On the Road to Discovering Urgently Needed Antibiotics: So Close Yet So Far Away.

The Pew Charitable Trusts' 2016 publication "A Scientific Roadmap for Antibiotic Discovery" provided a consensus approach to accelerating the discovery of novel antibiotics targeting Gram-negative pathogens. Since then, encouraging initiatives have launched to catalyze antibiotics discovery, particularly by improving knowledge sharing and making discovery efforts more efficient and effective. However, because the global pipeline remains insufficient to address current and future unmet needs, existing initiatives are not enough. Sustained public funding is critical, particularly as private funding continues to dwindle. And with public funding comes the responsibility of sharing what has been learned. Finally, a "precompetitive" R&D model in which the financial return on investment is not a primary driver warrants further consideration.

Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells.

Her2 is a receptor tyrosine kinase overexpressed in 25% of breast tumors. We have shown that the 88 kDa autocrine growth and survival factor GP88 (progranulin) stimulated Her2 phosphorylation and proliferation and conferred Herceptin resistance in Her2-overexpressing cells. Herein, we report that GP88 stimulates c-myc phosphorylation and upregulates c-myc levels in Her2-overexpressing cells. c-myc phosphorylation and upregulation by GP88 were not observed in non-Her2-overexpressing breast cancer cells. c-myc activation was inhibited upon treatment with ERK, PI3 kinase, and c-src pathway inhibitors, U0126, LY294002, and PP2. GP88 also stimulated c-src phosphorylation, a known upstream regulator of c-myc. Thus, we describe here a signaling pathway for GP88 in Her2-overexpressing cells, with GP88 stimulating Src phosphorylation, followed by phosphorylation and upregulation of c-myc. These data would suggest that targeting GP88 could provide a novel treatment approach in breast cancer.

Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma.

INTRODUCTION: GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients. METHODS: Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis. RESULTS: GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments. CONCLUSIONS: The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.

PC cell-derived growth factor stimulates proliferation and confers Trastuzumab resistance to Her-2-overexpressing breast cancer cells.

PURPOSE: Trastuzumab is only effective in 25% to 30% of the administered breast cancer patients who overexpress the erbB2/Her-2 oncoprotein. PC cell-derived growth factor (PCDGF/GP88) is an 88-kDa glycoprotein growth factor overexpressed in 80% invasive ductal carcinomas. Our objective was to determine whether the increased levels of PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing breast cancer cells. EXPERIMENTAL DESIGN: The ability of PCDGF to induce erbB2 phosphorylation and to confer Trastuzumab resistance was studied in erbB2-overexpressing MCF-7 and SKBR3 breast cancer cell lines. RESULTS: PCDGF/GP88 added exogenously induced the phosphorylation of erbB2 in a dose-dependent and time-dependent manner in erbB2-overexpressing breast cancer cells. In addition, the overexpression of PCDGF/GP88 conferred Trastuzumab resistance in erbB2-overexpressing cells. Furthermore, overexpression of PCDGF/GP88 in erbB2-overexpressing cells provided a growth advantage over erbB2-overexpressing cells that do not have increased levels of PCDGF/GP88. Lastly, PCDGF/GP88 induced the phosphorylation of mitogen-activated protein kinase in a time-dependent manner in erbB2-overexpressing cells, and pretreatment with Trastuzumab was not able to attenuate the phosphorylation levels of mitogen-activated protein kinase induced by PCDGF/GP88. CONCLUSION: These data suggest that PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing cells. Thus, the increase in PCDGF/GP88 levels may indicate Trastuzumab unresponsiveness in breast cancer patients.

PC cell-derived growth factor (granulin precursor) expression and action in human multiple myeloma.

PURPOSE: Multiple myeloma (MM) is a clonal B-cell neoplasm. PC cell-derived growth factor (PCDGF) is a M(r) 88,000 glycoprotein growth factor. Our objective was to investigate the expression, function, and signaling pathways of PCDGF in human MM. EXPERIMENTAL DESIGN: PCDGF expression, function, and signaling pathways in human MM were studies using two human MM cell lines: ARP-1 and RPMI 8226. In addition, PCDGF expression in MM patients was examined using 13 human bone marrow biopsy samples. RESULTS: PCDGF mRNA and protein expression was detected in human MM cell lines such as ARP-1 and RPMI 8226. PCDGF added exogenously stimulated cell growth and sustained cell survival of both ARP-1 and RPMI 8226 cells in a dose- and time-dependent fashion. Conversely, treatment with neutralizing anti-PCDGF antibody inhibited the growth of RPMI 8226 cells suggesting that PCDGF acts as an autocrine growth factor for MM cells. Studies of signal transduction pathways showed PCDGF stimulated mitogen-activated protein kinase and phosphatidylinositol 3'-kinase pathways but not the Janus-activated kinase-signal transducer and activator of transcription pathway. Immunohistochemical analysis of bone marrow smears obtained from MM patients indicated that PCDGF expression was associated with myeloma cells from MM patients and correlated with the presence of MM disease. CONCLUSION: These data suggest that PCDGF is an autocrine growth factor in the cell growth and survival of human MM cells, and may be a potential candidate as a biomarker of MM cells.

N-arylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: phenylpropylamines as potential leads for selective sigma-2 agents.

To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands.