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ACC is a rare malignant tumor with a poor prognosis. Current treatments for advanced-stage tumors are mostly ineffective. Therefore, there is an urgent need for new therapies for this type of cancer. For several years, our laboratory has been actively engaged in preclinical research for new pharmacological agents to treat ACC. In recent years, our most significant results have concerned two classes of molecules:
– Dual PI3K/mTOR inhibitors.
Previous studies conducted by our team and other groups have shown the effectiveness of drugs targeting IGF-1R and mTOR in inhibiting ACC cell proliferation in vitro and in xenograft models (Barlaskar et al., 2009; Doghman et al.( ., 2010). However, a potential problem with rapamycin analogs, which inhibit mTOR activity, is the induction of upstream tyrosine kinase receptor signaling and Akt activation. Dual inhibitors of PI3 kinase (PI3K), which directly regulates Akt activity, and mTOR have been developed and their efficacy demonstrated in preclinical models of several cancer types. We have shown that the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) significantly inhibits ACC cell proliferation in vitro and in the form of xenografts and that its action can be potentiated by the inhibition of Erk, which has increased activity following treatment with BEZ235 (Doghman et al., 2012).
– Inhibitors of the chemotherapy resistance activity of the receptor for Hedgehog, Patched (project leader: I. Mus-Veteau).
The Hedgehog (Hh) signaling pathway controls cell differentiation and proliferation, playing a key role during embryonic development, stem cell homeostasis, and tissue regeneration in adulthood. Furthermore, Hh signaling is also implicated in cancer development, progression, and metastasis. Indeed, aberrant activation of Hh signaling and overexpression of the Hh receptor Patched have been identified in numerous aggressive cancers, such as breast, lung, colorectal, ovarian, pancreatic, melanoma, and ACC, particularly in cells resistant to chemotherapeutic agents. We have shown for the first time that Patched is a cholesterol transporter (Bidet et al., 2011) and that it carries out drug efflux activity that may contribute to cancer cell resistance to chemotherapeutic agents (Bidet et al.( ., 2012). This advance allowed us to propose Patched as a new target to improve the efficacy of conventional chemotherapy treatments for cancer and reduce the risk of recurrence and metastasis (patent WO2012-080630). We developed a yeast screening assay to identify molecules capable of inhibiting the drug efflux activity of Patched. As a proof of principle, we showed that panicein, a family of natural compounds purified from a marine sponge, increases the cytotoxicity of doxorubicin, a widely used agent in cancer chemotherapy, on human melanoma cells overexpressing Patched. These compounds represent the first inhibitors of Patched-mediated efflux activity (Fiorini). et al., 2015; patent PCT/EP2015/074771). Primary tumors and ACC cell lines express Patched, suggesting that it may be involved in ACC resistance to chemotherapeutic treatments. By screening a library of drugs approved for clinical use, we identified compounds that enhance the cytotoxic effect of doxorubicin on an ACC cell line. Furthermore, we showed that Patched is responsible for doxorubicin efflux into ACC cells and that these compounds inhibit doxorubicin efflux from these cells. Experiments in vivo have shown that treatment with a Patched inhibitor significantly increases the effect of doxorubicin on the size of ACC cell xenografts (Hasanovic) et al., 2018). Overall, our results suggest that the use of Patched inhibitors could significantly improve the efficacy of doxorubicin treatment in preclinical cancer models.