作者: De Laurenzi, Vincenzo ; Del Pizzo, Francesco ; Grottola, Tommaso ; Gunnarsdottir, Helga Sigrun ; Iacobelli, Stefano ; Capone, Emily ; Cela, Ilaria ; Pinti, Morena ; Dufrusine, Beatrice ; Lattanzio, Rossano ; Tryggvason, Thordur ; Sala, Gianluca

HER-3 (also known as ErbB-3) is a human epidermal growth factor receptor tyrosine kinases family member, and its expression in CRC (colorectal cancer) tissues was previously associated with poor prognosis. In this study, HER-3 expression was analyzed by immunohistochemistry in two cohorts of early and advanced metastatic CRC patients. The first cohort included 180 patients diagnosed with CRC in absence of lymph nodes or distant metastases (Stage I and Stage II), while the second was obtained from 53 advanced metastatic CRC patients who developed synchronous (SM) and metachronous (MM) liver metastases. In the first early-stage CRC cohort, 86 out of 180 (47.8%) tumors showed membranous expression of HER-3, with a mean percentage of positive tumor cells of 25.7%; conversely, in advanced metastatic CRC primary tumors, HER-3 was detected in all specimens, with a mean percentage of positive tumor cells of 76.1%. Kaplan-Meier curves showed that in the advanced metastatic CRC group, patients with HER-3^high tumors had a significantly lower Cancer-Specific Survival (CSS) rate compared to patients with HER-3^low tumors (p = 0.021). Importantly, this worse CSS rate was observed only in the MM subgroup of patients with HER-3^high tumors (p = 0.002). Multivariate analysis confirmed that high HER-3 expression represents a significant and strong risk factor for death in patients developing MM liver metastases (Hazard Ratio = 64.9; 95% Confidence Interval, 4.7-886.6; p = 0.002). In addition, using a specific anti-HER-3 antibody-drug conjugate, named EV20/MMAF, we showed that HER-3 + CRC cells can be efficiently targeted in vitro and in vivo. Overall, this study confirms that surface HER-3 is highly expressed in CRC and reveals that HER-3 expression increases in metastatic CRC patients compared to early stage. Importantly, the results suggest that HER-3 has a prognostic and therapeutic value in patients developing MM liver metastases.

2020-05-08·EMBO Molecular Medicine1区 · 医学

HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

1区 · 医学

ArticleOA

作者: Ocaña, Alberto ; Pandiella, Atanasio ; Gandullo‐Sánchez, Lucía ; Sala, Gianluca ; Iacobelli, Stefano ; Capone, Emily

Despite impressive clinical benefit obtained with anti-HER2-targeted therapies, in advances stages, especially in the metastatic setting, HER2-positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody-drug conjugate EV20/MMAF exerted potent anti-tumoral properties against several models of primary resistance and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab-emtansine. HER3 was expressed in these HER2⁺ breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2⁺ cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2⁺ cancer clinic, including situations in which HER2⁺ tumors become refractory to approved anti-HER2 therapies.

2018-05-01·Journal of Controlled Release1区 · 医学

EV20-mediated delivery of cytotoxic auristatin MMAF exhibits potent therapeutic efficacy in cutaneous melanoma

1区 · 医学

Article

作者: Iacobelli, Stefano ; De Laurenzi, Vincenzo ; Rossi, Cosmo ; Lamolinara, Alessia ; Sala, Gianluca ; D'Agostino, Daniela ; Capone, Emily ; Iezzi, Manuela

Cutaneous melanoma is one of the cancers with the fastest rising incidence and in its advanced metastatic form is a highly lethal disease. Despite the recent approval of several new drugs, the 5-year overall survival rate for advanced cutaneous melanoma is still below 20% and therefore, the development of novel treatments remains a primary need. Antibody-Drug Conjugates are an emerging novel class of anticancer agents, whose preclinical and clinical development has recently seen a remarkable increase in different tumors, including melanoma. Here, we have coupled the anti-HER-3 internalizing antibody EV20 to the cytotoxic drug monomethyl auristatin F (MMAF) to form a novel antibody-drug conjugate (EV20/MMAF). In a panel of human melanoma cell lines, this novel ADC shows a powerful, specific and target-dependent cell killing activity, independently of BRAF status. Efficacy studies demonstrated that a single administration of EV20/MMAF leads to a long-lasting tumor growth inhibition. Remarkably, the effect of this novel ADC was superior to the BRAF inhibitor vemurafenib in preventing kidney, liver and lung melanoma metastases. Overall, these results highlight EV20/MMAF as a novel ADC with promising therapeutic efficacy, warranting extensive pre-clinical evaluation in melanoma with high levels of HER-3 expression.

100 项与 EV20/MMAF 相关的药物交易

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