R01CA251858

Dissecting Single-Cell Response or Resistance to Novel Combination Therapy in AML Using Mass Cytometry - Project Summary

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-034.

Acute Myeloid Leukemia (AML) is among the deadliest blood cancers, with over 10,000 patients dying annually in the U.S. AML displays notorious genetic heterogeneity, with thousands of mutations described across AML patient tumors to date. AML has benefited from the rise of targeted therapies, although the clinical impact of individual targeted agents has been modest.

In AML, impressive initial response rates of 60-80% have been observed in elderly patients using the combination of venetoclax, a BCL2 inhibitor, and hypomethylating agents. Yet, survival at one year is only 30-40%, suggesting more to learn about the efficacy of this combination. Novel ex vivo drug screening platforms have identified additional venetoclax combinations. In particular, venetoclax with ruxolitinib, a JAK tyrosine kinase inhibitor, is a promising combination therapy. Based on this preclinical data, a novel clinical trial has been initiated for patients with relapsed or refractory AML.

Cancer drug combination decisions are primarily made on the basis of mutational heterogeneity, yet evidence of non-genetic drug resistance among isogenic cells is mounting, particularly with single-cell analysis. Despite advances in single-cell technologies, there are currently no strategies for making drug combination decisions that utilize single-cell platforms to explicitly address intratumoral heterogeneity.

Leveraging the strengths of CyTOF and addressing the need for analysis approaches, we developed a novel algorithm (DRUG-NEM) that analyzes single-cell, single-drug perturbation responses on individual leukemia cells to identify optimized drug combination strategies for the individual patient. Using mass cytometry analysis with a focus on AML phenotype, signaling, and metabolism, we will determine ex vivo response to single-agent venetoclax or ruxolitinib or the combination.

Using the single-agent treatment data, we will use DRUG-NEM to predict response to the combination and compare it to patient samples obtained on trial after starting combination therapy. If predictions are accurate, it provides proof of concept for using single-agent drug data to inform combination therapy, thus a more efficient and practical approach to study future combination treatments. This approach will also inform sensitivity or resistance to venetoclax in combination with ruxolitinib in patients with AML.

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

Bioengineering Research Grants (BRG) (R01 Clinical Trial Not Allowed) (PAR-19-158)

Amendment Since initial award the End Date has been extended from 03/31/22 to 03/31/26 and the total obligations have increased 397% from $615,576 to $3,056,754.