Only a minority of patients with acute myeloid leukemia (AML) will be cured of the disease despite high-dose, cytotoxic chemotherapy. An alternative therapeutic strategy is to induce differentiation of the leukemia cells, an approach that has been integrated successfully into the treatment of patients with the AML subtype acute promyelocytic leukemia by using the drug all-trans-retinoic acid. We have focused on the discovery of new approaches to induce AML differentiation by deploying a chemical genomics approach. We identified and validated the cytoplasmic kinase spleen tyrosine kinase (SYK) as a new target in AML and have characterized upstream activators (i.e., Integrin ?3) and downstream effectors (PI3K and MAPK) of SYK in AML and discovered a new oncogenic partnership with FLT3, one of the most frequently mutated genes in AML. In this proposal, we expect to delineate the critical mechanistic underpinnings of the oncogenic cooperation between SYK and FLT3 in AML and to identify a new oncogenic partnership between SYK and KIT in AML. We will also perform the essential preclinical studies toward the testing of a SYK inhibitor as a single agent, and in highly efficacious drug combinations, for patients with mutations in the PDGFR family member genes (FLT3 and KIT) in AML. We have organized our studies into the following Specific Aims:
Aim 1. Is SYK inhibition of therapeutic benefit in FLT3-mutated AML? Aim 2. What are the mechanisms of SYK and FLT3 cooperativity in AML? Aim 3. Is SYK a critical regulator of other PDGFR family member kinases? In Aim 1 we will test the hypothesis that FLT3-mutated AML will be highly sensitive to FLT3 inhibitors. We will test the activity of SYK-directed shRNA and SYK small-molecule inhibitors, alone and in combination with FLT3 inhibition, in this patient population in vitro and in vivo, using cell line models, primary patien AML samples, and a bone marrow transplantation model of FLT3-ITD and highly activated SYK.
In Aim 2, we will determine the mechanism by which SYK is highly activated in FLT3-ITD-positive AML and test the hypothesis that the SYK/FLT3 leukemogenic partnership is vis-?-vis activation of a MYC transcriptional program. Finally, in Aim 3, we will test the hypothesis that SYK regulates and cooperates with the PDGFR family member kinase KIT in AML. These studies are expected to identify and validate new therapeutic approaches for one of the worst prognosis groups of patients with AML, those with FLT3-ITD, and possibly for patients with myeloid malignancies harboring other PDFR family member kinase mutations. Our studies will guide future clinical trials testing SYK inhibitors in patients with AML.
Acute myeloid leukemia (AML), the most common cause of acute leukemia in adults and the second most common cause of leukemia in children, remains a treatment challenge, with the majority of diagnosed patients dying of the disease. This proposal seeks to validate a new target in AML, spleen tyrosine kinase (SYK), to determine the oncogenic partners of SYK, to identify the patients with AML most likely to respond to SYK inhibitors, and to discover highly effective combinations of drugs with SYK inhibitors. The long-term objective is to guide the effective clinical translation of drugs inhibiting SYK to patients wth AML
