|Laurence Lafanechère |
04 76 54 95 71
Microtubules, post-translational modifications, kinases, Chemotherapy, Cancer
ACTIVITES DE RECHERCHE / SERVICES
Our team studies how the plasticity of the cellular microtubule and the actin filaments cytoskeleton is regulated in response to environmental cues, and deregulated in cancer. Microtubules targeting agents (MTA), such as vinca-alcaloids and taxanes, are widely used in the treatment of breast cancers. However they are toxic for many proliferating cells and peripheral neurons, inducing severe adverse effects. In addition, many tumors show resistance to these compounds. There is thus an urgent need to develop new drugs, less toxic. Increasing evidence indicates that functions other than mitosis may be involved in the therapeutic effects of MTA, such as regulation of microtubule dynamics in interphase. Thus, targeting microtubule-regulating proteins which are deregulated during cancer progression, is a promising alternative strategy. In this context, this team has focused on LIM kinase (LIMK), a kinase that controls both actin and microtubule dynamics and is overexpressed in many invasive cancers. Upon LIMK inhibition, microtubules are stabilized and actin filaments are disorganized (Prudent et al., Cancer Res. 2012). Notably, the team has shown that pharmacological inhibition of LIMK has a strong effect on the growth and metastasis of breast tumors in animal models (Lagoutte et al., Sci. Rep. 2016; Prunier et al., Cancer Res. 2016). Such a treatment had no detectable undesirable side effect and showed efficacy even on taxane resistant tumors. A project of the team is the identification of microtubule-associated LIMK substrates and of the therapeutic interest of targeting LIMK in acute myeloid leukemia (INCA, PLBIO 2016-165). To that aim, we are currently invalidating LIMK in cells using the CRISPR/CAS9 system. We have observed that the modified cells show transitory phenotypes, that we would like to quantify.
The team has also recently selected an interesting compound that sensitizes cancer cells to low (1nM) doses of Taxol, with an original mechanism of action).
Moreover, the team plans now to select new pharmacological agents that target tubulin carboxy-peptidase, a microtubule-regulatory proteins that has been shown to be deregulated in breast cancer. Overall these projects can lead to the identification of attractive drug candidates to target breast tumors of poor prognosis.
COMPETENCES / MOYENS TECHNIQUES
We make an extensive use of phenotypic screening, i.e;.screening of chemical libaries using cell-based assays that probe for microtubule dynamics and functions.
We have acquired some expertise in the subsequent identification of the cell target of the compounds.
We also benefit from the close proximity of the platform OPTIMAL (IAB, Grenoble), to analyse in vivo the therapeutic efficacy of the compounds we are interested in on mice models of cancer.
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Centre de Recherche UGA / Inserm U 1209 / CNRS UMR 5309 Institute for Advanced Biosciences (IAB)
Site santé, allée des Alpes
38700 La Tronche