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Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers.
Fondevila, F, Méndez-Blanco, C, Fernández-Palanca, P, González-Gallego, J, Mauriz, JL
Experimental & molecular medicine. 2019;(9):1-15
Abstract
Regorafenib is a sorafenib-derived chemotherapy drug belonging to the multikinase inhibitor family. This agent effectively targets a wide range of tyrosine kinases involved in cancer biology, such as those implicated in oncogenesis, angiogenesis, and tumor microenvironment control. The beneficial effects of regorafenib in clinical trials of patients who suffer from advanced hepatocellular carcinoma (HCC), colorectal cancer (CRC) or gastrointestinal stromal tumors (GISTs) refractory to standard treatments led to regorafenib monotherapy approval as a second-line treatment for advanced HCC and as a third-line treatment for advanced CRC and GISTs. Multiple in vitro and in vivo studies have been performed over the last decade to reveal the molecular mechanisms of the favorable actions exerted by regorafenib in patients. Given the hypothetical loss of sensitivity to regorafenib in tumor cells, preclinical research is also searching for novel therapeutic approaches consisting of co-administration of this drug plus other agents as a strategy to improve regorafenib effectiveness. This review summarizes the anti-tumor effects of regorafenib in single or combined treatment in preclinical models of HCC, CRC and GISTs and discusses both the global and molecular effects that account for its anti-cancer properties in the clinical setting.
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Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review).
Liu, M, Liu, H, Chen, J
Oncology reports. 2018;(3):901-911
Abstract
An uncontrolled cell cycle is an obvious marker of tumor cells. The G1‑S phase is an important restriction point in the normal cell cycle, but in cancer cells the restriction function is reduced, leading to uncontrolled cell proliferation. Two cyclin‑dependent kinases (CDKs), CDK4 and CDK6, play a crucial role in the G1‑S phase transition. Inhibitors of CDK4/6 are presently the subjects of numerous studies, and PD 0332991, an inhibitor of CDK4/6, has been used to treat hormone receptor (HR)‑positive, advanced‑stage breast cancer. This inhibitor has also been studied in other cancers, such as lung cancer. In this review, we will discuss the regulation of the normal cell cycle transition from G1 to S phase, the most promising inhibitor of CDK4/6, PD 0332991, as applied in different cancers, and finally we propose a mechanism of acquired resistance as well as the incredible potential for CDK4/6 inhibitors in the treatment of cancer. Briefly, we assert that, going forward, a new treatment pattern for cancer may be a combination therapy with a cell cycle inhibitor and a molecular targeted drug.
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3.
[Edoxaban for stroke prevention in atrial fibrillation and treatment of venous thromboembolism: an expert position paper].
Weiss, TW, Rohla, M, Dieplinger, B, Domanovits, H, Fries, D, Vosko, MR, Gary, T, Ay, C
Wiener medizinische Wochenschrift (1946). 2018;(5-6):133-143
Abstract
Edoxaban is the most recent available representative of the Non-Vitamin K antagonist oral anticoagulants (NOAC). The approval was based on the largest phase III trials of NOACs for stroke prevention in patients with non-valvular atrial fibrillation (AF, ENGAGE-AF), and for the treatment of venous thromboembolism (VTE, HOKUSAI-VTE). In both trials, edoxaban was associated with similar efficacy and a significant reduction in bleeding events with respect to the pre-defined primary safety endpoints, as compared to warfarin.Additionally, the once daily dosing of edoxaban, the clinically investigated strategy for dose-reduction based on clearly defined criteria and the favorable pharmacokinetic profile might further support the clinical applicability of the substance.In the light of recent data, this expert consensus document aims to summarize the latest clinical trial results while providing a concise overview of current guideline recommendations on the management of patients with non-valvular AF and VTE.
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4.
Regorafenib for the treatment of hepatocellular carcinoma.
Tovoli, F, Granito, A, De Lorenzo, S, Bolondi, L
Drugs of today (Barcelona, Spain : 1998). 2018;(1):5-13
Abstract
Hepatocellular carcinoma (HCC) is a worldwide problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries as well. Its close association with chronic liver diseases and liver cirrhosis represents a significant challenge in its treatment. A front-line systemic treatment for unresectable cases of HCC (sorafenib) was identified only in 2007. Following a decade of failed clinical trials with a wide range of drugs for second-line treatment, regorafenib proved its efficacy as a second-line treatment in 2016, when the randomized, placebo-controlled, phase III RESORCE trial demonstrated a meaningful increase in overall survival in the regorafenib treatment arm compared with the placebo arm (10.6 vs. 7.8 months). In this monograph we review the main preclinical and clinical findings in the trials assessing regorafenib for the treatment of HCC patients.
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An update of treatments of hepatocellular carcinoma in patients refractory to sorafenib.
Ielasi, L, Sansone, V, Granito, A, Benevento, F, De Lorenzo, S, Tovoli, F
Drugs of today (Barcelona, Spain : 1998). 2018;(10):615-627
Abstract
Hepatocellular carcinoma (HCC) remains among the neoplastic diseases with the most unfavorable prognosis. Historically, systemic treatments for HCC have been scarce. In particular, sorafenib was the only registered drug for the treatment of unresectable HCC until 2017. Last year, regorafenib was approved by the global regulatory agencies as second-line therapy. Since then, further randomized, controlled trials have been successful in this patient population. This paper deals with the most recent data concerning cabozantinib and ramucirumab, the two drugs that have recently demonstrated efficacy in phase III, randomized, controlled trials in HCC patients who failed previous treatment with sorafenib.
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Secondary prevention in non-valvular atrial fibrillation patients: a practical approach with edoxaban.
Masjuan, J, DeFelipe, A
The International journal of neuroscience. 2017;(8):716-725
Abstract
Patients with atrial fibrillation and prior stroke or transient ischemic attack exhibit a very high risk of recurrence. Secondary prevention with oral anticoagulants is mandatory. Overall, clinical guidelines recommend the use of target-specific oral anticoagulants over vitamin K antagonists for secondary prevention of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation and previous stroke are not receiving the appropriate antithrombotic treatment, perhaps due to the perceived risks of anticoagulation including the risk of hemorrhagic transformation of an ischemic stroke. The ENGAGE AF-TIMI 48 trial showed that although edoxaban 60 mg and warfarin reduced the risk of stroke to a similar extent, edoxaban exhibited a lesser risk of bleeding, particularly intracranial hemorrhage. Importantly, these data were independent of the presence of prior stroke or transient ischemic attack. Therefore, edoxaban can be used in both primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. The aim of this review was to update the available evidence about edoxaban in the clinical management of secondary prevention in individuals with non-valvular atrial fibrillation.
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7.
Edoxaban in Atrial Fibrillation and Venous Thromboembolism-Ten Key Questions and Answers: A Practical Guide.
De Caterina, R, Ageno, W, Boriani, G, Colonna, P, Ghirarduzzi, A, Patti, G, Rossini, R, Rubboli, A, Schinco, P, Agnelli, G
Advances in therapy. 2017;(3):620-637
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Abstract
Edoxaban is the fourth non-vitamin K antagonist oral anticoagulant now available for clinical use in the prevention of stroke/systemic embolism in atrial fibrillation (AF) and in the treatment of venous thromboembolism (VTE), after the completion of large-scale randomized comparative clinical trials with the vitamin K antagonist warfarin. Edoxaban has some peculiar pharmacological properties and outcome data. Here a group of experts in AF and VTE answers a set of questions on its practical use, trying to define the profile of patients that would be most appropriate for its use.
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Edoxaban in patients with atrial fibrillation.
Eisen, A, Ruff, CT
Therapeutic advances in cardiovascular disease. 2017;(3):81-90
Abstract
Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.
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Significant efficacy and well safety of apatinib in an advanced liver cancer patient: a case report and literature review.
Kou, P, Zhang, Y, Shao, W, Zhu, H, Zhang, J, Wang, H, Kong, L, Yu, J
Oncotarget. 2017;(12):20510-20515
Abstract
Apatinib is a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. Previous studies have suggested that apatinib is safe and effective in some solid tumors. We report one case with advanced hepatocellular carcinoma (HCC), who received apatinib combined with transhepatic arterial chemotherapy and embolization (TACE), and chemotherapy respectively. TACE was administered three times once a month, using lipiodol 10ml, oxaliplatin 150mg, and tegafur 1g. The dose of apatinib was 500 mg/d from day 4 to 24. After TACE, the patient received chemotherapy of regimen FOLFOX4, oxaliplatin intravenously at 85 mg/m2 on day 1, calcium levofolinate 200 mg/m2 on day 1 and 2, 5-fluorouracil 400 mg/m2 intravenously and 5-fluorouracil 600 mg/m2 intravenously pumped for 22h on day 1 and 2, cycled every two weeks for seven cycles. He took concurrently apatinib with a dose of 500mg daily from 1 to 10 days per cycle. He was confirmed as partial response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST). The level of serum alpha-fetoprotein (AFP) decreased from 60500 ng/ml to 12.7 ng/ml, and the progression free survival (PFS) time was more than eight months. It indicated that apatinib may be a superior choice for HCC patients.
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10.
Targeting CDK4/6 in patients with cancer.
Hamilton, E, Infante, JR
Cancer treatment reviews. 2016;:129-38
Abstract
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer.