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Journal of Hematology & Oncology Dec 2018FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the... (Review)
Review
FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; fms-Like Tyrosine Kinase 3
PubMed: 30514344
DOI: 10.1186/s13045-018-0675-4 -
CNS Oncology 2016A Phase II trial of bevacizumab plus tandutinib.
AIM
A Phase II trial of bevacizumab plus tandutinib.
METHODS
We enrolled 41 recurrent, bevacizumab-naive glioblastoma patients for a trial of bevacizumab plus tandutinib. Median age was 55 and 71% were male. Treatment consisted of tandutinib 500 mg two-times a day (b.i.d.) and bevacizumab 10 mg/kg every 2 weeks starting day 15. Of 37 (90%) evaluable, nine (24%) had partial response.
RESULTS & CONCLUSION
Median overall and progression-free survival was 11 and 4.1 months; progression-free survival at 6 months was 23%. All patients suffered treatment-related toxicities; common grade ≥3 toxicities were hypertension (17.1%), muscle weakness (17.1%), lymphopenia (14.6%) and hypophosphatemia (9.8%). Four of six with grade ≥3 tandutinib-related myasthenic-like muscle weakness had electromyography-proven neuromuscular junction pathology. Tandutinib with bevacizumab was as effective but more toxic than bevacizumab monotherapy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Disease-Free Survival; Female; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Piperazines; Quinazolines
PubMed: 26860632
DOI: 10.2217/cns-2015-0010 -
Biomarker Research 2019FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in... (Review)
Review
FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.
PubMed: 31528345
DOI: 10.1186/s40364-019-0170-2 -
Neuro-oncology Apr 2017Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens.
Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma.
BACKGROUND
Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens.
METHODS
We report the results of feasibility, phase I, and phase II studies of tandutinib (MLN518), an orally bioavailable inhibitor of type III receptor tyrosine kinases including PDGF receptor-β, Fms-like tyrosine kinase 3, and c-Kit in patients with recurrent glioblastoma.
RESULTS
In an initial feasibility study, 6 patients underwent resection for recurrent glioblastoma after receiving tandutinib 500mg twice daily for 7 days. The mean ratio of tandutinib concentration in brain tumor-to-plasma was 13.1±8.9 in 4 of the 6 patients. In the phase I study, 19 patients were treated at 500, 600, and 700mg twice daily dose levels. The maximum tolerated dose was found to be 600mg twice daily, and 30 patients were treated with this dose in the phase II study. The trial was closed after interim analysis, as the prespecified goal of patients alive and progression-free survival at 6 months was not achieved. Biomarker studies suggested that tandutinib treatment could lead to vascular disruption rather than normalization, which was associated with rapid progression.
CONCLUSIONS
Tandutinib readily distributed into the brain following oral administration and achieved concentrations within the tumor that exceed the corresponding concentration in plasma. The phase II study was closed at interim analysis due to lack of efficacy, although this study was not enriched for glioblastomas with alterations of the PDGF pathway.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Brain; Brain Neoplasms; Disease-Free Survival; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Piperazines; Quinazolines; Receptor, Platelet-Derived Growth Factor beta; Tissue Distribution; Treatment Outcome
PubMed: 27663390
DOI: 10.1093/neuonc/now185 -
Neurology Jan 2011Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the...
BACKGROUND
Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined.
METHODS
Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394).
RESULTS
Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single-fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib.
CONCLUSION
These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction.
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Electromyography; Female; Glioblastoma; Humans; Male; Middle Aged; Myasthenia Gravis; Neuromuscular Diseases; Neuromuscular Junction; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Syndrome
PubMed: 21242491
DOI: 10.1212/WNL.0b013e3182074a69 -
Molecular Cancer Therapeutics May 2013The c-Kit receptor can activate distinct signaling pathways including phosphoinositide 3-kinase (PI3K)/Akt and mTOR. Aberrant c-Kit activation protects cells from...
The c-Kit receptor can activate distinct signaling pathways including phosphoinositide 3-kinase (PI3K)/Akt and mTOR. Aberrant c-Kit activation protects cells from apoptosis and enhances invasion of colon carcinoma cells. Tandutinib is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases including c-Kit. We determined the effect of tandutinib on colon cancer growth and identified a mechanism of action. Tandutinib inhibited phosphorylation of c-Kit, Akt, mTOR, and p70S6 kinase. In addition, tandutinib significantly inhibited the proliferation and colony formation ability of colon cancer cell lines but did not affect normal colonic epithelial cells. There were increased levels of activated caspase-3 and Bax/Bcl2 ratio, coupled with a reduction in cyclin D1, suggesting apoptosis. There was also a downregulation of COX-2, VEGF, and interleukin-8 expression, suggesting effects on cancer-promoting genes. In addition, overexpressing constitutively active Akt partially suppressed tandutinib-mediated colon cancer cell growth. In vivo, intraperitoneal administration of tandutinib significantly suppressed growth of colon cancer tumor xenografts. There was a reduction in CD31-positive blood vessels, suggesting that there was an effect on angiogenesis. Tandutinib treatment also inhibited the expression of cancer-promoting genes COX-2 and VEGF and suppressed the activation of Akt/mTOR signaling proteins in the xenograft tissues. Together, these data suggest that tandutinib is a novel potent therapeutic agent that can target the Akt/mTOR/p70S6K signaling pathway to inhibit tumor growth and angiogenesis.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Neovascularization, Pathologic; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-kit; Quinazolines; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 23427297
DOI: 10.1158/1535-7163.MCT-12-0907 -
Journal of Pediatric Hematology/oncology Mar 2012Overexpression of platelet-derived growth factor receptor alpha (PDGFR-A) has been documented in association with primary tumors and metastasis in medulloblastoma....
Overexpression of platelet-derived growth factor receptor alpha (PDGFR-A) has been documented in association with primary tumors and metastasis in medulloblastoma. Tumors from our genetically engineered sonic hedgehog-driven medulloblastoma mouse model overexpress PDGFR-A in primary tumors and thus this mouse model is a good platform with which to study the role of PDGFR-A in this central nervous system malignancy. We hypothesized that inhibition of PDGFR-A in medulloblastoma can slow or inhibit tumor progression in living individuals. To test our hypothesis, we targeted PDGFR-A mediated tumor growth in vitro and in vivo using the tyrosine kinase inhibitor, tandutinib (MLN-518), which strongly inhibits PDGFR-A. Although PDGFR-A inhibition by this agent resulted in reduced mouse tumor cell growth and increased apoptosis in vitro, and reduced tumor cell proliferation in vivo, tandutinib did reduce tumor volume at the doses tested (360 mg/kg) in vivo. Thus, tandutinib may be an agent of interest for sonic hedgehog-driven medulloblastoma if a synergistic drug combination can be identified.
Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Separation; Cerebellar Neoplasms; Disease Models, Animal; Flow Cytometry; Immunohistochemistry; Medulloblastoma; Mice; Mice, Transgenic; Piperazines; Quinazolines; Receptor, Platelet-Derived Growth Factor alpha; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 22146535
DOI: 10.1097/MPH.0b013e3182309fe4 -
British Journal of Cancer Nov 2012Vascular endothelial growth factor (VEGF)-mediated angiogenesis mediates tumour growth and metastasis. Meningiomas are primarily benign, slow-growing, highly...
BACKGROUND
Vascular endothelial growth factor (VEGF)-mediated angiogenesis mediates tumour growth and metastasis. Meningiomas are primarily benign, slow-growing, highly vascularised tumours. Aside from VEGF, there is little data on the function of major angiogenic proteins in meningiomas.
METHODS
The VEGFA, platelet-derived growth factor B (PDGFB), and their respective receptors - VEGF receptor 2 (KDR) and PDGF receptor β (PDGFRβ) - were quantified using real-time PCR and a TaqMan Protein Assay in meningiomas in vivo and in vitro. The effect of VEGFA and PDGFB on cell proliferation and the tyrosine phosphorylation of PDGFRβ were examined.
RESULTS
Most meningiomas displayed no KDR protein expression but elevated PDGFRβ levels. Exogenous VEGFA stimulation significantly increased cell proliferation. The PDGFRβ inhibition before stimulation with VEGFA abolished the proliferative stimuli. The VEGFA induced concentration-dependent PDGFRβ tyrosine phosphorylation comparable to PDGFB-induced PDGFRβ tyrosine phosphorylation. The PDGFRβ inhibitors gambogic acid, sunitinib, and tandutinib equally impaired the migration of meningioma cells. In addition, gambogic acid suppressed the VEGFA-induced PDGFRβ tyrosine phosphorylation.
CONCLUSION
Collectively, our data suggest that VEGFA primarily regulates VEGF-mediated migration through PDGFRβ in meningiomas. The inhibitory effect of gambogic acid and tandutinib against meningioma growth in vitro suggests that selective PDGFRβ inhibitors, in combination with VEGF inhibitors, should be evaluated further as potential therapies for recurrent and malignant meningiomas.
Topics: Angiogenic Proteins; Cell Proliferation; Humans; Indoles; Meningeal Neoplasms; Meningioma; Neovascularization, Pathologic; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-sis; Pyrroles; Quinazolines; Receptor, Platelet-Derived Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sunitinib; Tumor Cells, Cultured; Tyrosine; Vascular Endothelial Growth Factor A; Xanthones
PubMed: 23047550
DOI: 10.1038/bjc.2012.459 -
Oncology Reports Jun 2013It is well established that ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) is one of the major mechanisms that causes resistance to...
It is well established that ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) is one of the major mechanisms that causes resistance to antineoplastic drugs in cancer cells. ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering their cytotoxic activity. One of these transporters, the multidrug resistance protein 7 (MRP7/ABCC10), has already been shown to produce resistance to antineoplastic drugs by increasing the efflux of the drugs. In the present study, we investigated whether tandutinib, an FMS-like tyrosine kinase 3 (FLT3) inhibitor, has the potential to reverse MRP7-mediated MDR. Our results revealed that tandutinib significantly enhanced the sensitivity of MRP7-transfected HEK293 cells to the 2 established MRP7 substrates, paclitaxel and vincristine, whereas there was less or no effect on the control vector-transfected HEK293 cells. [³H]-paclitaxel accumulation and efflux studies demonstrated that tandutinib increased the intracellular accumulation of [³H]-paclitaxel and inhibited the efflux of [³H]-paclitaxel from HEK-MRP7 cells. In addition, western blot analysis showed that tandutinib did not significantly affect MRP7 expression. Thus, we conclude that the FLT3 inhibitor tandutinib can reverse MRP7-mediated MDR through inhibition of the drug efflux function and may have potential to be used clinically in combination therapy for cancer patients.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Inhibitory Concentration 50; Multidrug Resistance-Associated Proteins; Paclitaxel; Piperazines; Quinazolines; Vincristine
PubMed: 23525656
DOI: 10.3892/or.2013.2362 -
Scientific Reports Dec 2018Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which the only curative approach is allogeneic stem cell transplant (Allo-HSCT). The...
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which the only curative approach is allogeneic stem cell transplant (Allo-HSCT). The recognition and elimination of leukemic clones by donor T-cells contribute significantly to Allo-HSCT success. FLT3-ITD, a common mutation in AML, is associated with poor prognosis. Recently, midostaurin became the first FDA approved FLT3-inhibitor for pre-transplant patients with FLT3-ITD in combination with standard therapy. In addition to their multikinase activity which may affect T-cell signaling, FLT3-inhibitors induce apoptosis of malignant cells which may also enhance antigen presentation to activate T-cells. Considering the increased clinical use of these inhibitors in patients with AML, and the limited clinical benefit derived from their use as single agents, understanding how FLT3-inhibitors affect T cell population and function is needed to improve their clinical benefit. We examined the effect of four different FLT3 inhibitors (midostaurin, sorafenib, tandutinib, and quizartenib) on T cell populations in peripheral blood mononuclear cells (PBMC) obtained from healthy donors and from patients with AML. Midostaurin exhibited a significant decrease in CD4 + CD25 + FOXP3+ T cell population and FOXP3 mRNA expression in healthy and AML PBMCs. Similarly, samples collected from patients with AML treated with midostaurin showed a reduction in Tregs markers. Interferon-γ(IFN-γ), tumor necrosis factor-α(TNF-α), and IL-10 levels were also reduced following midostaurin treatment. Considering the FDA approval of midostaurin for use in patients with AML in the pre-transplant setting, our finding will have important clinical implication as it provides the rationale for functional investigation of the use of midostaurin in post-transplant patients.
Topics: Antigens, Differentiation; Cytokines; Female; Humans; Leukemia, Myeloid, Acute; Male; Signal Transduction; Staurosporine; T-Lymphocytes, Regulatory; fms-Like Tyrosine Kinase 3
PubMed: 30510164
DOI: 10.1038/s41598-018-35978-0