Patients with relapsed or refractory acute leukemias and elderly patients with previously untreated acute leukemia who are unfit for standard induction have a dismal prognosis with conventional chemotherapy. The development of more effective and less toxic therapies will require the identification of the molecular abnormalities contributing to leukemogenesis and the identification of drugs that specifically block the activity of these lesions. We hypothesize that aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of acute leukemia, and our preliminary data suggest that the molecular abnormalities causing aberrant kinase activation are unique in a significant number of patients. Thus, effective therapies for acute leukemia will need to be determined on an individual patient basis. To address this need, we have developed a small-molecule kinase inhibitor assay that can identify therapeutic targets in tyrosine kinase signaling pathways in primary acute leukemia samples and provide individualized therapeutic options in a clinically relevant time frame. The primary goals of the proposed project will be to validate the role of our pre- clinical kinase inhibitor screen in predicting effective individualized therapies and to explore the molecular abnormalities underlying drug sensitivity. Accordingly, the first aim is to evaluate the efficacy of an in-vitro inhibitor sensitivity assay for prediction of clinically effective individualized/targeted therapies for acute leukemia patients in a single-arm phase II pilot trial enrolling 24 patients. Inclusion criteria will be limited to relapsed/refractory acute leukemia patients as well as elderly patients not eligible for conventional chemotherapy with in vitro sensitivity to one or more drugs in the inhibitor assay. The primary objective is to determine the clinical activity, defined as >25% decrease in bone marrow blast counts at 28 days after initiation of therapy.
The second aim i s to rapidly identify the genetic etiology underlying aberrantly activated tyrosine kinase pathways in leukemia samples from individual patients. The small molecule kinase inhibitor assay will be used to identify activated kinase pathways that are crucial for malignant cell viability in individual samples, and the mechanism of activation will be explored using high-throughput sequence and expression profiling. By utilizing our pre-clinical assay to select individualized leukemia therapies, we hope to create a platform upon which we can rapidly test the effectiveness of individualized kinase therapy and apply this information to enhance development of new drugs and new drug combinations in leukemia patients. It is also our hope to establish a paradigm in which patient-tailored therapies can be offered to all patients with cancer.
The development of more effective and less toxic therapies for acute leukemia will require identification of the causative molecular abnormalities and identification of drugs that specifically block the activity of these abnormalities. We hypothesize that these abnormalities are unique in many leukemia patients and that these patients will require individualized therapies to target their unique lesions. Our proposed clinical trial that integrates molecular target identification with individualized treatment will help to establish a paradigm where cancers are defined by molecular targets and patients are matched with specific targeted therapies to yield improved therapeutic outcomes.
|Spurgeon, Stephen E; Coffey, Greg; Fletcher, Luke B et al. (2013) The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. J Pharmacol Exp Ther 344:378-87|