Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromothripsis is a unique type of genomic instability and is recognized in various cancers. In myeloid neoplasms (MNs), chromothripsis was linked to poor prognosis and specific genetic alterations (complex karyotype, 5q deletions, and loss of TP53). However, the clinicopathologic features of MNs with chromothripsis have not been thoroughly characterized. We identified chromothripsis in 11 cases of MNs (9 acute myeloid leukemia [AML] and 2 myelodysplastic syndrome [MDS] cases) and noted that all chromothripsis-positive AML cases were AML with myelodysplasia-related changes (AML-MRC). We performed a comparative clinicopathologic and genetic characterization of AML-MRC cases with and without chromothripsis. AML-MRC with chromothripsis is associated with lower white blood cell and platelet counts and higher degree of karyotypic complexity. Chromothripsis in AML-MRC most frequently involves chromosomes 8 and 11 with consequent amplification of either MYC or KMT2A. Comparative morphologic assessment of blast morphology revealed unique features characteristic of AML-MRC with chromothripsis: a variable degree of cytoplasmic vacuolization, granulation, and blebbing. These morphologic markers in the context of AML-MRC may prompt additional studies to identify cases with chromothripsis.
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PMID:Unique morphologic and genetic characteristics of acute myeloid leukemia with chromothripsis: a clinicopathologic study from a single institution. 3208 9

RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as "undruggable." Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.
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PMID:Drugging "undruggable" genes for cancer treatment: Are we making progress? 3263 80

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
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PMID:Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. 3264 16

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. Here we characterize the immunological features of the malignant clone and alterations in the immune microenvironment in TP53 mutant and wild type MDS and sAML patients. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of TP53 mutant patients, which is associated with MYC upregulation and marked down-regulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, TP53 mutant patients display significantly reduced numbers of bone marrow infiltrating OX40+ cytotoxic T-cells and helper T-cells, as well as decreased ICOS+ and 4-1BB+ NK cells. Further, highly immunosuppressive regulatory T-cells (i.e., ICOSHigh/PD-1neg) and MDSCs (PD-1low) are expanded in TP53 mutant cases. Finally, a higher proportion of bone marrow infiltrating ICOSHigh/PD-1neg Tregs is a highly significant independent predictor of overall survival. We conclude the microenvironment of TP53 mutant MDS and sAML has an immune privileged, evasive phenotype that may be a primary driver of poor outcomes, and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly-defined subpopulation.
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PMID:TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype. 3273 May 93


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