PTRC Proteogenomic Translational Research Center
EMSL Project ID
60241
Abstract
Due to the complexity of signaling and sequence modifications in cancer, predictions of pathway regulation and dependence based upon genomic data alone is challenging. This research proposal will explore a compelling alternative approach involving the use of comprehensive proteomics and phosphoproteomics to identify and characterize the auxiliary components that modulate and, therefore, predict response to targeted inhibitors as well as the pathways that precipitate drug resistance. Although targeted therapies based on known molecular alterations have significantly improved the clinical outcome for chronic myelogenous leukemia (CML) and other malignancies, the identification of suitable molecular targets in individual patients remains a daunting challenge, and drug resistance is a pervasive problem, even with initial therapeutic success. While the initial choice of therapeutic targets is often driven by knowledge of known molecular aberrations, such as the BCR-ABL fusion gene in CML or FLT3 alterations in acute myelogenous leukemia (AML), the choice of therapeutic targets is complicated by the extensive crosstalk between multiple pathways involving dysregulation of signaling, epigenetic, and splicing pathways to activate oncogenic programs. This crosstalk has the potential to affect both the initial response to targeted therapies and the eventual development of resistance, by providing alternate routes for pathways supporting leukemia cell survival and growth. The dramatic success of ABL kinase inhibitors in the treatment of CML has generated intense research into similar strategies for AML and other hematological malignancies, especially because of morbidities associated with other treatments, such as bone marrow transplantation. However, unlike Philadelphia chromosome positive CML, AML is not characterized by a single driving mutation, but by over 30 frequently mutated genes and thousands of rarely mutated genes. Consequently, our research is focused on three substantial unmet clinical needs associated with AML: 1) the identification of the most effective first-line targeted therapeutic; 2) characterization of the interaction between multiple therapies, particularly tyrosine kinase inhibitors (TKIs), other small molecule inhibitors, and induction chemotherapy; and 3) identifying the most effective second round therapy following relapse after initial TKI therapy. We plan to address these clinical needs by using proteomics to enable the construction of predictive models of signal transduction and crosstalk in response to drug treatment. We will do this by leveraging the extensive proteomics capabilities at PNNL, including significantly improved approaches for ultrasensitive targeted proteomics and increased throughput and depth of coverage in global discovery proteomics. A combination of isobaric labeling and extensive fractionation will be used to provide deep quantitative proteomic and phosphoproteomic coverage in preclinical model systems based on primary patient-derived AML cells exposed to TKIs and other small molecule inhibitors ex vivo, while ultrasensitive targeted proteomics will be used to test the resulting signatures in clinical model systems based on primary cells obtained from AML patients before and after treatment in NCI-sponsored clinical trials of targeted inhibitors, alone or in combination with standard of care induction chemotherapy.
Project Details
Start Date
2021-10-05
End Date
N/A
Status
Active
Released Data Link
Team
Principal Investigator
Team Members