Mechanisms of Resistance and new Targets: from Molecular to Clinical pharmacology (RTMC)
Since over 20 years, novel therapies targeting intra- and extra-cellular signaling are developed. These therapies annihilate major oncogenic pathways, that drive tumorigenesis in each cancer sub-types. The most recent & spectacular example is represented by a mutated B-Raf inhibitor (Vemurafenib) with which, under treatment, partial and complete remissions were observed in metastatic melanoma patients. Compounds inhibiting PI3K signalling pathway are also under clinical trials, with a compound targeting PI3Kδ GS-1101 (Idelalisib/CAL-101) in immune compartment, being the first PI3K inhibitor to be approved for clinical use. These therapies, however, rapidly induce resistance. These responses to treatment come from cancer and metastatic cells themselves, but also from the tumor in its microenvironment. Immunotherapy with check-point inhibitors came to complete this therapeutic arsenal. If the progress in therapy of cancer remains dependent of the development of new compounds, one source of treatment improvement will be a better individualization: how to select the right drug(s) for the right patient. Moreover, for several drugs such as cytotoxics and small targeted molecules, low drug exposure (i.e., area under the curve of plasma-drug concentration versus time) is associated with a decrease in antitumor effect. Personalized treatment should thus include dose individualization. The decrease in exposure to treatment is also extensively described in the literature by a lack of adherence to treatment by the patient.
There is a compelling need to understand the underlying mechanisms of response to treatments and the developed resistance to new therapies that target signaling enzymes. Improved understanding of the clinical, social, and molecular determinants that may limit therapeutic efficacy of targeted therapies will help optimize therapeutic strategies and improve patients’ outcomes.
CRCT researchers from the “Mechanisms of resistance and new targets: from molecular to clinical pharmacology” Integrated program 1 are advancing this research line with originality, identifying new therapeutic targets involved in metabolism balance, autophagy, immune check point regulation, lipid signalling, monitoring the adaptation of tumoral cells to such targeting in particular on miRNA networks or on DNA instability, in full integration with clinical trials and their pharmacokinetic follow-up. Our integrated program will help us to predict resistance to these signal-targeted therapies and to imagine future personalized anti-cancer treatments.
Mathematics, physics and computational tools in oncology
There is a growing trend to forge bridges between disciplines as researchers from CRCT attempt to solve complex problems and situations in oncology.
At the crux of this trend is the growing need for new kinds of knowledge, aside from that generated within one discipline or in temporary alliances among disciplines. With this in mind, this transversal research line of CRCT gathers and promotes research efforts conducted by investigators from different disciplines and institutions working jointly to create new conceptual, theoretical, methodological, and translational innovations that integrate and move beyond discipline-specific approaches to address a common problem in the field of cancer science.
The aim of this transdisciplinary research endeavor is to forge a new relationship between hard sciences and cancer science to further advance research. This research axis draws on the multidisciplinary expertise of the faculty of the CRCT and of the LAAS (Laboratoire d’Analyse et d’Architecture des Systèmes), the IMT (Institut de Mathématique de Toulouse) and the IRIT (Institut de Recherche en Informatique de Toulouse) as main partners.
We will build on “Oncodevice”, our first successful close encounter of the third kind to move beyond our penchant for specializations because oncology is far too complex for one point of view. This program is designed to increase the understanding of the determinants of tumor heterogeneity, to:
- translate these findings into patient management opportunities and actionable therapeutic interventions,
- train the next generation of investigators in physics, mathematics and computing science and cancer,
- and disseminate this knowledge and develop translational strategies with IUCT-O to defeat cancer.
This program is headed by Pierre Cordelier.