine biomarkers that are predictive of both host-tumor interactions and responses to anticancer therapy. These biomarkers will subsequently be used to develop prognostic (predictive) tools.

Responses to anticancer therapy depend on whether anticancer drugs are activated or detoxified by the body. In this process, bioactivation enzyme activity is important. Therefore, we will evaluate this activity as well as the genes related to enzymes that are required for the metabolism of anticancer drugs. We will determine both tumor response as well as undesired cytotoxicity. Acquired resistance to anticancer therapy is an important problem. There are indications that this may be related to increased DNA repair activity in tumor cells. We will investigate such a relationship in both patient material and a panel of human cancer cell lines using expression analysis and whole-genome expression profiling.

We aim to gain detailed understanding of the role of the surrounding tissue in the growth and spreading of a tumor, thereby generating new leads for anticancer drugs (e.g. anti-angiogenesis modalities). Our studies into the body’s response to high risk HPV are targeted towards the development of immunotherapy for persistent HPV infections and the associated (pre-)malignant lesions. Finally, we aim to develop new prognostic tools to predict a patient's response to chemotherapy, in order to increase efficacy of the treatment track and decrease unwanted side-effects.