The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved that target these two proteins. Less attention, however, has been paid to the role of this family in mediating cancer cell survival and drug tolerance. To better understand the complex signal transduction network triggered by the ErbB receptor family, we built a computational model that quantitatively captures the dynamics of ErbB signaling. Sensitivity analysis identified ErbB3 as the most critical activator of phosphoinositide 3-kinase (PI3K) and Akt signaling, a key pro-survival pathway in cancer cells. Based on this insight, we designed a fully human monoclonal antibody, seribantumab (MM-121), that binds to ErbB3 and blocks signaling induced by the extracellular growth factors heregulin (HRG) and betacellulin (BTC). In this article, we present some of the key preclinical simulations and experimental data that formed the scientific foundation for three Phase 2 clinical trials in metastatic cancer. These trials were designed to determine if patients with advanced malignancies would derive benefit from the addition of seribantumab to standard-of-care drugs in platinum-resistant/refractory ovarian cancer, hormone receptor-positive HER2-negative breast cancer, and EGFR wild-type non-small cell lung cancer (NSCLC). From preclinical studies we learned that basal levels of ErbB3 phosphorylation correlate with response to seribantumab monotherapy in mouse xenograft models. As ErbB3 is rapidly dephosphorylated and hence difficult to measure clinically, we used the computational model to identify a set of five surrogate biomarkers that most directly affect the levels of p-ErbB3: HRG, BTC, EGFR, HER2, and ErbB3. Preclinically, the combined information from these five markers was sufficient to accurately predict which xenograft models would respond to seribantumab, and the single-most accurate predictor was HRG. When tested clinically in ovarian, breast and lung cancer, HRG mRNA expression was found to be both potentially prognostic of insensitivity to standard therapy and potentially predictive of benefit from the addition of seribantumab to standard of care therapy in all three indications. In addition, it was found that seribantumab was most active in cancers with low levels of HER2, consistent with preclinical predictions. Overall, our clinical studies and studies of others suggest that HRG expression defines a drug-tolerant cancer cell phenotype that persists in most solid tumor indications and may contribute to rapid clinical progression. To our knowledge, this is the first example of a drug designed and clinically tested using the principles of Systems Biology.
These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.
The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened twelve HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent anti-tumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT and ERK in vivo. Our current work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.
BACKGROUND Although heregulin and HER3 are frequently expressed at high levels in head and neck cancer, their prognostic value remains unclear. We explored the prognostic significance of heregulin/HER3 expression in patients with oropharyngeal squamous cell carcinoma (OPSCC), taking into account other HER family members as well as p16 status. METHODS Ninety-six primary tumor specimens from OPSCC patients were retrospectively collected and analyzed for heregulin mRNA by in situ hybridization and for HER3, EGFR, and HER2 by quantitative immunohistochemistry. Heregulin and HER3 mRNA levels were also examined among different tumor types using The Cancer Genome Atlas (TCGA) database. RESULTS High heregulin mRNA (> median) correlated significantly with poor OS (HR: 8.48; 95% CI: 2.17–33.17; P = 0.002) but not DFS (HR: 1.52; 95% CI: 0.64–3.65; P = 0.344), in OPSCC patients. Heregulin mRNA correlated negatively with OS in both p16-positive (P = 0.049) and p16-negative (P = 0.091) OPSCC patients on univariate analysis. High HER3 (> median) also correlated with poor OS (HR: 4.68; 95%CI: 1.47–14.90; P = 0.009) on multivariate analysis. EGFR levels independently correlated with DFS (P = 0.025) and inversely correlate with p16 status (P = 0.012). In addition, TCGA data showed that head and neck squamous cell carcinoma exhibits higher heregulin expression compared to other solid tumor types examined. CONCLUSION: High heregulin mRNA and high HER3 protein levels independently correlate with poor OS in OPSCC. These data support targeting HER3 in heregulin-high OPSCC and warrant further clinical investigation.
Our knowledge of the extinct West Indian monk seal, Monachus tropicalis, is scant due to heavy exploitation following European colonization of the New World. We present previously unknown accounts of the species, including unpublished field notes of biologist E. W. Nelson, who observed a small number of wild seals in June of 1900. Records indicate that M. tropicalis may have had a long pupping season, occurred in large groups (up to 100) when abundant, probably ate fish and crustaceans, were preyed upon by sharks, and that young and adult seals may have assorted themselves into different age groups when hauled out. Additional records extend the known range of M. tropicalis to include the north coast of South America as far east as Guyana. We also present previously unavailable measurements from a large series of adult skulls and mandibles (n= 48). Two cases of histocytosis X, carcinoma, or other disease of the hard palate are documented from among these specimens.
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