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1.
RAF kinase dimerization: implications for drug discovery and clinical outcomes.
Brummer, T, McInnes, C
Oncogene. 2020;(21):4155-4169
Abstract
The RAF kinases activated by RAS GTPases regulate cell growth and division by signal transduction through the ERK cascade and mutations leading to constitutive activity are key drivers of human tumors, as are upstream activators including RAS and receptor tyrosine kinases. The development of first-generation RAF inhibitors, including vemurafenib (VEM) and dabrafenib led to initial excitement due to high response rates and profound regression of malignant melanomas carrying BRAFV600E mutations. The excitement about these unprecedented response rates, however, was tempered by tumor unresponsiveness through both intrinsic and acquired drug-resistance mechanisms. In recent years much insight into the complexity of the RAS-RAF axis has been obtained and inactivation and signal transduction mechanisms indicate that RAF dimerization is a critical step in multiple cellular contexts and plays a key role in resistance. Both homo- and hetero-dimerization of BRAF and CRAF can modulate therapeutic response and disease progression in patients treated with ATP-competitive inhibitors and are therefore highly clinically significant. Ten years after the definition of the RAF dimer interface (DIF) by crystallography, this review focuses on the implications of RAF kinase dimerization in signal transduction and for drug development, both from a classical ATP-competitive standpoint and from the perspective of new therapeutic strategies including inhibiting dimer formation. A structural perspective of the DIF, how dimerization impacts inhibitor activation and the structure-based design of next-generation RAF kinase inhibitors with unique mechanisms of action is presented. We also discuss potential fields of application for DIF inhibitors, ranging from non-V600E oncoproteins and BRAF fusions to tumors driven by aberrant receptor tyrosine kinase or RAS signaling.
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2.
Molecular therapies for HCC: Looking outside the box.
Faivre, S, Rimassa, L, Finn, RS
Journal of hepatology. 2020;(2):342-352
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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3.
Effect of high-fat diet on the pharmacokinetics and safety of flumatinib in healthy Chinese subjects.
Kuang, Y, Song, HL, Yang, GP, Pei, Q, Yang, XY, Ye, L, Yang, S, Wu, ST, Guo, C, He, QN, et al
Cancer chemotherapy and pharmacology. 2020;(3):339-346
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Abstract
PURPOSE To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects. METHODS This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC0-t, AUC0-∞ and Cmax in plasma. RESULTS Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for flumatinib, Cmax, AUC0-t and AUC0-∞ were 281.65% (225.80-351.31%), 167.43% (143.92-194.79%), and 166.87% (143.47-194.09%); for M1, Cmax, AUC0-t, and AUC0-∞ were 188.59% (145.29-244.79), 163.94% (149.11-180.24%), and 164.48% (150.36-179.94%); for M3, Cmax, AUC0-t, and AUC0-∞ were 63.47% (54.02-74.57%), 85.23% (74.72-97.22%), and 96.73% (86.63-108.02%). CONCLUSION Among the subjects, oral administration of 400 mg of flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to flumatinib, therefore, fasting may be recommended. CLINICAL TRIAL REGISTRATION The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.
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4.
Novel therapeutic options for radioiodine-refractory thyroid cancer: redifferentiation and beyond.
Bulotta, S, Celano, M, Costante, G, Russo, D
Current opinion in oncology. 2020;(1):13-19
Abstract
PURPOSE OF REVIEW Radioiodine-refractory thyroid cancers represent the main cause of thyroid cancer-related death. At present, targeted therapies with multikinase inhibitors represent a unique therapeutic tool, though they have limited benefit on patient survival and severe drug-associated adverse events. This review summarizes current treatment strategies for radioiodine-refractory thyroid cancer and focuses on novel approaches to redifferentiate thyroid cancer cells to restore responsiveness to radioiodine administration. RECENT FINDINGS We summarize and discuss recent clinical trial findings and early data from real-life experiences with multikinase-inhibiting drugs. Possible alternative strategies to traditional redifferentiation are also discussed. SUMMARY The current review focuses primarily on the major advancements in the knowledge of the pathophysiology of iodine transport and metabolism and the genetic and epigenetic alterations occurring in thyroid neoplasia as described using preclinical models. Results of clinical studies employing new compounds to induce thyroid cancer cell redifferentiation by acting against specific molecular targets are also discussed. Finally, we describe the current scenario emerging from such findings as well as future perspectives.
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A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study.
Seiwert, TY, Kochanny, S, Wood, K, Worden, FP, Adkins, D, Wade, JL, Sleckman, BG, Anderson, D, Brisson, RJ, Karrison, T, et al
Cancer. 2020;(14):3237-3243
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Abstract
BACKGROUND Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance. METHODS In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes. RESULTS Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms. CONCLUSIONS The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.
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Sorafenib for the treatment of hepatocellular carcinoma: a single-centre real-world study.
Hanzel, J, Kosir Bozic, T, Stabuc, B, Jansa, R
Radiology and oncology. 2020;(2):233-236
Abstract
Background Sorafenib is an oral multi-kinase inhibitor used for the treatment of hepatocellular carcinoma. Its efficacy in randomised controlled trials was demonstrated in patients with well-preserved liver function and good functional status. In the real-world setting, treatment is often offered to patients outside these criteria. We therefore performed a single-centre real-world cohort study on the efficacy of sorafenib in patients with hepatocellular carcinoma. Patients and methods We identified all patients with hepatocellular carcinoma initiating treatment with sorafenib between January 2015 and January 2018. The primary endpoint was overall survival (OS) since starting sorafenib. Clinical and demographic variables associated with survival were studied. Results The median OS was 13.4 months (95% CI 8.2-18.6). Multivariable Cox's regression identified worse ECOG performance status (HR 2.21; 95% CI 1.56-3.16; P < 0.0001), Child-Pugh class C (HR 52.4; 95% CI 3.20-859; P = 0.005) and absence of prior locoregional treatment (HR 2.30; 95% CI 1.37-3.86; P = 0.002) to be associated with increased mortality. Conclusions Careful selection of patients for treatment with sorafenib is of paramount importance to optimize outcomes.
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Imatinib is not a potent anti-SARS-CoV-2 drug.
Zhao, H, Mendenhall, M, Deininger, MW
Leukemia. 2020;(11):3085-3087
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Tyrosine Kinase Inhibitors and Hepatocellular Carcinoma.
da Fonseca, LG, Reig, M, Bruix, J
Clinics in liver disease. 2020;(4):719-737
Abstract
Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.
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Expert Perspectives On Clinical Challenges: Expert Perspectives: Challenges in Scleroderma.
Simms, RW
Arthritis & rheumatology (Hoboken, N.J.). 2020;(9):1415-1426
Abstract
You are consulted to evaluate a 56-year-old woman with known Raynaud's phenomenon, finger swelling of several; months' duration, and new hypertension with a blood pressure of 160/100 mm/Hg. She also reports progressive shortness of breath. Physical examination reveals telangiectasias, sclerodactyly, and proximal skin sclerosis (thick shiny skin on the chest and upper arms), and bibasilar crackles are found on chest examination. Laboratory tests reveal evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevation of the serum creatinine level (previously normal), and chest computed tomography shows evidence of ground-glass opacification in both lower lung fields.
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Effects of Food on the Pharmacokinetic Properties of Surufatinib: A Phase I, Single-dose, Randomized, Open-label Crossover Study in Healthy Subjects.
Qian, H, Wu, X, Chen, Q, Li, T, Wang, W, Jia, J, Yu, C, Li, K, Sai, Y, Su, W, et al
Clinical therapeutics. 2020;(9):1778-1786
Abstract
PURPOSE Surufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. METHODS A total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250-mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). FINDINGS The 90% CIs of the geometric mean ratios of AUC0-t and AUC0-∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. IMPLICATIONS The bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.