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Diagnostics (Basel, Switzerland) Dec 2023Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in... (Review)
Review
Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease.
PubMed: 38201389
DOI: 10.3390/diagnostics14010080 -
Annals of Hematology Mar 2024
Topics: Humans; Staurosporine; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Mutation
PubMed: 38195923
DOI: 10.1007/s00277-024-05614-1 -
Frontiers in Pharmacology 2023ARLs, which are a class of small GTP-binding proteins, play a crucial role in facilitating tumor tumorigenesis and development. ARL4C, a vital member of the ARLs...
ARLs, which are a class of small GTP-binding proteins, play a crucial role in facilitating tumor tumorigenesis and development. ARL4C, a vital member of the ARLs family, has been implicated in the progression of tumors, metastatic dissemination, and development of resistance to therapeutic drugs. Nevertheless, the precise functional mechanisms of ARL4C concerning tumor prognosis and immunotherapy drug susceptibility remain elusive. By combining the GTEx and TCGA databases, the presence of ARL4C was examined in 33 various types of cancer. Immunohistochemistry and immunofluorescence staining techniques were utilized to confirm the expression of ARL4C in particular tumor tissues. Furthermore, the ESTIMATE algorithm and TIMER2.0 database were utilized to analyze the tumor microenvironment and immune infiltration associated with ARL4C. The TISCH platform facilitated the utilization of single-cell RNA-seq datasets for further analysis. ARL4C-related immune escape was investigated using the TISMO tool. Lastly, drug sensitivity analysis was conducted to assess the sensitivity of different types of tumors to compounds based on the varying levels of ARL4C expression. The study found that ARL4C was highly expressed in 23 different types of cancer. Moreover, the presence of high ARL4C expression was found to be associated with a poor prognosis in BLCA, COAD, KIRP, LGG, and UCEC. Notably, ARL4C was also expressed in immune cells, and its high expression was found to be correlated with cancer immune activation. Most importantly, the drug sensitivity analysis revealed a positive correlation between ARL4C expression and the heightened sensitivity of tumors to Staurosporine, Midostaurin, and Nelarabine. The findings from our study indicate that the expression level of ARL4C may exert an influence on cancer development, prognosis, and susceptibility to immunotherapy drugs. In addition, the involvement of ARL4C in the tumor immune microenvironment has expanded the concept of ARL4C-targeted immunotherapy.
PubMed: 38178862
DOI: 10.3389/fphar.2023.1288492 -
Dermatologie (Heidelberg, Germany) Jan 2024Mastocytosis is a rare disease characterized by clonal expansion and accumulation of mast cells (MC) in various organs. Mastocytosis results from an activating mutation...
Mastocytosis is a rare disease characterized by clonal expansion and accumulation of mast cells (MC) in various organs. Mastocytosis results from an activating mutation of the KIT surface receptor leading to an increased proliferation of MC. There are significant differences between children and adult patients with mastocytosis. Children mainly present the cutaneous form, whereas adults more often exhibit the systemic form of mastocytosis. Patients with mastocytosis may be asymptomatic or affected by a variety of symptoms. Treatment is primarily supportive and aims at symptom control. New approved targeted therapies such as midostaurin and avapritinib changed the treatment paradigm in advanced forms of the disease, and next-generation inhibitors currently in clinical trials are expected in the near future.
Topics: Child; Adult; Humans; Proto-Oncogene Proteins c-kit; Mastocytosis; Mast Cells; Skin
PubMed: 38085334
DOI: 10.1007/s00105-023-05258-8 -
European Journal of Medicinal Chemistry Jan 2024FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem...
FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem duplication (ITD) mutations in the juxtamembrane region. Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. Midostaurin is a first-generation FLT3 inhibitor with minimal activity as monotherapy. Midostaurin lacks selectivity and is only approved by the USFDA for use in combination with other chemotherapy agents. The second-generation inhibitors quizartinib and gilteritinib display improved specificity and selectivity, and have been approved for use as monotherapy. However, their clinical efficacies are limited in part due to the emergence of drug-resistant FLT3 secondary mutations in the tyrosine kinase domain at positions D835 and F691. Therefore, in order to overcome drug resistance and further improve outcomes, new compounds targeting FLT3-ITD with secondary mutants are urgently needed. In this study, through the structural modification of a reported compound Ling-5e, we identified compound 24 as a FLT3 inhibitor that is equally potent against FLT3-ITD and the clinically relevant mutants FLT3-ITD/D835Y, and FLT3-ITD/F691L. Its inhibitory effects were demonstrated in both cell viability assays and western blots analyses. When tested against cell lines lacking activating mutations in FLT3, no non-specific cytotoxicity effect was observed. Interestingly, molecular docking results showed that compound 24 may adopt different binding conformations with FLT3-F691L compared to FLT3, which may explain its retained activity against FLT3-ITD/F691L. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.
Topics: Humans; Molecular Docking Simulation; Protein Kinase Inhibitors; Mutation; Leukemia, Myeloid, Acute; Pyridines; fms-Like Tyrosine Kinase 3
PubMed: 38056299
DOI: 10.1016/j.ejmech.2023.115977 -
British Journal of Haematology Feb 2024Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell... (Review)
Review
Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.
Topics: Humans; Mastocytosis, Systemic; Mast Cells; Leukemia, Mast-Cell; Cladribine; Mastocytosis; Proto-Oncogene Proteins c-kit
PubMed: 38054381
DOI: 10.1111/bjh.19245 -
Frontiers in Pharmacology 2023Disulfidptosis is a metabolically relevant mode of cell death, and its relationship with acute myeloid leukemia (AML) has not been clarified. In this study,...
Development and validation of a disulfidptosis-related scoring system to predict clinical outcome and immunotherapy response in acute myeloid leukemia by integrated analysis of single-cell and bulk RNA-sequencing.
Disulfidptosis is a metabolically relevant mode of cell death, and its relationship with acute myeloid leukemia (AML) has not been clarified. In this study, disulfidptosis scores were computed to examine the potential biological mechanisms. Consensus clustering was applied to detect disulfidptosis-related molecular subtypes. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a DRG prognostic model. DRGs are upregulated in AML and associated with poor prognosis. The higher the disulfidptosis activity score, the worse the clinical outcome for patients, accompanied by increased immune checkpoint expression and tumor marker pathway activity. The two molecular subtypes exhibited distinct prognoses and tumor microenvironment (TME) profiles. A prognostic risk score model was established using six DRGs, and the AML cohort was divided into high- and low-risk score groups. Patients in the high-risk group experienced significantly worse prognosis, which was validated in seven AML cohorts. Receiver Operating Characteristic (ROC) curve analysis indicated that the area under the curve values for risk score prediction of 1-, 3-, and 5-year survival were 0.779, 0.714, and 0.778, respectively. The nomogram, in conjunction with clinicopathological factors, further improved the accuracy of prognosis prediction. The high-risk score group exhibited a higher somatic mutation frequency, increased immune-related signaling pathway activity, and greater immune checkpoint expression, suggesting a certain degree of immunosuppression. Patients with advanced age and higher cytogenetic risk also had elevated risk scores. According to drug prediction and AML anti-PD-1 therapy cohort analysis, the low-risk score group displayed greater sensitivity to chemotherapy drugs like cytarabine and midostaurin, while the high-risk score group was more responsive to anti-PD-1 therapy. Finally, clinical samples were collected for sequencing analysis, confirming that the progression of myeloid leukemia was associated with a higher risk score and a negative disulfidptosis score, suggesting that the poor prognosis of AML may be associated with disulfidptosis resistance. In conclusion, a systematic analysis of DRGs can help to identify potential disulfidptosis-related mechanisms and provide effective new biomarkers for prognosis prediction, TME assessment, and the establishment of personalized treatment plans in AML.
PubMed: 38053840
DOI: 10.3389/fphar.2023.1272701 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2024The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). However, the response... (Review)
Review
The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). However, the response is heterogeneous with 10% to 50% of newly diagnosed AML patients not responding to hypomethylating agent (HMA) and VEN. Furthermore, up to 40% of responding patients relapse shortly. This review discusses the mechanism of action of Venetoclax and the major mechanisms of inherent and acquired resistance to VEN. VEN is highly specific to BCL-2 binding, as such other antiapoptotic proteins in BCL-2 family induce resistance. These antiapoptotic proteins can also be upregulated via a number of compensatory cell signaling pathways including PI3K/AKT/mTOR, the MAPK/ERK pathway, and mutant FLT3-ITD. Mutations can occur in BCL-2 and BAX proteins, or they can be silenced by TP53 mutations and other epigenetic changes. Changes to mitochondrial structure and metabolism can induce resistance. Key metabolic regulators include OXPHOS and alternative amino acid metabolism. Finally microenvironmental factors can influence VEN responses. This paper evaluates subsets of AML by differentiation, histology, cytogenetics and molecular markers and their different responses to VEN; with spliceosome mutations, ASXL1, NPM1 and IDH1/2 being favorable while others such as FLT3, TP53 and BCL-2 mutations being less responsive. Currently intensive multiagent chemotherapy and Venetoclax combinations such as 7+3+VEN are favored in fit younger AML patients. However, with resistant patients' subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next-generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors in addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance.
Topics: Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-bcl-2; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 38007372
DOI: 10.1016/j.clml.2023.10.006 -
Annals of Hematology Nov 2023Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized overall by an aggressive clinical course. The underlying genetic abnormalities present in... (Review)
Review
Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized overall by an aggressive clinical course. The underlying genetic abnormalities present in leukemic cells contribute significantly to the AML phenotype. Mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most common genetic abnormalities identified in AML, and the presence of these mutations strongly influences disease presentation and negatively impacts prognosis. Since mutations in FLT3 were identified in AML, they have been recognized as a valid therapeutic target resulting in decades of research to develop effective small molecule inhibitor treatment that could improve outcome for these patients. Despite the approval of several FLT3 inhibitors over the last couple of years, the treatment of patients with FLT3-mutated AML remains challenging and many questions still need to be addressed. This review will provide an up-to-date overview of our current understanding of FLT3-mutated AML and discuss what the current status is of the available FLT3 inhibitors for the day-to-day management of this aggressive disease.
PubMed: 37975931
DOI: 10.1007/s00277-023-05545-3 -
ChemMedChem Jan 2024FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential...
FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.
Topics: Humans; Antineoplastic Agents; Chronic Pain; Mutation; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Proto-Oncogene Proteins c-ret
PubMed: 37971283
DOI: 10.1002/cmdc.202300442