Background: Triple negative (TN) breast cancers account for 15% of all breast cancers, are two-fold higher in African American women, have high histological grade, a poor prognosis and until recently no viable therapeutic targets. Epidermal growth factor receptor (EGFR) is over-expressed in more than 50% of triple negative breast cancers, but the use of agents blocking EGFR has produced disappointing results in metastatic breast cancer. Inhibitors of Mammalian Target of Rapamycin (mTOR) have demonstrated moderate activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated synergistic antitumor effects with combined mTOR and EGFR inhibition in TN breast cancers. Eukaryotic translation initiation factor (eIF4E) is a protein downstream of mTOR and a target of PI3K/Akt and Erk signaling, and is important in mRNA translation, cell proliferation and apoptotic resistance. We evaluated the effects of EGFR and mTOR inhibition on apoptotic markers, and correlated these effects with eIF4E protein expression.Methods: Apoptotic assay and colony formation analysis were performed following mTOR inhibition with rapamycin and EGFR inhibition with lapatinib or erlotinib in TN breast cancer cells (MDA-MB-231, MDA-MB-468, HCC1806). Effects of EGFR and mTOR inhibition on downstream proteins in TN breast cancer in vitro and in vivo were examined through western blotting analysis with p-EGFR, pAkt, p-Erk, p-S6, and p-eIF4E.Results: We observed differential apoptotic effects of EGFR and mTOR inhibition in TN breast cancers cells. The combination resulted in a significant increase in apoptosis in MDA-MB-468 cells in vitro, but no increase in apoptosis was seen in MDA-MB-231 or HCC1806 cells. As expected, correlating with the apoptotic effects, expression of p-eIF4E was decreased in MDA-MB-468 cells treated with the combination of mTOR and EGFR inhibition in vitro. In contrast, both MDA-MB-231 and HCC1806 cells had high baseline levels of eIF4E, which increased in response to treatment with EGFR and mTOR inhibitors. Using a colony forming assay, we demonstrated that the combination of EGFR and mTOR inhibition resulted in cytostatic effects in HCC1806 cells. The combination of EGFR and mTOR inhibition did not result in apoptosis in MDA-MB-231 cancers in vivo, and these xenograft tumors had high level of eIF4E at baseline.We are currently evaluating the effects of lapatinib and rapamycin on apoptotic pathways in MDA-MB-468 cancers in vivo.Conclusion: Based on our previous findings, we are developing a clinical trial in which patients with metastatic TN breast cancers are treated with lapatinib and everolimus. These results suggest that this combination may be more effective in TN breast cancers with low levels of eIF4E, and this will be explored using metastatic research biopsies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5078.
lowest vs highest; HR 1.12, 95%CI 1.07-1.16), grade (high vs low, HR 1.72, 95%CI 1.63-1.82), tumour size (2-5 cm vs 1-2 cm; HR 1.46, 95%CI 1.40-1.51), and a higher number of positive lymph nodes (1-3 vs 0; HR 1.40, 95%CI 1.34-1.46 and > 10 vs 0; HR 3.19, 95%CI 3.00-3.39) influenced death, all to a larger extent than surgical volume did. ConClusions: In the Netherlands, surgical hospital volume influences 10-year overall survival only marginally, and far less than patient and tumour characteristics. No difference in survival was revealed for invasive non-metastatic breast cancer patients in hospitals with 75-99 operations per year compared with hospitals with over 200 operations per year.objeCtives: For patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), prognosis is poor, with a median survival of one to two years, and treatment options are very limited. In a recent phase II trial (PCYCY-1104), Ibrutinib (Imbruvica™), a first-in-class oral once a day covalent Bruton's tyrosine kinase inhibitor, was associated with a median progression-free survival (PFS) of 13.9 months. After a median follow-up of 15.3 months, 63% of patients were alive.The aim of the current study was to evaluate the projected life years (LYs) and quality-adjusted LYs (QALYs) associated with ibrutinib and other treatments for R/R MCL. Methods: Patients with R/R MCL were simulated to receive treatment in a health state, survival partition model. Patients received ibrutinib, bendamustine and rituximab (BR), fludarabine, mitoxantrone, and cyclophosphamide (FMC), temsirolimus, or other comparators until death or until progression of disease, at which point they were modeled to receive a subsequent line of treatment or best supportive care. Clinical inputs for ibrutinib were informed by PCYC-1104 trial data; OS was extrapolated to estimate survival outcomes. Clinical inputs for comparators were informed by published sources identified through a systematic literature review. Utility values were informed by published studies. Outcomes were discounted by 3.5%. Results: Treatment with ibrutinib resulted in better health outcomes, incrementally increasing overall LYs by 0.92, 0.86, and 0.92 and PFS LYs by 0.87, 0.87, and 0.87 compared to BR, FMC, and temsirolimus, respectively. Ibrutinib was associated with 0.71, 0.70, and 0.72 overall incremental QALYs compared to BR, FMC, and temsirolimus, respectively. ConClusions: Compared with other therapies, Ibrutinib yielded an average incremental benefit of 0.90 LYs for R/R MCL patients, largely driven by the significant incremental improvement in duration of PFS. Currently a phase III trial is ongoing, the data from which will be used to validate the model.
PTHrP (Parathyroid Hormone-Related Protein) is a proteinaceous hormone and its signalling and functional regions are believed to be essential regulators for development for bone. Here, we report OSE2 element and PTH1R/PKA -independent physiology PTHrP C-terminus functions in bone. Using genetic models, we systematically interrogated PTHrP regions in various backgrounds in gene regulation, conducted on Ocy454 osteocytes overexpressing full-length PTHrP (Ocy454PTHrPFL), and mutant forms of PTHrP (Ocy454PTHrPΔNLSΔC, Ocy454PTHrPΔNLS, Ocy454PTHrPΔSec). PTHrP C-terminus, but not the PTHrP-NLS, remarkably limits magnitude- and numbers- dependencies of PTH/PTHrP signalling activated genes in osteocytes and osteoblastic-like osteosarcoma. C-terminus plays protective effects in bone formation signaling by down-regulation of Bglap1/2, observed in PTH /PTHrP signaling driven signalings. Unexpectedly, C-terminus gene suppression effect is cytosolic and is not dependent on canonical PTHrP-cAMP/PKA promoted signalling, nor is regulated by phosphorylated Runx2 binding to the OSE2 cis-regulatory elements. Instead, we show that PTHrP C-terminus mediated Bglap reduction results from stimulating Wnt signalling through an inhibition of Wnt inhibitor Dkk1. Collectively, our work identifies non-canonical PKA/cAMP/CREB response-independent functions of cytosolic PTHrP C-terminus to suppress Bglap, and unravel its complex endegenous C-terminus region-PTHrP interactions role in bone.
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