Presentation

Context:

It is widely admitted that efficacy of traditional anti-cancer treatments such as chemotherapy and radiation therapy are frequently limited due to unexpected drug-associated side-effects, low concentration at the tumor site and development of resistances to treatments. However, in the past decade, the validation of new anti-cancer targets and the recognition that cancer is a heterogeneous disease has led to the development of personalized medicine and targeted therapies. In 2013, 80% of commercialized anti-cancer drugs in Europe and in USA were molecularly targeted therapeutics classified as anti-proliferative drugs. The benefit of anti-cancer targeted therapies is demonstrated, for example, with the treatment of chronic myeloid leukemia or acute lymphoblastic leukemia using Imatinib as well with introduction of trastuzumab in the treatment of breast cancer (www.inserm.fr). In spite of these advances, the delivery of anti-cancer agents to tumor sites remains an important challenge, particularly with solid tumors. The recent development of ligand-targeted nanomedicines represents a real new opportunity towards this goal in oncology, although several major difficulties must be overcome

In this context, our project exploits the fact that G-protein coupled receptors are expressed, and in some cases, over-expressed in cancers. We focus our activity on pharmacological targeting GPCRs over-expressed in tumors and use of endocytosic sorting of these receptors to deliver magnetic nanoparticules to tumors. Our working models is endocrine tumors due to frequent over-expression of several GPCRs in this category of tumors, and our targets is the receptor for the peptides cholecystokinin and gastrin (CCK2R) and the receptors for incretins (Glucose-dependent Insulinotropic and Glucagon-like peptide-1 (GIP, GLP1) because of the incidence and levels of expression of these receptors.

Recent results:Endosomes CCK2R B-arrestin copie

The common receptor to gut hormones gastrin and cholecystokinin, (the CCK2R) is expressed at significant levels in several types of digestive cancers and over-expressed in many types of endocrine tumors making it a potential diagnosis and therapeutic target (Gastroenterol). Following previous analysis of the signaling pathways linking CCK2R activation and cancer cell proliferation and migration, we investigated pharmacological regulation of CCK2R signaling and internalization. We demonstrated that the CCK2R is endowed of biased signaling capability. We identified several biased agonists which differently trigger G-protein dependent signaling pathways or β-arrestin-dependent pathways (leading to CCK2R internalization)(J Biol Chem). We also identified a high affinity competitive antagonist of the CCK2R on Gq-protein-dependent signaling pathway which is inefficient on β-arrestin dependent pathways (J Am Chem Soc).

Our search for new receptors expressed in tumors led us to discover that the Glucose-insulinotropic Polypeptide receptor (GIPR) is over-expressed in a number of endocrine tumors, including tumors negative for somatostatin receptor expression (J Clin Endocrinol Metab). This opened new research directions which led us to demonstrate feasibility of imaging GIP receptor-positive tumors and to characterize cellular and molecular mechanisms and consequences of GIPR internalization in tumoral cells (J Nu Med). By doing so, we identified the first biased agonist of the GIPR (Mol Endocrinol).

nanoparticules in lysosomes

We also developed a strategy of nanotherapy by taking advantage of the ability of cancer cells over-expressing GPCRs to internalize receptor-bound agonists. A nanoplatform composed of magnetic nanoparticles grafted with a CCK2R peptidic agonist was synthesized. We showed that this nanoplatform specifically recognizes tumoral cells expressing CCK2R, undergoes internalization and trafficking to lysosomes. Furthermore, exposure of tumoral cells containing nanoparticules to an alternating magnetic field caused apoptosis and cell death (30% of the population) in absence of perceptible temperature rise. Cell death occurred via a lysosomal death pathway which has recently emerged as an efficient way to kill apoptosis resistant cancer cells (ACS Nano).

 

Future directions

Our research aims for the next contract will be: 1- to study mechanisms whereby small quantities of iron oxide nanoparticles confined to lysosomes cause tumoral cell death upon exposure to an alternating high frequency magnetic field in spite of their poor heating power. 2- to launch pre-clinical tests of targeted magnetic nanotherapy on a validated mice model of pancreatic endocrine tumors over-expressing the CCK2R; 3- to explore multi-targeting strategies using multifunctional magnetic nanoparticles;