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Molecular Biology of Cancer: Translation to the Clinic: Volume 95
If you do not want to accept these cookies, indicate so here. Ga direct naar de inhoud , het hoofdmenu , het servicemenu of het zoekveld. He was drawn back in by the prospect of being able to rapidly translate basic research directly into clinical applications, and heads his own research group focusing on cancer. His group develops and utilizes sophisticated mouse models as critical tools to identify novel breast cancer genes and to learn how breast cancers grow and metastasize. They are also using them to test novel tumor intervention strategies that could improve treatment outcomes of breast cancer patients in the clinic.
More about the Jos Jonkers group. In the clinic, we mainly use anticancer drugs based on outcomes of clinical trials that have been carried out in the general breast cancer population, whereas little is known about the molecular mechanisms underlying differential drug sensitivity. The same holds true for other cancer types, including gastrointestinal malignancies, and ovarian cancer.
The focus of our research line is to unravel these molecular mechanisms in order to develop tests that may guide treatment decisions in the clinic and ultimately improve survival. For this purpose we use several genome-wide approaches and molecular techniques, in order to dissect the mechanisms that divide clinically well-defined cohorts of breast, gastrointestinal, and ovarian cancer patients into resistant and sensitive to a particular drug. We have a close collaboration with the groups of Jos Jonkers, Sven Rottenberg and Wilbert Zwart, who use conditional mouse models for breast cancer, derived clonal cell lines, and human cancer cell lines to study differential drug sensitivity in a controlled fashion.
A second research line focuses on the impact of prognostic molecular classifiers on adjuvant systemic treatment advice in breast cancer. More about the Sabine Linn group.
Molecular Biology Of Cancer: Translation To The Clinic
Cancer is a heterogeneous disease; tumors consist of multiple cells types and cancer cells with various genetic alterations. For example, only a few cells out of the billions of cells within a primary tumor acquire traits that enable them to metastasize.
To study this heterogeneity of cell behavior at the single cell level, the van Rheenen lab develops state-of-the-art imaging techniques to visualize and study individual cells in real-time in living animals, often referred to as intravital microscopy. Using intravital imaging, we revealed multiple important factors within the single cell heterogeneity that are crucial in the processes of tissue homeostasis, tumor initiation and tumor progression.
Our research focuses on four areas are 1 The cellular mechanisms of tissue development and homeostasis, tumor initiation, and tumor progression; 2 The cellular mechanisms of migration and metastasis of cancer; 3 The role of microvesicles in tumor heterogeneity and tumor progression; 4 The molecular and cellular mechanisms of chemotherapy resistance and side effects. More about the Jacco van Rheenen group.
Chemical Biology and Molecular Medicine
Her group was established in and focuses on the effects of genetic variants on risk, prognosis and long-term outcome of breast cancer. She also has an interest in the etiology of the development of specific breast cancer subtypes, which are strongly related to breast cancer outcome. Therapy and follow-up recommendations for breast cancer patients are based on the estimated average risk of tumor relapse and death, which is mostly based on tumor characteristics but not on patient genotype. Studying the impact of germline variants on the development of contralateral breast cancer subtype, treatment response and long-term survival, may eventually lead to inclusion of this information in guidelines or prediction tools for improved disease management, or in the pre-selection of women for breast cancer screening programs.
We closely work together with treating clinicians, clinical geneticists, and molecular biologists. A second research line focuses on patient information and consent procedures, and return of results from research using human materials. It set me on a course that I continue today. My research remains highly translational; it is about taking insights from the clinic into the lab, whether from the operating room or patient management.
Today, I spend about 60 percent of my time doing surgery and taking care of patients, and about 40 percent of my time on running the laboratory and administrative work. Our lab has been focused on identifying new therapeutic and imaging targets in cancer. We have developed a series of different antibodies against prostate cancers, aimed both at therapies and at imaging for surgery or disease monitoring.
We have a definite interest in cancer stem cells. In the late s, we first identified prostate stem cell antigen PSCA as a cell-surface marker overexpressed in prostate cancer. Early on, I wrote a number of papers with the hypothesis that prostate cancers arise from stem cells in the basal cell layers, and, interestingly, the field has evolved to suggest that this is actually true!
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We are still interested in understanding the evolution of differentiated cell types from these stem cells, in particular, the evolution into neuroendocrine tumors. In , we published a paper in Nature Medicine in which we showed that N-cadherin, a mesenchymal cadherin associated with epithelial-to-mesenchymal transition EMT , was reproducibly upregulated in several models of castration-resistant cancer. We showed that the ectopic expression of N-cadherin is sufficient for converting androgen-dependent prostate cancer into invasive, metastatic, and castration-resistant prostate cancer in animal models, and that these effects can be inhibited by N-cadherin-specific antibodies.
We are now trying to understand the role N-cadherin plays in the transdifferentiation process. Prostate cancer can be successfully eradicated through surgery, but a major correlate or predictor of failure is the presence of cancer at the margins of a tumor that is excised. Surrounding the prostate are nerve bundles that control the bladder, urethra, etc…, making surgery particularly challenging.
You are always trying to split hairs: preserving normal function while getting cancer out. It is almost impossible to do that perfectly. If we could see the edges of the cancer, we could do a better job of excising it.
In order to address this problem, we are engineering antibodies to PCSA that are conjugated to different fluorophores that could help us visualize the cancer cells in the operating theater. In addition, we have developed different animal models that can replicate the kinds of problems we see in the operating room in order to test our antibodies. Over the years, my closest collaborator has been Anna Wu, Ph. She has a background in radioimmunotherapy. I have clinical insight into the problems that can be addressed through antibody targeting; she has expertise in antibody engineering and radiobiology.
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My lab does the target identification and animal modeling; her lab reengineers the antibodies. We have taken several antibodies into clinical trials and even started a few companies. My first commercial experience was with an antibody company spun out of my department; it licensed one of the antibodies that was developed in our laboratory. Then I went to business school, and eventually started a company in to develop a prostate imaging agent and an imaging agent to track the immune system during immunotherapy.