U01CA271412

Proteogenomic Characterization of Early and Late Resistance Mechanisms in Acute Myeloid Leukemia - Project Summary/Abstract

Acute Myeloid Leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. After 30-40 years without a change in treatment strategy, the past 2 years have seen several drug approvals, including recent approvals for the FLT3 inhibitor, gilteritinib, and the BCL2 inhibitor, venetoclax. While response rates to both of these agents are encouraging, drug resistance and relapse remain problematic for nearly all patients.

For the past decade, we have executed a functional proteogenomics platform applied directly to primary samples from patients with AML and other hematologic malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens. Through integration of these data with expansive proteomic, phospho-proteomic, transcriptomic, genomic, metabolomic, genome-wide CRISPR screens, and detailed clinical annotations, we have defined biomarkers and mechanisms underlying response as well as early and late resistance to both FLT3I and BCL2I. Consequently, we have started clinical trials testing combinations that may mitigate these resistance mechanisms.

For this project, our long-term goals are to translate FLT3I and BCL2I therapeutic regimens such that resistance can be prevented with up-front combinations and/or mitigated with sequential therapies. Our immediate goals are to define and optimize specific biomarkers of response and resistance to these agents. Based on the central hypothesis that examination of global proteomic features of AML provides predictors of drug response and also identifies the dynamic changes during the development of drug resistance, yielding mechanistic insight to generate novel, improved drug combinations.

To accomplish these goals, preclinical and clinical work is proposed:

Training of proteogenomic biomarkers on cell line models of early and late resistance – We will perform proteogenomic analyses of a panel of cell lines that have been derived to exhibit drug resistance resembling clinical features of resistance.

Validation of signatures in archival patient sample material – We have a substantial biorepository of specimens from AML patients, a subset of which are from patients treated with FLT3I or BCL2I as standard-of-care or as part of our ongoing clinical trials. We will test our cell line-derived biomarkers in these banked patient specimens, and we will also use cutting-edge proteomics technology that enables low input material to study fractionated cell populations.

Clinical validation of biomarkers of sensitivity and resistance – We have opened clinical trials testing FLT3I and BCL2I combinations in AML. We will have access to prospective, longitudinal specimens from patients on these trials. We will perform proteogenomic analyses on these prospective specimens to evaluate the ability of our signatures to predict clinical responses.

Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies and predictive biomarkers.

Oregon Health & Science University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Portland, Oregon 972393011 United States

Single Zip Code

Proteogenomic Translational Research Centers (PTRCs) for Clinical Proteomic Tumor Analysis Consortium (U01 Clinical Trial Not Allowed) (RFA-CA-21-025)

Amendment Since initial award the total obligations have increased 290% from $1,181,536 to $4,603,890.