Carine Michiels
Head & neck cancer radiosensitization
Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging and survival rates remain stagnant. Non-surgical approaches typically comprise radiotherapy and cisplatin-based chemotherapy.
Targeting therapies have an increasing role in the treatment of HNSCC. Anti-EGFR antibody cetuximab demonstrated enhanced radiosensitivity in a phase III trial. Anyway, combined to radiochemotherapy, it failed to improve outcome. EGFR overexpression is detected in more than 90 % of HNSCC
and enhanced levels of EGFR are associated with poorer prognosis. However, resistance to EGFR-targeted molecules is common, probably due to the overactivation of the other members of the ErbB family. These findings led to the development of inhibitors targeting the kinase domain of all members, the most promising one being afatinib. Afatinib has been shown to enhance radiation effects in several cancer cell types but not yet in HNSCC. Neither is known the potential benefit of combining afatinib to cisplatin and radiotherapy, nor the optimal administration schedule. The objective of this project is to define the best time schedule for the use of afatinib in radiosensitization, with or without cisplatin. This will be studied both in vitro using different radiosensitive and radioresistant human HNSCC lines and in vivo in appropriate murine tumor models. Cell survival, gene expression, cell cycle change, EMT, stemness property, migration and invasion will be studied. Ectopic xenografts using HNSCC cell lines and patient-derived xenografts will be established to evaluate the effects of afatinib and/or cisplatin combined with ionizing radiation on tumor growth and metastasis. The results of this project have major potential clinical implications by determining the optimal treatment schedule of this combined therapy in locoregionally advanced HNSCC patients. Combining molecular targeted therapies and radiation may allow a better tumor local control, thereby improving treatment outcome.
Inflammation in cancer
Tumor microenvironment, including endothelial cells and tumor associated macrophages (TAMs) but also hypoxia, favors tumor growth. Hypoxia initiates angiogenesis, recruitment of monocytes, which become TAMs, and favors cancer cell resistance to anti-cancer agents. If these effects are well described, few data are available regarding the reciprocal effects of TAMs on endothelial cells and on cancer cells. Even less known is the influence of hypoxia on these parameters. In this context, we developed unique cell models which were instrumental to demonstrate that TAMs induce tumor chemoresistance and that cycling hypoxia initiates a positive endothelial-dependent pro-inflammatory feedback. In this project we now aim to investigate whether cycling or chronic hypoxia modulates or drives thedialogue between the different cell types present in tumors and to study the consequences of these interactions on tumor growth and resistance. These studies will be performed in vitro, in mice models as well as in patients.
Targets could be identified to design new treatments to be combined with targeted or classical chemotherapy.
Radiotherapy : tumor-endoth interactions
Radiotherapy is currently used in more than 60% of cancer treatments. However, its efficacy is often limited by cancer cell intrinsic resistance as well as by toxicity in surrounding healthy tissues. Hadontherapy, which uses particles instead of photons as in conventional radiotherapy, allows to overcome these limitations. Moreover, a tumor is not only composed of cancer cells but it also contains new blood vessels and numerous immune cells including TAMs (tumor associated macrophages) which FORT modulates the response of cancer cells to various therapies, including radiotherapy. The objective of this work is to better understand the reciprocal dialogue between cancer cells on one hand and endothelial cells or TAM on the other hand, which influences the tumor response to radiotherapy. These studies will be performed comparatively for classical radiotherapy and for hadrontherapy, both in vitro using co-cultures but also in vivo in murine tumor models. They will aim at identifying the entities (proteins, lipids and/or exosomes) that are involved in the dialog between these different cell types and that may be responsible for radioresistance. These molecular processes may be targeted in the future for increasing the radiosensitivity of tumors regarded as a complex structure rather than a “simple” mass of cancer cells.
Resistance to treatments in cancer
Successful remission can be achieved with chemotherapy in most cases of cancer but refractory diseases and relapses remain a major obstacle. Multiple processes influence tumor response to therapies. Recently, we developed unique cell models which were instrumental to demonstrate that tumor microenvironment, and more specifically hypoxia, favors tumor growth as well as resistance to treatments. We also identified an unknown protein, TMEM45A, as being strongly implied. Our working hypothesis is that high levels of TMEM45A in tumors may be indicative of potential resistance to cancer therapy. In this project, complementary integrated expertise from oncologists (L. D’Hondt and C. Graux) and one tumor molecular biology researcher (C. Michiels) will be joined to validate this hypothesis, using a three level experimental strategy: in patients, in mice models and in vitro using culture cancer cells. New treatments to be combined with targeted or classical chemotherapy as well as biomarkers for cancer relapse may be discovered.
RES-pro
Pancreatic adenocarcinomas are one of the most aggressive solid cancers with a median survival of less than 12 months. The best treatment in this type of pathology is the surgical resection but in most cases, the diagnosis is made after the tumor has already spread to the adjacent organs. In this case, only chemotherapy associated with radiotherapy is possible, but this combination shows limited effects and displays an important toxicity for the patient. Recently, proton beam therapy has become an important alternative in the treatment of cancer by decreasing toxicity to surrounding organs compared to conventional radiotherapy. The interest of its use in the treatment of pancreatic adenocarcinoma is important by limiting the side effects on the healthy tissues such as the stomach, the liver or the kidneys.
In this study, we propose to determine the genes involved in the resistance of pancreas tumors to proton beam therapy and thus to better determine the doses to be administered to patients and the chemotherapies to be used in combination. To reach our objective, we will use in vitro models of pancreatic adenocarcinomas in which we will screen more than 18,000 genes potentially involved in these resistance mechanisms by using the CRISPR / Cas9 technique. Finally, this work will allow us to better understand by which mechanisms the pancreatic adenocarcinomas respond to the proton therapy but also to propose combinations with chemotherapies to bypass their intrinsic resistance to protons.
