R01CA257655

Circulating Genomic Determinants of Treatment Failure in Hodgkin Lymphoma - Project Summary/Abstract

PIs: Ash Alizadeh, M.D./Ph.D. & Maximilian Diehn, M.D./Ph.D.

Classical Hodgkin Lymphoma (HL) is among the most curable human malignancies. However, strategies to personalize HL therapies and to minimize long-term attendant toxicities of chemotherapy are currently limited to baseline risk factors and imaging. This is due to our incomplete understanding of targetable pathways and lack of good biomarkers. Because of the low fraction of malignant cells in tumor tissue and consecutive technical challenges, the landscape of HL is not well-defined.

Our long-term goal is to study the ability of baseline and dynamic risk factors, including genetic mutations, circulating tumor DNA (ctDNA), and imaging studies (PET), to accurately predict treatment outcomes in HL patients and to provide a basis for individualized precision medicine. Our central hypothesis is that clinical and biological heterogeneity in HL reflects distinct genomic features that are noninvasively measurable using ultrasensitive ctDNA techniques, and that refining early response assessment integrating interim PET and blood-based methods improves prognostication.

We will test our hypotheses via three specific aims:

(1) To noninvasively define the genomic landscape of somatic variations in HL and to determine the relationship of genomic variants with biological heterogeneity at initial disease presentation.

(2) To associate molecular features at baseline and molecular response with ultimate therapeutic outcome, and to integrate clinical and molecular biomarkers in a personalized dynamic risk model for predicting HL outcomes.

(3) To functionally characterize novel mutations in interleukin-4 receptor (IL4R) resulting in gain-of-function IL4/STAT6 signaling, and to test the utility of precision therapeutic targeting of these mutations.

If successful, our project will lead to novel ways to select better therapies for patients at highest risk of failure and to minimize toxicity for the majority of patients responding well to standard therapy. Our innovative approach, in which we will combine blood-based methods for genotyping and disease monitoring with imaging studies, will provide the basis for a personalized treatment approach in HL.

The Leland Stanford Junior 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]

Stanford, California 94305 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 391% from $654,694 to $3,211,729.