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Targeted therapy for hepatocellular carcinoma.
Huang, A, Yang, XR, Chung, WY, Dennison, AR, Zhou, J
Signal transduction and targeted therapy. 2020;(1):146
Abstract
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
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Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies.
Martin, P, Gillen, M, Ritter, J, Mathews, D, Brealey, C, Surry, D, Oliver, S, Holmes, V, Severin, P, Elsby, R
Drugs in R&D. 2016;(1):93-107
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Abstract
BACKGROUND AND OBJECTIVES Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. RESULTS Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113). CONCLUSION Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.
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Novel immunosuppressive agent caerulomycin A exerts its effect by depleting cellular iron content.
Kaur, S, Srivastava, G, Sharma, AN, Jolly, RS
British journal of pharmacology. 2015;(9):2286-99
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Abstract
BACKGROUND AND PURPOSE Recently, we have described the use of caerulomycin A (CaeA) as a potent novel immunosuppressive agent. Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation and treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. The objective of this study was to identify cellular targets of CaeA and decipher its mechanism of action. EXPERIMENTAL APPROACH Jurkat cells were treated with CaeA and cellular iron content, iron uptake/release, DNA content and deoxyribonucleoside triphosphate pool determined. Activation of MAPKs; expression level of transferrin receptor 1, ferritin and cell cycle control molecules; reactive oxygen species (ROS) and cell viability were measured using Western blotting, qRT-PCR or flow cytometry. KEY RESULTS CaeA caused intracellular iron depletion by reducing its uptake and increasing its release by cells. CaeA caused cell cycle arrest by (i) inhibiting ribonucleotide reductase (RNR) enzyme, which catalyses the rate-limiting step in the synthesis of DNA; (ii) stimulating MAPKs signalling transduction pathways that play an important role in cell growth, proliferation and differentiation; and (iii) by targeting cell cycle control molecules such as cyclin D1, cyclin-dependent kinase 4 and p21(CIP1/WAF1) . The effect of CaeA on cell proliferation was reversible. CONCLUSIONS AND IMPLICATIONS CaeA exerts its immunosuppressive effect by targeting iron. The effect is reversible, which makes CaeA an attractive candidate for development as a potent immunosuppressive drug, but also indicates that iron chelation can be used as a rationale approach to selectively suppress the immune system, because compared with normal cells, rapidly proliferating cells require a higher utilization of iron.
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Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.
Mulder, SF, Jacobs, JF, Olde Nordkamp, MA, Galama, JM, Desar, IM, Torensma, R, Teerenstra, S, Mulders, PF, Vissers, KC, Punt, CJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;(13):4541-9
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Abstract
PURPOSE The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. PATIENTS AND METHODS Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. CONCLUSION We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.