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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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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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 >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 >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).

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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).

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Previous work has shown that the three-dimensional (3D) nuclear organization of telomeres is altered in cancer cells and the degree of alterations coincides with aggressiveness of disease. Nuclear pores are essential for spatial genome organization and gene regulation and XPO1 (exportin 1/CRM1) is the key nuclear export protein. The Selective Inhibitor of Nuclear Export (SINE) compounds developed by Karyopharm Therapeutics (KPT-185, KPT-330/selinexor, and KPT-8602) inhibit XPO1 nuclear export function. In this study, we investigated whether XPO1 inhibition has downstream effects on the 3D nuclear organization of the genome. This was assessed by measuring the 3D telomeric architecture of normal and tumor cells in vitro and ex vivo. Our data demonstrate for the first time a rapid and preferential disruption of the 3D nuclear organization of telomeres in tumor cell lines and in primary cells ex vivo derived from treatment-naïve newly diagnosed multiple myeloma patients. Normal primary cells in culture as well as healthy lymphocyte control cells from the same patients were minimally affected. Using both lymphoid and non-lymphoid tumor cell lines, we found that the downstream effects on the 3D nuclear telomere structure are independent of tumor type. We conclude that the 3D nuclear organization of telomeres is a sensitive indicator of cellular response when treated with XPO1 inhibitors. This article is protected by copyright. All rights reserved.
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