A5049134775- Acute Myeloid Leukemia Research
- MicroRNA in disease regulation
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Cancer, Lipids, and Metabolism
- Chronic Myeloid Leukemia Treatments
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Chronic Lymphocytic Leukemia Research
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
- Epigenetics and DNA Methylation
- Cell death mechanisms and regulation
- Acute Lymphoblastic Leukemia research
- Autophagy in Disease and Therapy
- Microtubule and mitosis dynamics
- Cancer therapeutics and mechanisms
- Lymphoma Diagnosis and Treatment
- Drug Transport and Resistance Mechanisms
- Mitochondrial Function and Pathology
- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Nuclear Structure and Function
- Cancer-related gene regulation
The University of Texas MD Anderson Cancer Center
2015-2024
The University of Texas Health Science Center at Houston
2023
Keio University
2004-2017
Institute for Advanced Medical Research
2009-2017
Keio University Hospital
2012
Shizuoka Red Cross Hospital
2007
The mitochondrial caseinolytic protease P (ClpP) plays a central role in protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the selectively kills cancer cells, independently p53 status, selective degradation its respiratory chain substrates disrupts structure function, while it does not affect non-malignant cells. We identified imipridones as potent activators ClpP. Through biochemical studies crystallography,...
ONC201 triggers an apoptotic cellular stress response in both solid and blood tumors.
Leukemia cells in the bone marrow must meet biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations nutrient oxygen availability. Thus, targeting metabolic abnormalities leukemia located is a novel therapeutic approach. In this study, we investigated role adipocytes supporting growth leukemic blasts. Prevention starvation-induced apoptosis adipocytes, as well molecular mechanisms involved process, was using various analytic techniques....
Objective Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet role of mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect SOX9-mediated cancer stemness attributes advanced gastric adenocarcinoma (GAC) novel therapeutic discoveries. Methods Bulk RNAseq/scRNA-seq, patient-derived cells/models extensive functional studies were used identify expression functions its target vitro...
Abstract BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is clinically combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists under investigation. Yet, resistance single combinatorial BH3-mimetic therapies eventually ensues. Integration multiple genome-wide CRISPR/Cas9 screens revealed that loss mitophagy...
The nuclear transporter exportin‐1 ( XPO 1) is highly expressed in mantle cell lymphoma MCL ) cells, and believed to be associated with the pathogenesis of this disease. 1‐selective inhibitors export SINE compounds have been shown induce apoptosis cells. Given that p53 a cargo protein 1, we sought determine significance activation through 1 inhibition ‐induced We investigated prognostic impact expression cells using Oncomine analysis. mutational/functional status on sensitivity models...
Disease recurrence is the major problem in treatment of acute myeloid leukemia (AML). Relapse driven by stem cells, a chemoresistant subpopulation capable re-establishing disease. Patients with p53 mutant AML are at an extremely high risk relapse. B-cell-specific Moloney murine virus integration site 1 (BMI-1) required for self-renewal and maintenance cells. Here we studied effects novel small molecule inhibitor BMI-1, PTC596, Treatment PTC596 reduced MCL-1 expression triggered several...
The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been attributed to transcriptional downregulation cellular anabolic antiapoptotic processes, but its on the bone marrow microenvironment, a sanctuary favoring persistence leukemic stem/progenitor cells, is unexplored. Sustained degradation BETP with small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in marked surface CXCR4...
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to inhibition. Therefore, more potent and biomarkers predictive tumor sensitivity needed. The novel inhibitor DS-3032b is 10-fold than the first-generation nutlin-3a. mutations were resistance DS-3032b, allele frequencies negatively correlated with DS-3032b. However, varied greatly....
In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. inhibitor (MDM2i) monotherapy in AML has shown modest responses clinical trials but combining options MDM2i with other potent AML-directed agents like cytarabine venetoclax could improve its efficacy. We conducted a phase I trial (NCT03634228) to study the safety efficacy milademetan (an MDM2i) low-dose (LDAC)±venetoclax adult patients relapsed...
In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. contrast, no phosphatase substrates LATS1/WARTS kinase, mammalian equivalent Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase–targeting subunit 1) as a new substrate for LATS1. directly preferentially phosphorylated serine 445 (S445) MYPT1. An mutant (S445A) failed to...
Targeted therapies against FLT3-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition secondary mutations in FLT3 and persistent activation downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, STAT5. Activation these additional kinases may also result phosphorylation tumor suppressor proteins promoting their nuclear export. Thus, co-targeting export (e.g., XPO1) concomitantly be therapeutically effective. Here we report on...
The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner cancers and reactivated by inhibiting its negative regulators. We here cotarget MDM2 the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated p53 elicited 25- 60-fold increase targets. regulates MYC , disrupted c-MYC–regulated transcriptome, resulting synergistic induction apoptosis acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express...
Mantle cell lymphoma (MCL) is an aggressive B-cell characterized by the aberrant expression of several growth-regulating, oncogenic effectors. Exportin 1 (XPO1) mediates nucleocytoplasmic transport numerous molecules including growth-regulating factors, RNAs, and ribosomal subunits. In MCL cells, small molecule KPT-185 blocks XPO1 function exerts anti-proliferative effects. this study, we investigated molecular mechanisms putative anti-tumor effect on cells using growth/viability assays,...
Cdh1 is an activator of the anaphase-promoting complex/cyclosome and contributes to mitotic exit G(1) maintenance by targeting cell cycle proteins for degradation. However, expressed active in postmitotic or quiescent cells, suggesting that it has functions other than control. Here, we found homozygous gene-trapped (Cdh1(GT/GT)) mouse embryonic fibroblasts (MEFs) Cdh1-depleted HeLa cells reduced stress fiber formation significantly. The GTP-bound Rho protein was apparently decreased cells....
Curing patients with acute myeloid leukemia (AML) remains a therapeutic challenge. The polycomb complex protein B-cell-specific Moloney murine virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of stem cells. We investigated prognostic significance BMI-1 in AML effects novel small molecule selective inhibitor BMI-1, PTC-209. expression was determined 511 newly diagnosed together 207 other proteins using reverse-phase array technology. Patients unfavorable...
In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for drugs that can overcome prolong patient survival after failure standard therapies. The imipridone ONC201 causes downstream inactivation ERK1/2 signaling has tumoricidal activity against a variety tumor types, while its efficacy preclinical models myeloma remains unclear. this study, we treated human cell...