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Damage and Repair in Cancer Development and Cancer Treatment (DARE)

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​​​​​​​​​​​​​​​​​​​​​Cancer is a genetic disease caused by inherited or acquired DNA alterations. The specific genetic make-up of healthy cells as well as that of cancer cells has a profound influence on the risk of developing cancer, on cancer cell behavior as well as on the effects of treatment on cancer cells. The genetic make-up of cancer patients also affects the long-term effects of cancer treatment. The DARE research program brings together scientists who investigate treatment consequences in normal and cancerous cells and stem cells, both at a basic mechanistic level and through preclinical and clinical studies. The program also investigates the immediate effects of treatment (palliation, curation), the long-term adverse effects of treatment in cancer survivors and the prevention of these effects.

The DARE program brings together basic, preclinical and clinical researchers who study different aspects of cellular damage, its repair and the clinical consequences thereof. Ultimately, DARE aims to create a scientific atmosphere that inspires bachelor’s, master’s and PhD students, stimulates scientific collaboration between clinicians, epidemiologists and basic scientists and encourages the initiation of cooperative research projects. By coordinating research activities fundamental to clinical content, DARE aims to better understand the molecular and cellular mechanisms of damage repair and translate these findings into improved patient selection and better treatment of cancer patients.​

Mission  

The aim of the “Cellular Damage and Repair in Cancer and Cancer Treatment” programme is to coordinate research activities on the mechanistic insight and clinical implications of short and long-term effects of anti-cancer treatments and preventive strategies. The activities are focused on three levels:

 

  1. Genetic and chromosomal damage in tumorigenesis and ageing.
  2. Short- and long-term responses to anti-cancer treatments in normal and cancer tissues.
  3. The short- and long-term effects of cancer, anti-cancer treatments and preventive strategies on health-related outcomes and quality of life in cancer survivors.
Programme Leaders   Principal Investigators   Description of the Programme  

The aim of the “Cellular Damage and Repair in Cancer” programme is to coordinate research activities on the roles of genetic and chromosomal damage in tumorigenesis and ageing, treatment responses to genotoxic anti-cancer treatments, and long-term effects.

DARE’s goal is to connect basic, preclinical and clinical researchers who investigate different aspects of cellular damage, its repair and its clinical consequences. The program aims to do this through the creation of a scientific atmosphere that inspires bachelor’s, master’s and PhD students, stimulates scientific collaboration and encourages initiation of cooperative research projects. By coordinating research activities fundamental to clinical content, we aim to better understand the molecular and cellular mechanisms of damage repair and translate these findings into improved patient selection and better treatment of cancer patients.

The research program “Cellular Damage and Repair in Cancer” coordinates both basic research as well as translational and clinical studies in the field of cancer-related and cancer treatment-related cellular damage in tumors and healthy tissue.

1. The role of chromosomal and genetic defects in tumorgenesis and ageing

Cancer is a genetic disease. Epidemiological studies as well as studies in model organisms have shown that mutations in our DNA lead to accelerated cellular and organismal ageing and cancer. Within this program we investigate which gene mutations interfere with genomic maintenance and predispose to cancer development. In addition, we analyze large databases to improve the estimates for the risk of developing cancer. These prognostic models include data on the mutation spectra of established tumor suppressors as well as associated clinical data and data from families.

2. Responses of normal and cancer cells to genotoxic agents

The successful response of cancer patients to often genotoxic therapies relies on many diverse factors. Within this research program we study how DNA damage repair, pro-apoptotic signaling and pro-survival signaling are involved in the response to commonly used and experimental anti-cancer therapeutics. Moreover, specific subsets of treatment-responsive and treatment-resistant cancer and normal tissue cells are studied to ultimately identify the mechanisms of treatment response. In addition, within our program, analyses of patient-derived material are used to identify and validate predictive and prognostic markers in several tumor types – including head-and-neck tumors – and in normal tissues.

3. Long-term effects of genotoxic anti-cancer therapeutics

Increasingly, better treatment results in more cancer survivors. Unfortunately, anticancer therapeutics also affect normal cells, which may lead to profound adverse effects. These adverse effects include altered metabolism, cardiovascular events, normal tissue dysfunction and secondary cancers, many of which can be denominated by accelerated ageing. Within this research program, basic cellular studies aim to identify the effects of radio/chemotherapy on normal and cancerous cells and stem cells, and their regenerative potential. In addition, clinical studies are performed to investigate the incidence of long-term outcomes in terms of cardiovascular dysfunction, but also on measures such as fatigue and depression, sexual functioning and quality of life, as we suspect that these are interrelated. To this end, we study cohorts in general practice as these are unselected, and pharmacological databases. Additionally, we are working on an infrastructure in which we – with the patient’s consent – collect patient’s clinical data as well as biomaterial and assess quality-of-life data which is organized within OncoLifeS. We intend to evaluate the short- and long-term outcomes of cancer and cancer-related treatment on mortality, morbidity and quality of life. This also gives us the opportunity to develop tools for prediction, which will lead to better patient selection for treatment and prevention, and to enable the study of repair of late-stage adverse effects of cancer-therapies.

The “Cellular Damage and Repair in Cancer” programme organizes monthly meetings in which PhD students, post-docs, undergraduate students, technicians and PIs discuss research progress. These cross-disciplinary and inter-departmental meetings are aimed at creating an atmosphere in which scientific insight and techniques are exchanged in order to optimally stimulate interaction and collaboration.

Relevance to Healthy Ageing  

Cancer is a genetic disease. Epidemiological studies as well as studies in model organisms have shown that mutations in our DNA lead to cancer. The process of tumorigenesis, however, is a multistep process that may take years to decades until cancer clinically manifests. For this reason, cancer risk rises with age and clearly prevents healthy ageing.

Paradoxically, whereas DNA damage causes cancer, also the treatment of cancer classically depends on DNA damaging agents. Unfortunately, these treatments are often not sufficiently effective. Efforts to improve these therapies and to identify those patient subgroups that benefit most from treatment, will ultimately help to increase the percentage of cancer survivors and their quality of life.

Improved cancer therapies and early-detection screening programs have resulted in increased numbers of cancer survivors. These individuals have often undergone intense genotoxic therapies resulting in cellular depletion, inflammation and adverse metabolic and cardiovascular effects, resulting in normal tissue hypo-function. Strikingly, these effects significantly resemble accelerated ageing effects of non-cancer patients. Insight into how therapy-induced damage to and repair of normal tissues results in accelerated ageing will improve mechanistic insight into physiological processes of ageing and will clarify how we can improve anti-cancer therapy to secure healthy ageing of cancer survivors.

Scientific and Societal output