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Control of mutant BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Up-regulation of growth factor receptor such as platelet-derived growth factor receptor (PDGFR)β or insulin-like growth factor receptor (IGFR) is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that up-regulation of PDGFRα, a growth factor receptor which markedly differs in its functional properties from its family member PDGFRβ, causes BRAF-I resistance in vitro and in vivo. PDGFRα inhibition by PDGFRα-specific short hairpin RNA (shRNAs) and by clinically available PDGFRα inhibitors (sunitinib, imatinib and crenolanib) 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 the novel small molecule LDE225 restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. These effects are mediated by PDGFRα down-regulation and by inhibition of ERK and AKT activation. 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 Citation Format: Francesco Sabbatino, Yangyang Wang, Xinhui Wang, Keith T. Flaherty, David Pepin, Giosuè Scognamiglio, Ling Yu, Zachary A. Cooper, Stefano Pepe, John M. Kirkwood, Dennie T. Frederick, Jennifer A. Wargo, Soldano Ferrone, Cristina R. Ferrone. PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2014-3703

TPS9105 Background: Preliminary evidence in the literature suggests that interferon receptor subunit IFNAR1 is down-regulated in melanoma cells harboring a mutated active BRAF. This possibility is ...

In the US, about 10-20% of breast cancers are found to be triple-negative breast cancer(TNBC). Because of the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification, TNBC does not benefit from the currently available targeted therapies. Furthermore, recent molecular analysis of TNBC cell lines and lesions has suggested that these tumors might be enriched with cancer initiating cells (CICs). This possibility is consistent with the failure of conventional therapies to control disease progression, because according to the cancer stem cell theory, CICs play a major role in disease recurrence and metastatic spread, the two major causes of patient mortality. These findings and the lack of curative therapy for any TNBC patient with metastatic disease emphasize the need to develop effective novel therapies for this type of breast cancer. To address this need, we have developed a combinatorial immunotherapy, which eliminates both differentiated TNBC cells and TNBC CICs. The tumor antigen we have selected as a target is chondroitin sulfate proteoglycan (CSPG)4, since this membrane bound tumor antigen is expressed at high levels on both differentiated TNBC cells and TNBC CICs. CSPG4 plays a crucial role in the biology of TNBC cells, since it is involved in ERK and FAK signaling pathways which are associated with TNBC cell proliferation and migration. Furthermore, it is upregulated on activated pericytes in the tumor microenvironment. CSPG4-specific mAb 225.28 inhibits TNBC cell growth and migration. Moreover, it inhibits signaling pathways associated with TNBC cell growth and survival. It also can selectively inhibit neoangiogenesis in the tumor microenvironment, contributing to the elimination of TNBC cells, even those that do not express CSPG4. To enhance the targeting of TNBC CICs, immunotherapy is combined with the administration of an inhibitor (cyclopamine/ LDE225) of the Sonic Hedgehog Homolog (SHH) pathway which is activated in TNBC cells and, especially in TNBC CICs. Inhibition of TNBC CIC growth by mAb 225.28 is around 10%, but is enhanced up to about 70% when mAb 225.28 is combined with a SHH pathway inhibitor. Our in vitro findings strongly suggest that targeting CSPG4 with mAb 225.28 in combination with a SHH inhibitor may represent an effective strategy to eliminate differentiated TNBC cells and TNBC CICs. Citation Format: Yangyang Wang, Francesco Sabbatino, Soldano Ferrone, Xinhui Wang. Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2013-4741

Poly (ADP-Ribose) polymerase-1 (PARP-1) is involved in the DNA repairing system by sensing and signaling the presence of DNA damage. Inhibition of PARP-1 is tested in combination with DNA damaging agents such as topoisomerase I inhibitors or ionizing radiations (RT) for the treatment of glioblastoma (GBM). Disruption of p53, widely prevalent in GBMs, plays a major role in DNA repairing system. The current study investigates whether p53 activity has an effect on the sensitivity of human GBM cells to PARP-1 inhibitors in combination with topoisomerase I inhibitor topotecan (TPT) and/or RT. Human GBM cell lines carrying a different functional status of p53 were treated with PARP-1 inhibitor NU1025, in combination with TPT and/or RT. Cytotoxic effects were examined by analyzing the antiproliferative activity, the cell cycle perturbations, and the DNA damage induced by combined treatments. PARP inhibition enhanced the antiproliferative activity, the cell cycle perturbations and the DNA damage induced by both TPT or RT in GBM cells. These effects were influenced by the p53 activity: cells carrying an active p53 were more sensitive to the combination of PARP inhibitor and RT, while cells carrying an inactive p53 displayed a higher sensitivity to the combination of PARP inhibitor and TPT. Our study suggests that p53 activity influences the differential sensitivity of GBM cells to combined treatments of TPT, RT, and PARP inhibitors. © 2014 International Society for Advancement of Cytometry.