imatinib

In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

P3, N=680, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Jul 2024

Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.

P2, N=112, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2023 --> Dec 2024

The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.

This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options.

The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA)...Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

Owing to these merits, the proposed fluorescence sensor was utilized to detect IMB in drug tablets and human plasma, and satisfactory results (99.3-100.4 %) were obtained. Thus, the synthesized fluorescence sensor is a promising platform for IMB sensing in various applications.

It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. In contrast, the allosteric inhibitor asciminib strongly reduces Abl's activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.

Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL...More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin...These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.

Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

P1, N=78, Recruiting, Taiho Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=38, Active, not recruiting, National Cancer Institute (NCI)

These observations strongly indicate that TORin-1 acts as PAK1-blockers, instead of TOR-blockers, in vivo. Thus, it is most likely that melanogenesis in cell culture could enable us to discriminate PAK1-blockers from TORblockers.

CML presenting with hearing loss is rare, believed to be related to the infiltration of leukemic cells in the inner ear or microvascular complications. Treatment with tyrosine kinase inhibitors such as Imatinib can improve hematologic parameters, but the effect on hearing loss is uncertaint.

This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

P2, N=28, Recruiting, Reema A. Patel | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2024 --> Dec 2025

Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.

However, oncogenic fusions involving transcription factors such as PAX3-FOXO1 in alveolar fusion gene-positive rhabdomyosarcoma (FP-RMS) have been difficult to inhibit due to the apparent lack of tractable drug-like binding sites comparable to that recognized by Gleevec (imatinib mesylate) on the BCR-ABL1 tyrosine kinase fusion protein...To facilitate single-cell clonal isolation of knock-ins, the homology-directed repair template encoding HiBiT was followed by a P2A self-cleaving peptide for coexpression of an mCherry fluorescent protein as a fluorescence-activated cell sorter (FACS)-selectable marker. HiBiT tagging thus allows highly sensitive luminescence detection of endogenous PAX3-FOXO1 levels permitting quantitative high-throughput screening of large compound libraries for the discovery of PAX3-FOXO1 inhibitors and degraders.

Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1-rearranged neoplasms...Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL-5 receptor antibody benralizumab, IL-5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN-eo-TK, are under active investigation.

Here, we review the development of BCR::ABL1-specific TKIs from the discovery of imatinib in 1996 to the more recent second- and third-generation TKIs and emerging specifically targeting the ABL myristoyl pocket (STAMP) inhibitors. We will also evaluate the current evidence for treatment of BCR::ABL1-positive leukaemias, including TKI discontinuation in optimally responding CP-CML patients.

Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

P2, N=500, Recruiting, National University Hospital, Singapore

P2, N=28, Not yet recruiting, Asan Medical Center

P1, N=68, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

Five patients were treated according to EsPhALL 2004, which involved starting imatinib later in a discontinuous manner [resulting in both five-year overall survival (OS) and progression-free survival (PFS) of 60%]...Conclusions Although initially associated with a poor prognosis, the ALL Ph+ paradigm is drastically shifting. Further studies will hopefully clarify the outcomes in this population and help understand the role of central nervous system (CNS) prophylaxis, alloHSCT, and MRD quantification.

In this study, we delved into the underlying mechanisms of specific BCR-ABL tyrosine kinase inhibitors (imatinib, nilotinib, ZM-306416, and AT-9283) in human melanoma A375P cells. Consequently, the expression of the E2F target genes (CCNA2, CCNE1, POLA1, and TK-1) was markedly suppressed in nilotinib and AT9283-treated A375P cells. In summary, our findings suggest that BCR-ABL tyrosine kinase inhibitors may regulate the G1-to-S transition in human melanoma A375P cells by modulating the RB-E2F complex.

After treatment with imatinib for 4 months, the patient achieved complete cytogenetic response (CCyR) and early molecular response (EMR). This is the first report of complex chromosomal karyotype involving six-way translocation in CML; the combination of chromosome analysis and FISH techniques is an effective strategy in determining the karyotype result.

Analysis of global gene expression changes in imatinib-treated, PRDX1-deficient cells revealed that the nonhomologous end-joining (NHEJ) DNA repair is a novel vulnerability of Ph+ B-ALL cells. Accordingly, PRDX1-deficient Ph+ B-ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph+ B-ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph+ B-ALL.

P2, N=1500, Recruiting, QuantumLeap Healthcare Collaborative | Trial completion date: Nov 2024 --> Jul 2030 | Trial primary completion date: Jul 2023 --> Jul 2028

DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast ) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax ) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model-informed drug development or the support of model-informed precision dosing.

P2, N=406, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P2b --> P2

Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events.

She was discharged 45 days after first operation. Currently, 9 months after the operation, patient has been prescribed imatinib and is alive without recurrence.

In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.

In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace Hyper-CVAD cycle 1 when combined with imatinib in adults with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). Despite a non-inferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.

P3, N=238, Active, not recruiting, Il-Yang Pharm. Co., Ltd. | Trial completion date: Dec 2023 --> Jun 2025

These findings suggest that flumatinib is a safe and effective tyrosine kinase inhibitor (TKI) for achieving CMR and MRD negativity in patients with Ph+ ALL, as supported by this small series of patients.

Such treatment, markedly reduced reactive oxygen species levels, as measured by flow‑cytometry, in K‑562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.