Document text
Principal Investigator: E Premkumar Reddy
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $187,642
Funding agency: National Cancer Institute
Abstract
Approximately one third of patients suffering from acute myeloid leukemia (AML) harbor an internal
tandem duplication in the FLT3 gene (FLT3-ITD), which is clinically associated with an increased rate of
relapse in response to standard therapies. As a result, targeted small molecules such as quizartinib, a
type 2 FLT3 inhibitor that induces differentiation of AML cells, have garnered attention as a means by
which relapsed FLT3-ITD+ AML can be effectively treated. Unfortunately, the median duration response
of these patients to quizartinib was found to be 12.1 weeks due to the acquisition of secondary mutations
at the D835 locus in the FLT3 gene. A second type 1 inhibitor of FLT3-ITD, midostaurin, was developed
by Novartis, which, as a single agent failed to induce complete remission (CR) and when bone marrow
was analyzed, there was no significant difference seen between the midostaurin-treated and placebo
groups. However, in combination with chemotherapy, the CR rate was 59% compared to 54% CR
induced by chemotherapy alone. Midostaurin, in combination with daunorubicin and cytarabine,
decreased the risk of AML-related death by 22% compared with placebo and was approved by the FDA
for the treatment of AML. To explain the lack of efficacy of midostaurin as a single agent, it has been
proposed that AML cells often overexpress SRC family kinases and their elevated expression may
provide a survival advantage. This theory was further supported by studies which showed that
combination of midostaurin and dasatinib (a SRC inhibitor) were more effective in killing FLT3-ITD+
cell lines (in vitro) than single agent therapy. These observations suggest that there is a need to develop
additional FLT3 inhibitors which can induce complete remission in AML patients harboring mutant
FLT3. To address this medical need, we developed a compound that inhibits both FLT3 and SRC family
kinases (150030). 150030 is a Type I inhibitor that inhibits the FLT3-ITD as well as the D835 mutant forms.
Cell viability assays showed that 150030 induced apoptosis of FLT3-mutant AML cells while sparing
AMLs with WT-FLT3. 150030 is orally bioavailable, exhibited excellent pharmacological profile and
induced complete regression of tumors in nude mouse xenograft assays. The studies proposed are aimed
at further evaluating the mechanism of action and therapeutic potential of 150030 in an effort to advance
this compound to clinical trials. The aims are: (1) To compare the effects of midostaurin and 150030 on
the growth and differentiation of murine myeloid cell line, 32Dcl3, co-expressing FLT3-ITD and SRC
family kinases and determine the effects of these two compounds on leukemia progression in syngeneic
animal models; (2) To compare the efficacy of 150030 and midostaurin in clinically relevant PDX models
of AML to develop protocols for a single agent and combination therapy; and (3) To determine the
resistance mechanisms associated with 150030.
Terms: <1.beta.-D-Arabinofuranosylcytosine><AML - Acute Myeloid Leukemia><ARA-cell><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Alexan><Animal Model><Animal Models and Related Studies><Animals><Arabine><Arabinofuranosylcytosine><Arabinosylcytosine><Aracytidine><Aracytin><Aracytine><Aspartate><Assay><Athymic Mice><Athymic Nude Mouse><Attention><Binding><Bioassay><Bioavailability><Biologic Models><Biological Assay><Biological Availability><Biological Models><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><Calcium Phospholipid-Dependent Protein Kinase><Calcium-Activated Phospholipid-Dependent Kinase><Cell Body><Cell Line><Cell Survival><Cell Viability><CellLine><Cells><Cerubidin><Cessation of life><Clinical><Clinical Research><Clinical Study><Clinical Trials><Combined Modality Therapy><Conduct Clinical Trials><Cytarabine><Cytarabinum><Cytarbel><Cytosar><Cytosar-U><CytosarU><Cytosine Arabinoside><Cytosine-.beta.-arabinoside><Dasatinib><Dauno-Rubidomycine><Daunoblastina><Daunoblastine><Daunomycin><Daunorrubicina><Daunorubicin><Death><Differentiation and Growth><Disease Progression><Disease remission><Drugs><Erpalfa><Exhibits><Extracellular Signal-Regulated Kinase Gene><FDA approved><FLK2><FLT3><FLT3 gene><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><Genes><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetics-Mutagenesis><Goals><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Heterograft><Heterologous Transplantation><In Vitro><In complete remission><Induction of Apoptosis><Kinases><L-Aspartate><Leukaemomycin C><MAP Kinase Gene><MAPK><MGF protein><MGSNF protein><Malignant><Malignant - descriptor><Measures><Medical><Medication><Methods><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Model System><Modeling><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Myeloid Cells><Nature><Nude Mice><Ondena><Oral><PDX model><PI-3K/AKT><PI3K/AKT><PKC-412><PKC412><PTK Receptors><Pathway interactions><Patient derived xenograft><Patients><Pharmaceutical Preparations><Phospholipid-Sensitive Calcium-Dependent Protein Kinase><Phosphotransferase Gene><Phosphotransferases><Physiologic Availability><Placebos><Population><Process><Protein Kinase C><Protocol><Protocols documentation><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recombinant DNA Technology><Recurrent disease><Relapse><Relapsed Disease><Remission><Remission Induction><Resistance><Risk><Route><Rubidomycin><Rubilem><Rubomycin><Rubomycin C><STAT5><STAT5A><STAT5A gene><STAT5a Transcription Factor><STK-1 kinase><STK1><Sham Treatment><Signal Pathway><Signal Transducer and Activator of Transcription 5A><Stat5 protein><Stat5a protein><Stat5alpha protein><Stem Cell Tyrosine Kinase 1><Strains Cell Lines><Survival Rate><System><Tarabine PFS><Testing><Therapeutic><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tumor Cell><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Udicil><Work><Xenograft><Xenograft procedure><Xenotransplantation><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cerubidine><chemotherapy><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><comparable efficacy><comparative efficacy><compare effectiveness><compare efficacy><complete response><conformation><conformational><conformational state><conformationally><conformations><cultured cell line><determine efficacy><drug detection><drug testing><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><fetal liver kinase-2><fetal liver kinase-3><genetically engineered><genome mutation><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><inhibitor><kinase inhibitor><leukemia><leukemia treatment><leukemic therapy><mammary gland factor><mammary gland-specific nuclear factor><model of animal><multi-modal therapy><multi-modal treatment><mutant><neoplastic cell><overexpress><overexpression><pathway><patient derived xenograft model><patient response><patient specific response><pharmacologic><placebo group><relapse patients><resistance mechanism><resistant><resistant mechanism><response><responsive patient><sham group><sham therapy><signal tranducer and activator of transcription 5><small molecular inhibitor><small molecule><small molecule inhibitor><src Kinases><src Protein-Tyrosine Kinases><src Tyrosine Kinases><src-Family Kinases><src-Family Tyrosine Kinases><theories><tumor><xeno-transplant><xeno-transplantation>