Our general research focus consists of two main parts: 1) understanding the cancer-host interaction through analysis of the tumor microenvironment with emphasis on endothelial and mesenchymal progenitor cells, and 2) understanding the tumor cell machinery with emphasis on genetic changes. Together, these approaches should lead to the personalized treatment of cancer using targeted therapies.
BACKGROUND
Development of resistance to chemotherapy is one of the most significant obstacles to effective anti-cancer treatment. Although various tumor cell intrinsic mechanism of resistance have been identified, it is becoming increasingly clear that the tumor microenvironment plays a key role in determining response to therapy. Tumors actively generate their micro-environment by recruiting various types of bone-marrow derived progenitor cells (BMDC). It was recently shown that chemotherapy can increase this release of various BMDC in an immediate “seek and repair” manner, presumably in order to support tissue regeneration, resulting in a diminished anti-tumor effect of the chemotherapy. Main players in this process are endothelial progenitor cells (EPC) which contribute to neo-angiogenesis, haematopoietic progenitor cells (HPC) which form a pre-metastatic niche and mesenchymal progenitor cells (MPC). We identified a whole novel mechanism of induction of resistance to chemotherapy by the microenvironment via the release of specific fatty acids by activated MPCs. In response to platinum-based chemotherapy the MPC secrete platinum-induced fatty acids (PIFAs) which induce resistance to a broad spectrum of chemotherapeutics in a paracrine fashion. The identified fatty acids are very novel, and up to now no clear function of these fatty acids has been described.
EXPERIMENTAL APPROACH
The current research is comprised of a more biochemical and fundamental project in which we investigate the role of the identified fatty acids in resistance to chemotherapy and cellular protection. Secondly, we are investigating different strategies to intervene with this process and enhance chemotherapy efficacy. This last project is very translational and we aim to translate our findings into the clinical by designing and performing clinical trials.
In these projects we use both in vitro as in vivo experiments using different mouse models and different types of clinically relevant chemotherapies. Furthermore we use bioluminescence imaging techniques, GFP positive bone marrow and fluorescent tumor cells for confocal imaging, immunohistochemistry, micro-arrays, RNA sequencing, mass spectrometry and flowcytometry analysis of blood and tissue.
Besides these mice models we collect to patient material to translate our findings into the clinic.
CLINICAL RELEVANCE
Understanding the host response to cancer and to anti-cancer treatment will facilitate new approaches to further improve treatment outcome.
Techniques: Mouse cancer models, tissue culture, immunohistochemistry, confocal microscopy, flowcytometry, intervention strategies.
BACKGROUND
Understanding the genetic basis of cancer will enable us to develop more efficient therapies with fewer side effects. In the last decade, novel therapies were developed based on targeting single point mutations or copy number variations. As a result, our current cancer diagnostics is using mutational status, of e.g. KRAS or EGFR, for clinical decision making. Recently it became apparent that a more complete mutational profiling of signaling pathways, allows a better stratification of patients, increasing the efficiency of therapies. Additionally, since the cancer genome is genetically instable, significant differences in genetic variations between the primary tumor and the metastatic sample could affect the outcome of targeted therapies. A more detailed mutational profiling of targetable signaling pathways and processes will therefore be a major improvement towards personalized treatment of cancer.
GENOME SEQUENCING PROCEDURE
Our research group uses NGS technology to detect genetic variations that predict response to therapy in cancer patients. Our first project was to determine the genetic differences between primary tumors and its matching metastases. We chose to use targeted re-sequencing of a set of about 2000 cancer relevant genes, functioning in cancer relevant signaling pathways and processes. This analysis revealed a significant difference in mutational load for primary colorectal tumors and its matching metastasis. This is highly relevant since current clinical decision-making on treatment allocation is primarily based on the characteristics of the primary tumor. These data reinforce the need for recent tumor biopsy material to stratify patients for targeted therapy. The approach of a more comprehensive sequence analysis of the lesion to be treated is our suggested way forward.
EXPERIMENTAL APPROACH
Our current project aims to validate our main hypothesis: Selecting the right drug for the right patient can be achieved using large-scale analyses of the genetic make-up of cancer cells. We created the Center for Personalized Cancer Treatment (CPCT), an initiative of the UMC Utrecht, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital, and the Erasmus MC/Daniel den Hoed clinic to obtain sufficient amounts of high quality fresh tumor biopsies with accompanying clinical data on response to therapy. Within the CPCT we have developed several clinical trials in order to identify genetic markers or profiles, predictive for the response of targeted therapies. The combination of state-of-the-art sequencing facilities with the combined strength of 3 major clinical cancer research centers allows us to interrogate whether changes in genetic profiles derived from actual metastatic lesions can be used to predict response to therapy. The CPCT is uniquely positioned centre to enable personalized cancer care for patients with metastatic cancer and to produce high quality scientific data that will advance the understanding of tumor genetics.
Techniques: DNA analysis, next generation sequencing platforms, systems biology , pathology