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Generation and characterization of the human iPSC line PBMC1-iPS4F1 from adult peripheral blood mononuclear cells.

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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A Phase 1 Study of Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, in Japanese Patients.

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.

Pasireotide therapy of Multiple Endocrine Neoplasia type 1 (MEN1)-associated neuroendocrine tumors (NETs) in female mice deleted for an Men1 allele (Men1(+/-)) improves survival and reduces tumor progression.

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&lt;0.05), with fewer mice developing pancreatic NETs (86.9% (pasireotide) vs. 96.9% (PBS), P&lt;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&lt;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&lt;0.001), with decreased proliferation in pancreatic NETs (0.35 ±0.03% (pasireotide) vs. 0.78 ±0.08% (PBS), P&lt;0.0001) and pituitary NETs (0.73 ±0.07% (pasireotide) vs. 1.81 ±0.15% (PBS), P&lt;0.0001), but increased apoptosis in pancreatic NETs (0.42 ±0.05% (pasireotide) vs. 0.19 ±0.03% (PBS), P&lt;0.001) and pituitary NETs (14.75 ±1.58% (pasireotide) vs. 2.35 ±0.44% (PBS), P&lt;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.

Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing’s family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression.

To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI).
Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing’s sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting.
Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for &gt;100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was &gt;100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines.
In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Longitudinal noninvasive imaging of progesterone receptor as a predictive biomarker of tumor responsiveness to estrogen deprivation therapy.

To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [(18)F]FDG (to measure glucose uptake), [(18)F]FES [to measure estrogen receptor (ER) levels], or [(18)F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy.
[(18)F]FDG, [(18)F]FES, and [(18)F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [(18)F]FFNP uptake in ERα(+) mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC).
The levels of [(18)F]FES and [(18)F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [(18)F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [(18)F]FFNP tumor uptake, indicating that [(18)F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy.
Monitoring the acute changes in ERα activity by measuring [(18)F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [(18)F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment.
©2014 American Association for Cancer Research (AACR) (Free AACR Whitepaper).