China
Africa
Explore chapters and articles related to this topic
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Targeted small molecule inhibitors—multiple intracellular signaling pathways are therapeutically targetable in FL. Abnormal signaling in FL through the PI3K/AKT/mTOR pathway can be targeted using the PI3K class of small molecular inhibitors (including idelalisib [PI3Kδ], copanlisib [PI3Kα/δ], and duvelisib [PI3Kδ/γ]). These agents have reasonable response rates (approximately 30%–50%); however toxicity (particularly gastrointestinal and pulmonary) can be an issue. Approximately 30% of patients with relapsed/refractory FL harbor activating mutations in EZH2 which results in a “locking in” of the malignant cell into the germinal center transcriptional program. Tazemetostat is an oral inhibitor of EZH2 and shows relatively high response rates in EZH2-mutated FL (approximately 70%) and is generally well-tolerated. Other targeted therapies include BTK inhibitors (e.g., ibrutinib) and BCL2 inhibitors (e.g., venetoclax).
Atypical Teratoid / Rhabdoid Tumors – AT/RT
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Michael C. Frühwald, Jaclyn A. Biegel, Susan N. Chi
Tazemetostat suppressed H3K27 trimethylation (H3K27Me3) in vitro in human lymphoma cells and induced selective cell killing.117 In EZH2-mutant xenografts tazemetostat caused dose-dependent tumor growth inhibition, reduction in H3K27Me3 levels in tumors and normal tissues. Furthermore, it was demonstrated that EZH2 inactivation increases the radiosensitivity of rhabdoid tumor cells.118,119 In a phase I trial of tazemetostat (EPZ-6438) in 30 adult patients with solid tumors (including 5 patients with MRT) and 21 patients with B-cell non-Hodgkin’s lymphoma, 1 patient with MRT achieved a complete response. There were also 2 patients with stable disease, 1 patient with a partial response, and 1 with progressive disease (www.epizyme.com/wp-content/uploads/2015/09/Tazemetostat-ESMO-Phase-1-Trial-September-26–2015.pdf). A pediatric clinical phase I/II trial employing tazemetostat for patients with rhabdoid tumors and other INI-deficient tumors is currently recruiting (NCT02601937, NCT02601950).
Pharmacotherapeutic strategies for epithelioid sarcoma: are we any closer to a non-surgical cure?
Published in Expert Opinion on Pharmacotherapy, 2023
Magdalena Meissner, Andrea Napolitano, Khin Thway, Paul Huang, Robin L Jones
Tazemetostat (an EZH2 inhibitor) as a single agent is less toxic than conventional chemotherapy. However, in terms of efficacy, tazemetostat has similar efficacy to standard chemotherapy. Therefore, the results of ongoing clinical trials that assess the combination of tazemetostat with chemotherapy are eagerly awaited. In addition, due to recent developments in the genomics of ES, the treatment with single-agent tazemetostat might be less effective for patients with classic ES with dysfunctional INI1, who might require a different therapeutic approach. This needs to be explored in future clinical trials. In addition, tazemetostat has the potential to modulate tumor immunogenicity and anti-tumor immune response and therefore is being further evaluated in combination with immunotherapy.
A patent review of EZH2 inhibitors from 2017 and beyond
Published in Expert Opinion on Therapeutic Patents, 2023
Guoquan Wan, Huan Feng, Chang Su, Yongxia Zhu, Lidan Zhang, Qiangsheng Zhang, Luoting Yu
Inhibitors targeting EZH2 have been extensively developed over the last decade. Novartis, GlaxoSmithKline, Pfizer and other pharmaceutical companies are conducting relevant research and have successively developed EZH2 inhibitors with different structures. Tazemetostat (EPZ6438) was approved by the FDA in January 2020. Tazemetostat was a selective EZH2 inhibitor with an IC50 value of 2.5 nM and showed significant antitumor activity both in vitro and in vivo [17,18]. The EZH1/2 inhibitor Valemetostat was approved in Japan in September 2022 for the treatment of T-cell leukemia or lymphoma. Notably, Valemetostat was the first dual inhibitor of EZH1 and EZH2 approved in the world. In addition to Tazemetostat, seven other inhibitors are in clinical trials (Table 1) and their structures are described in Figure 2.
What’s the latest with investigational drugs for soft tissue sarcoma?
Published in Expert Opinion on Investigational Drugs, 2022
Elena Cojocaru, Andrea Napolitano, Cyril Fisher, Paul Huang, Robin L Jones, Khin Thway
Epithelioid sarcoma is a rare subtype of sarcoma, with very high morbidity and mortality rate. Tazemetostat is an inhibitor of enhancer of zeste homologue 2 (EZH2), a methyltransferase that plays a role in epithelioid sarcoma pathogenesis [32]. Integrase interactor 1 (INI1) loss is present in >90% of patients with epithelioid sarcoma [33]. Preclinical in vitro and in vivo models show that loss or dysfunction of INI1 can lead to aberrant EZH2 activity, resulting in oncogenic dependence on EZH2 [34]. Targeting EZH2 in relapsed or refractory follicular lymphoma, resulted in 69% objective and prolonged responses [35]. Tazemetostat has further been investigated in patients with epithelioid sarcoma with INI1 loss, and the results of the phase 2 trial demonstrated an objective response rate (ORR) at the data cut-off (September 2018) of 15%, corresponding to nine of 62 evaluable patients which had a reduction of their tumor. Some responders had a long clinical benefit [36]. Tazemetostat proved to be a well-tolerated drug, with the most common side effects being fatigue, nausea, and vomiting. The grade 3–4 side effects included anemia and weight loss [35,36].