Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide, for treating pancreatic and pituitary NETs that develop in a mouse model of Multiple Endocrine Neoplasia Type 1 (MEN1). Men1(+/-) mice were treated from 12 months-of-age with 40 mg/kg pasireotide long-acting release (LAR) formulation, or phosphate-buffered saline (PBS), intramuscularly monthly for 9 months. The Men1(+/-) mice had magnetic resonance imaging at 12 and 21 months-of-age, and from 20 months-of-age oral 5-bromo-2-deoxyuridine for 1 month, to assess tumor development and proliferation, respectively. NETs were harvested at 21 months-of-age, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/-) mice had increased survival (80.9 (pasireotide) vs. 65.2% (PBS), P<0.05), with fewer mice developing pancreatic NETs (86.9% (pasireotide) vs. 96.9% (PBS), P<0.05) and smaller increases in pituitary NET volumes (pre-treated vs. post-treated = 0.803 ±0.058mm(3) vs. 2.872 ±0.728 mm(3) (pasireotide) compared to 0.844 ±0.066mm(3) vs. 8.847 ±1.948mm(3) (PBS), P<0.01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared to PBS-treated mice (2.36 ±0.25 vs. 3.72 ±0.32, respectively, P<0.001), with decreased proliferation in pancreatic NETs (0.35 ±0.03% (pasireotide) vs. 0.78 ±0.08% (PBS), P<0.0001) and pituitary NETs (0.73 ±0.07% (pasireotide) vs. 1.81 ±0.15% (PBS), P<0.0001), but increased apoptosis in pancreatic NETs (0.42 ±0.05% (pasireotide) vs. 0.19 ±0.03% (PBS), P<0.001) and pituitary NETs (14.75 ±1.58% (pasireotide) vs. 2.35 ±0.44% (PBS), P<0.001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.

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A 30-year-old Caucasian man presented with severe Cushing’s syndrome (CS) resulting from ectopic adrenocorticotropin syndrome (EAS) from a metastatic pancreatic neuroendocrine tumor. The patient remained hypercortisolemic despite treatment with steroidogenesis inhibitors, chemotherapy, and octreotide long-acting release (LAR) and was enrolled in a 24-week, phase 3 clinical trial of mifepristone for inoperable hypercortisolemia. After mifepristone was added to ongoing octreotide LAR treatment, EAS symptoms essentially resolved. Cortisol decreased dramatically, despite mifepristone’s competitive glucocorticoid receptor antagonist effects. The clinical and biochemical effects reversed upon mifepristone discontinuation despite the continued use of octreotide LAR therapy. Substantial improvement in octreotide LAR efficacy with mifepristone use was noted in this patient with ectopic CS, consistent with upregulation of somatostatin receptors previously downregulated by hypercortisolemia.

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This phase 1 study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n=6 each) to determine maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n=6). Most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 83%/67% (100 mg), 67%/33% (125 mg), 100%/83% (palbociclib plus letrozole); heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 versus 100 mg (mean area under plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single-dose], 2838 vs 1276 ng·h/mL [multiple-dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single-dose], 185.5 vs 77.4 ng/mL [multiple-dose]). Half-life was 23 to 26 hours. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in 1 patient with rectal cancer [100 mg] and 1 with esophageal cancer [125 mg]) in part 1; 2 had partial response, and 2 stable disease (both ≥24 weeks) in part 2. Palbociclib 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. A5481010; NCT01684215 This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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Hepatitis B virus (HBV) is a driver of hepatocellular carcinoma, and two viral products, X and large surface antigen (LHBS), are viral oncoproteins. During chronic viral infection, immune-escape mutants on the preS2 region of LHBS (preS2-LHBS) are gain-of-function mutations that are linked to preneoplastic ground glass hepatocytes (GGHs) and early disease onset of hepatocellular carcinoma. Here, we show that preS2-LHBS provoked calcium release from the endoplasmic reticulum (ER) and triggered stored-operated calcium entry (SOCE). The activation of SOCE increased ER and plasma membrane (PM) connections, which was linked by ER- resident stromal interaction molecule-1 (STIM1) protein and PM-resident calcium release- activated calcium modulator 1 (Orai1). Persistent activation of SOCE induced centrosome overduplication, aberrant multipolar division, chromosome aneuploidy, anchorage-independent growth, and xenograft tumorigenesis in hepatocytes expressing preS2- LHBS. Chemical inhibitions of SOCE machinery and silencing of STIM1 significantly reduced centrosome numbers, multipolar division, and xenograft tumorigenesis induced by preS2-LHBS. These results provide the first mechanistic link between calcium homeostasis and chromosome instability in hepatocytes carrying preS2-LHBS. Therefore, persistent activation of SOCE represents a novel pathological mechanism in HBV-mediated hepatocarcinogenesis.

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Here we describe the generation and characterization of the human induced pluripotent stem cell (iPSC) line PBMC1-iPS4F1 from peripheral blood mononuclear cells from a healthy female with Spanish background. We used heat sensitive, non-integrative Sendai viruses containing the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc, whose expression was silenced in the established iPSC line. Characterization of the PBMC1-iPS4F1 cell line included analysis of typical pluripotency-associated factors at mRNA and protein level, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation studies.
Copyright © 2015 Elsevier B.V. All rights reserved.

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