Person: Sabbatino, Francesco
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Sabbatino
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Francesco
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Sabbatino, Francesco
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Publication PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation(Impact Journals LLC, 2014) Sabbatino, Francesco; Wang, YangYang; Wang, Xinhui; Flaherty, Keith; Yu, Ling; Pepin, David; Scognamiglio, Giosue'; Pepe, Stefano; Kirkwood, John M.; Cooper, Zachary A.; Frederick, Dennie T.; Wargo, Jennifer Ann; Ferrone, Soldano; Ferrone, CristinaControl of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.Publication Ipilimumab in the treatment of metastatic melanoma: management of adverse events(Dove Medical Press, 2014) Della Vittoria Scarpati, Giuseppina; Fusciello, Celeste; Perri, Francesco; Sabbatino, Francesco; Ferrone, Soldano; Carlomagno, Chiara; Pepe, StefanoRecently, “ipilimumab,” an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. “CTLA-4” is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis.Publication Blocking the formation of radiation–induced breast cancer stem cells(Impact Journals LLC, 2014) Wang, YangYang; Li, Wende; Patel, Shalin; Cong, Juan; Zhang, Nan; Sabbatino, Francesco; Liu, Xiaoyan; Qi, Yuan; Huang, Peigen; Lee, Hang; Taghian, Alphonse; Li, Jian-Jian; DeLeo, Albert B.; Ferrone, Soldano; Epperly, Michael W.; Ferrone, Cristina; Ly, Amy; Brachtel, Elena; Wang, XinhuiThe goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.Publication HLA class I downregulation is associated with enhanced NK‐cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors(John Wiley and Sons Inc., 2015) Sottile, Rosa; Pangigadde, Pradeepa N.; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; Kärre, Klas; Colucci, Francesco; Carbone, EnnioThe frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B‐Raf kinase (BRAF inhibitors, BRAFi). We generated drug‐resistant cell variants in vitro from human BRAF‐mutant melanoma cell lines MEL‐HO, COLO‐38, SK‐MEL‐37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug‐resistant cell variants remained susceptible to lysis by IL‐2‐activated NK cells; and two BRAFi‐resistant lines (BRAFi‐R) became significantly more susceptible to NK‐cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD‐L1 upregulation on the drug‐resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi‐R and parental cells to NK‐cell‐mediated lysis, antibody‐mediated inhibition of PD1–PD‐L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi‐R melanoma variants thus appears to play a major role in their susceptibility to NK‐cell cytotoxicity. These findings suggest that NK‐cell‐based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors.