Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors

Abstract

Purpose

A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.

Methods

In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.

Results

A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUC_last, 0.95 (90 % CI 0.88–1.01); C _max, 0.98 (90 % CI 0.91–1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.

Conclusions

Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

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The UCA1/miR-204/Sirt1 axis modulates docetaxel sensitivity of prostate cancer cells

Abstract

Purpose

In this study, we firstly investigated the regulative effect of miR-204 on Sirt1 expression in prostate cancer cells. Then, we examined whether miR-204 downregulation in the cells is a result of UCA1 upregulation. In addition, the regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was studied.

Methods

QRT-PCR was performed to detect UCA1, miR-204 and Sirt1 mRNA expression. Western blot assay was performed to assess Sirt1, P-gp and caspase-3 expression. The regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was examined by measurement of docetaxel IC50, dictation of cleaved caspase-3 and flow cytometric analysis of cell apoptosis.

Results

MiR-204 negatively modulated Sirt1 expression in prostate cancer cells. UCA1 upregulation directly resulted in decreased miR-204 expression. UCA1 overexpression resulted in increased Sirt1 expression in PNT2 cells, while knockdown of endogenous UCA1 led to decreased Sirt1 in LNCaP and 22RV1 cells. UCA1 siRNA, Sirt1 siRNA and miR-204 mimics could enhance docetaxel-induced activation of caspase-3 and cell apoptosis in 22RV1/DR cells.

Conclusions

There is a UCA1/miR-204/Sirt1 axis in LNCaP and 22RV1 cells. The UCA1/miR-204/Sirt1 axis plays an important role in modulating in vitro docetaxel sensitivity of the prostate cancer cells.

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Oligometastatic Prostate Cancer

Opinion statement

The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

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Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy

ABSTRACT

Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. This article is protected by copyright. All rights reserved

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Stromal contributions to the carcinogenic process

Abstract

Tumor-associated stromal cells are dynamic characters that endorse the carcinogenic process in a multitude of ways. The tumor microenvironment plays a crucial role throughout the tumor progression, which includes initiation, growth, invasion, and metastasis. The tumor microenvironment consists of cellular and non-cellular components. Tumor-associated stromal cell types include the microbiome, immune cells including macrophages, dendritic and T-cells, cells associated with blood and lymphatic vessels including pericytes and endothelial cells, fibroblasts, neuronal cells, and adipocytes. The non-cellular components of the microenvironment include matrix proteins and secreted factors. The development of therapies that target the mechanisms by which stromal cells contribute to successful tumorigenesis is major goal of upcoming cancer research. The purpose of this review is to present a comprehensive discussion of the role of each of the tumor-associated stromal cell types in the carcinogenic process with a special focus on target development and therapeutic intervention. This article is protected by copyright. All rights reserved

http://ift.tt/2ezHPju

Oligometastatic Prostate Cancer

Opinion statement

The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

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Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy

ABSTRACT

Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. This article is protected by copyright. All rights reserved

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