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Cancer
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
Ablative treatments include hepatic arterial chemoembolization, selective internal radiation therapy, and radiofrequency ablation. All of these provide for palliation and cause tumor growth to become slower. They are done for patients awaiting liver transplantation. The radiofrequency ablation technique can be curative for tumors smaller than 2 cm. For tumors larger than 5 cm that are multifocal, have invaded the portal vein, or are metastatic, radiation therapy is usually ineffective. Sorafenib may slightly improve the patient’s condition. Newer agents can prolong survival for a longer time and/or cause fewer side effects. They include regorafenib, lenvatinib, and the immunotherapy agent called nivolumab. Levatinib is an alternative first-line therapy, providing progression-free survival that is better than with sorafenib.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Common side effects associated with sorafenib include GI disturbances (e.g., diarrhea, constipation, dyspepsia, dysphagia, and anorexia), skin disorders (e.g., rash, pruritus, erythema, dry skin, desquamation, acne, and hand-foot skin reactions), peripheral neuropathy, hypertension, hemorrhage, flushing, fatigue, asthenia, renal failure, hypophosphataemia, arthralgia, myalgia, and tinnitus.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
A significant breakthrough in the treatment of cancer across multiple cancer types is immunotherapy with monoclonal antibodies that target the immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathway (Chapter 14). Currently, this class of antibodies that activate the immune system, but not limited to, include ipilimumab that blocks CTLA-4, tremelimumab, pembrolizumab and nivolumab that inhibit PD-1, as well as avelumab, atezolizumab, and durvalumab that target the PD ligand 1 (PD-L1). The three PDL1 antibodies are approved for the treatment of metastatic Merkel-cell carcinoma, advanced bladder cancer or NSCLC. Ipilimumab and pembrolizumab are indicated in the treatment of a range of cancer types including metastatic melanoma, NSCLC, small cell lung cancer, and HNSCC, hormone-refractory prostate cancer and advanced cervical cancer. Nivolumab is indicated for both BRAF wildtype and BRAF V600 mutation-positive unresectable or metastatic NSCLC progressed on or after platinum-based chemotherapy. It is also used for advanced renal cell carcinoma, classical Hodgkin’s lymphoma, and hepatocellular carcinoma in patients previously treated with sorafenib. In June 2020, it was approved for patients with recurrent or metastatic esophageal squamous cell carcinoma after prior platinum- and fluoropyrimidine-based chemotherapy.
Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Reda G. Yousef, Alaa Elwan, Ibraheem M. M. Gobaara, Ahmed B. M. Mehany, Wagdy M. Eldehna, Souad A. El-Metwally, Bshra A. Alsfouk, Eslam B. Elkaeed, Ahmed M. Metwaly, Ibrahim H. Eissa
In the present work, sorafenib was used as a lead compound to design new derivatives with the same pharmacophoric features of VEGFR-2 inhibitors. Four modification strategies were carried out at the four pharmacophoric features of sorafenib. Firstly, the N-methylpicolinamide moiety of sorafenib was replaced by nicotinamide moiety via ring equivalent modification strategy. Second, the linker (phenoxy) moiety of sorafenib was subjected to liker contaction to be a phenyl group in the designed compounds. Third, the pharmacophore (urea moiety) of sorafenib was replaced by two different hydrazone derivatives. Fourth, the hydrazone derivatives are conserving the hydrogen bond donor and hydrogen bond acceptor atoms that can form the essential hydrogen bonding interactions at the DFG motif region. Simultaneously, the hydrophobic head of sorafenib was subjected to the strategy of variation in the substitution pattern to study the electronic and hydrophobic effect on biological activities (Figure 2).
Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms
Published in Journal of Chemotherapy, 2022
Sorafenib is an extensively orally used inhibitor of multikinase, with several targets at the molecular level, comprising of receptor tyrosine kinases [vascular endothelial growth factor receptor (VEGFR-1-3), platelet-derived growth factor receptor (PDGFR-β), Feline McDonough Sarcoma (fms) like tyrosine kinase (Flt-3), and stem cell growth factor receptor or c-Kit and Rapidly Accelerated Fibrosarcoma (Raf) serine/threonine kinases (oncogenic B-Raf V600E, wild-type B-Raf and Raf-1) [4]. Sorafenib inhibits/suppresses the tumour cell multiplication, infiltration, and angiogenesis, simultaneously inducing/promotes apoptosis in the diverse tumours. The efficacy and tolerance are limited by factors like systemic toxicity and low aqueous solubility/water immiscibility, which leads to lower absorption in the gastrointestinal tract (GIT) hence low bioavailability. These difficulties may be overcome by the nanocarrier application to enhance the delivery and controlled release. This may decline the drug toxicity while not affecting the non-tumour organs by a high dosage of the drug [5]. Sorafenib is mainly metabolized in the liver by UGT1A9- mediated glucuronidation and cytochrome p450 (CYP3A4)-mediated oxidation. CYP3A4 is a key member elimination of sorafenib by the metabolism of N-oxide through which a number of patients evolve the drug resistance [6].
Emerging drugs for the treatment of hepatocellular carcinoma
Published in Expert Opinion on Emerging Drugs, 2022
Walid S Ayoub, Patricia D. Jones, Ju Dong Yang, Paul Martin
Sorafenib is indicated for the treatment of liver, kidney, and thyroid cancer. Sorafenib blocks the RAF signaling pathway, the vascular endothelial growth factor (VEGF) receptor, the platelet-derived growth factor (PDGF) receptor, and KIT, resulting in antiproliferative and antiangiogenic effects [15]. The Sharp trial was a landmark study that included 602 patients with advanced HCC and Child A cirrhosis randomized to sorafenib vs placebo. It was the first trial to demonstrate survival benefit and resulted in an overall survival (OS) of 10.7 months vs 7.9 months in those treated with placebo with an HR of 0.69 (95%CI 0.55–0.87) [21]. The Asian-Pacific trial with 271 patients gave similar results with an HR of 0.68 (95%CI 0.5–0.93) but with a lower median survival of 6.5 months due to the inclusion of patients with more advanced disease than in the SHARP trial. Sorafenib was found to have a better activity in patients with HCV-associated HCC and without metastases according to a meta-analysis [24]. Sorafenib was the mainstay of therapy for one decade as multiple other therapies were investigated but failed to provide a survival benefit.