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Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Approaches in relapsed/refractory disease are diverse and include (i) the histone deacetylase inhibitor romidepsin which has demonstrated clinical activity alone or in combinations,104 (ii) hypomethylating agents (e.g., azacytidine) given the observation of mutation in genes controlling epigenetic regulation, and (iii) the use of immunomodulatory therapies such as cyclosporin.105
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
A histone deacetylase inhibitor approved in 2015 by the FDA is panobinostat; the drug inhibits HDACs I, II, and IV and is used—in combination with the anti-cancer drug bortezomib (see above) and the corticoid dexamethasone—to treat adult patients suffering from multiple myeloma. The inhibition of HDACs leads to a reactivation of the expression of tumor suppressor genes. As HDACs are also involved in the expression of proteins important for cell proliferation and differentiation, apoptosis, etc., panobinostat affects in addition the cell-cycle control system. Another HDCAi is romidepsin (opposite scheme), a bicyclic depsipeptide antibiotic produced by the bacterium Chromobacterium violaceum. It is a prodrug the disulfide bond of which is reduced to a thiol moiety within the cells where it interacts reversibly with the Zn2+ ion in the binding pocket of the enzyme and blocks its activity. DNA methyltransferase inhibitors are 5-azacytidine and its deoxy derivative decitabine (also known as 5-aza-2′-deoxycytidine) causing hypomethylation of DNA. They are employed for the treatment of the myelodysplastic syndrome as well as for acute myeloid leukemia. Azacitidine as a ribonucleoside is incorporated into RNA (and to a lesser extent in DNA) whereas decitabine, a deoxyribonucleoside, is only incorporate into DNA. A review of additional novel drugs targeting epigenetic proteins together with key examples of epigenetic dysregulation in tumors has been provided by Campbell and Tummino (2014), and Pachaiyappan and Woster (2014).
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
Several genetic factors correlate with the likelihood of severe and life-threatening drug toxicities. For instance, dihydropyrimine dehydrogenase (DPD) deficiency predispose patients to 5-fluorouracil (5-FU) toxicity as the DPD is the initial and rate-limiting enzyme in 5-FU catabolism (Chapter 11) [15]. It may improve efficacy and reduce toxicity by tailoring dosage of 5-FU through screening DPD activity before initiation of 5-FU [16]. The uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) gene genotypes have been identified as a major pharmacogenetic predictor of severe hematological toxicity (neutropenia) after irinotecan administration (Chapter 12) [17]. UGT1A1 genetic testing can detect the UGT1A1 6/6 (wildtype), UGT1A1 6/7 (heterozygous) and UGT1A1 7/7 (homozygous) genotypes in patients. A reduced initial irinotecan dose when administered in combination with other agents, or as a single agent should be considered for patients known to be homozygous 7/7 genotype (UGT1A1*28 allele) [18]. It is also suggested for use to reduce the starting dose of belinostat, a histone deacetylase inhibitor, in patients with the UGT1A1*28 allele. The enzyme thiopurine S-methyltransferase (TPMT) is implicated in the metabolism of thiopurine drugs such as mercaptopurine, 6-thioguanine and azathioprine (Table 1.2) [19]. TPMT deficiency and heterozygosity or genetic polymorphisms have been identified in patients who are intolerant or decreased tolerant to thiopurine and 6-mercaptopurine drug therapy [20]. Prior to initiation of therapy, TPMT activity or genotype testing is recommended and dose adjustments should be considered for patients with TPMT mutant genotype and with low or absent TPMT activity. Patients can be treated with these drugs without acute dose-limiting toxicity if the dosages were appropriately adjusted.
Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021
Published in Expert Opinion on Investigational Drugs, 2022
Zachary J. Brown, D. Brock Hewitt, Timothy M. Pawlik
Glypican-3 (GPC3) is an oncofetal proteoglycan normally detected in the fetal liver, but not in healthy adult liver, and is often overexpressed in HCC [114]. Codrituzumab is a humanized monoclonal antibody against GPC3 and interacts with CD16/FcγRIIIa thus triggering antibody-dependent cytotoxicity. In a phase II study, codrituzumab did not display a clinical benefit versus placebo with a median PFS and OS in the codrituzumab versus placebo groups of 2.6 versus 1.5 months, and 8.7 versus 10 months, respectively [115]. The addition of sorafenib to codrituzumab produced no responses and nine patients (25.7%) had stable disease [116]. The combination of cixutumumab, antibody directed against the human insulin-like growth factor-1 receptor, with sorafenib demonstrated limited anti-tumor activity with a median PFS of 6.0 months and OS of 10.5 months [117]. The combination of bavituximab, a human-mouse chimeric monoclonal antibody against phosphatidylserine, in combination with sorafenib produced inconclusive results with a median TTP of 6.7 months, a median OS of 6.1 months, and a median DSS of 8.6 months [118]. The combination of vorinostat, a histone deacetylase inhibitor, with sorafenib led to toxicities in most patients and a recommended phase II dose could not be identified [119].
Approved and emerging treatments of malignant pleural mesothelioma in elderly patients
Published in Expert Review of Respiratory Medicine, 2019
Giovanni Luca Ceresoli, Antonio Rossi
Based on preclinical data, several targeted therapies have been explored in MPM, mainly in the second-line setting, unfortunately with discouraging results [56]. Mesothelin, a glycoprotein surface antigen, is highly expressed in MPM, mainly in the epithelioid subtype [61]. A randomized phase II trial compared anetumab ravtansine (an antibody–drug conjugate) to vinorelbine in 248 pre-treated patients; their median age was 66.5 and 65.5 years in the two groups. The study failed to demonstrate an improvement in PFS with anetumab [62]. No outcome difference was observed in younger versus elderly patients, categorized according to a cutoff of 65 years. Similar, disappointing results were reported in a very large phase III, double-blind, placebo-controlled trial with vorinostat, a histone deacetylase inhibitor that changes gene expression and protein activity [63]. NGR-hTNF, a vascular-targeting drug that increases penetration of intra-tumoral chemotherapy and T-cell infiltration by modifying the tumor microenvironment, was investigated in patients with MPM who had progressed during or after a first-line treatment. A total of 400 patients were randomized to receive NGR-hTNF in combination with best investigator choice, single-agent chemotherapy in most cases, in a phase III, double-blind, placebo-controlled trial [64]. No difference in OS between the two arms was observed. Median patient age was 65 and 67 years in the experimental and placebo arms, respectively. No difference in OS was reported according to age < or ≥65 years.
Optimizing therapy in bortezomib-exposed patients with multiple myeloma
Published in Expert Review of Hematology, 2018
Magdalini Migkou, Maria Gavriatopoulou, Evangelos Terpos, Meletios Athanasios Dimopoulos
The addition of other agents to bortezomib is another option in patients with relapsed disease who had been previously exposed to bortezomib. One of the initial combinations studied the role of bortezomib with pegylated liposomal doxorubicin (PLD) (Caelyx) [9]. Median TTP was improved from 6.5 months for bortezomib alone to 9.3 months for PLD-bortezomib, and this was observed across all subgroups. Another treatment combination, bortezomib with panobinostat and dexamethasone, was compared with bortezomib-dexamethasone alone in the PANORAMA-1 study [10]. Panobinostat is a nonselective histone deacetylase inhibitor (pan-HDAC inhibitor). In preclinical studies bortezomib and panobinostat acted synergistically, by inhibition of both aggresome and proteasome pathways. Median progression-free survival was superior for the panobinostat arm compared to the placebo group, 12 vs. 8 months, with a hazard ratio of 0.63, and this was irrespective of previous exposure to bortezomib based regimens. The main adverse events were grade 3–4 of diarrhea (in 26% of patients) and asthenia or fatigue (in 24% of patients). However, all the above-mentioned studies included only bortezomib-sensitive patients and we cannot extrapolate these data on the bortezomib refractory group.