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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ponatinib (Iclusig™) (Figure 6.13) was given accelerated approval status by the FDA in 2012 for the treatment of resistant or intolerant chronic myeloid leukemia and Philadelphia chromosome–positive ALL, and was fully approved in 2016 for patients with chronic-, accelerated-, or blast-phase chronic myeloid leukemia, and Philadelphia chromosome–positive ALL for whom no other tyrosine kinase inhibitor therapy is indicated. Structure of ponatinib (Iclusig™).
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
In nearly two decades, several classes of the small-molecule kinase inhibitors have become effective treatment for cancer patients whose tumors harbor genetic aberrations such as gene mutation, amplification or chromosomal translocation in the target kinases. The fusion gene of the c-ABL proto-oncogene from chromosome 9 with the breakpoint duster region (BCR) on chromosome 22 (BCR-ABL fusion gene on chromosome 22) is referred to as the Philadelphia chromosome (Ph+). It encodes a constitutively active tyrosine kinase in chronic myelogenous leukemia (CML), some acute lymphoblastic leukemia, and acute myelogenous leukemia (Chapter 8). Patients with Ph+ disease respond to a class of the tyrosine kinase inhibitors (TKIs) targeting BCR-ABL such as imatinib, dasatinib or nilotinib. In addition, the FDA approved bosutinib and ponatinib to treat adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Ponatinib is an oral inhibitor of ABL1, SRC, and several other kinases, which was initially developed for patients with TKIs-resistant CML as a result of a T315I mutation, which is resistant to imatinib, dasatinib, bosutinib, and nilotinib.78 Subsequently, in a Phase II trial (PACE), it was found to have considerable activity in all patients with CML, irrespective of the presence or absence of the T315I mutation. In 2012, ponatinib was licensed for second-line use, and a Phase III randomized study (EPIC) for newly diagnosed patients with CML in CP was initiated. The study was closed in 2013 in view of an increased incidence of arterial thrombotic events, hypertension, and hepatitis in the longer-term follow-up of the PACE study, and further development of the drug for first-line use remains on hold. The considerable cardiovascular and other serious side effects appear to be dose-related, and efforts are now being made to assess lower doses. Ponatinib appears to be effective against diverse causes of TKI resistance, including T315I and compound mutations. Resistance to ponatinib as a consequence of new mutations, such as T315M and T315L, as well as compound mutations, has now been described.
Origanum Sipyleum Methanol Extract in Combination with Ponatinib Shows Synergistic anti-Leukemic Activities on Chronic Myeloid Leukemia Cells
Published in Nutrition and Cancer, 2022
Cagla Kayabasi, Sunde Yilmaz Susluer, Tugce Balci Okcanoglu, Besra Ozmen Yelken, Zeynep Mutlu, Bakiye Goker Bagca, Cansu Caliskan Kurt, Guray Saydam, Cenk Durmuskahya, Husniye Kayalar, Ahmet Ozbilgin, Cigir Biray Avci, Cumhur Gunduz
Chronic myeloid leukemia (CML) is a myeloproliferative clonal disorder characterized by t(9;22) which encodes the constitutively active tyrosine kinase BCR-ABL1 (10, 11). Imatinib, the first tyrosine kinase inhibitor (TKI), is effective in CML treatment, but patients develop resistance in time. Dasatinib or nilotinib are second generation of TKIs that efficiently inhibit the majority of mutated-BCR-ABL1 except T315I mutation (12). On the other hand, ponatinib is a third-generation TKI that was designed to target the BCR-ABL1 fusion protein with T315I mutation efficiently. Ponatinib can inhibit auto-phosphorylation of wild-type, T315I-mutant, and multiple imatinib-resistant ABL1. Ponatinib is also effective on other kinases, such as Src family kinases, PDGFRα, VEGFR2, and FGFR1 (12, 13). Nevertheless, ponatinib exhibited serious side effects in some CML cases during the treatment (14, 15). Ponatinib-resistant ABL1 isoform has also been reported (16).
Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma
Published in Experimental Lung Research, 2021
Yi-Wei Yang, Angelica Marrufo, Jillian Chase, Gavitt A. Woodard, David M. Jablons, Hassan Lemjabbar-Alaoui
In the present study, we show a dysregulated cAbl pathway in human MPM. Furthermore, we demonstrate that ponatinib treatment in 4 MPM cell lines reverted these cells' malignant phenotype in vitro and reduced MPM cell growth and cell migration (Figures 2 and 3). All MPM lines showed considerable pCrkl protein expression demonstrating a cAbl pathway activation (Figure 4). Additionally, we have found that the ponatinib treatment of MPM cell lines results in a significant reduction in the phosphorylation and activation levels of cAbl and its downstream effectors CrkL, ATK, and STAT5 (Figures 5 and 8). Also, ponatinib treatment amplified double-strand DNA breaks (DSDBs) revealed by an increased accumulation of γ-H2AX in MPM cells (Figure 6). In vivo, ponatinib reduced tumor growth (Figure 8).
Ponatinib use in two pediatric patients with relapsed Ph + ALL with ABL1 kinase domain mutations
Published in Pediatric Hematology and Oncology, 2019
Stephanie E. Gruner, Hadi Sayeed, Lizmery Suarez-Ferguson, Cintia Perez, Rayne Rouce, Kevin E. Fisher, Rachel E. Rau
Like all TKIs, ponatinib is associated with several potential toxicities 8–10 and both patients experienced adverse events. Patient 1 experienced severe fluid retention necessitating discontinuation of ponatinib. Fluid retention, specifically pleural effusion, is a known toxicity of all TKIs, reported most commonly with dasatinib.15 Based on a single-arm, open-label, international, multicenter trial in 449 adult patients with CML or Ph + ALL treated with ponatinib, fluid retention of any grade occurred in 23% (103/449) of patients, most commonly, peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Grade 3 or greater fluid retention occurred in only 3% (13/449). The severity of fluid retention may have also been exacerbated by concomitant voriconazole administration. Ponatinib is metabolized primarily by cytochrome CYP3A4 and voriconazole is a well-established inhibitor of this enzyme. This drug-drug interaction may have increased plasma concentrations of ponatinib despite appropriate dose reduction. Patient 2 experienced rash resulting in dose reduction of ponatinib. Rash is one of the most commonly reported non-hematologic adverse reactions (≥20%) and one of the most common adverse reactions prompting dose modifications in adults (11%).16