R01CA270027

Role of Decorin and Diffusion MRI in Anti-VEGF Efficacy for Recurrent Glioblastoma - Project Summary/Abstract

Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Despite modest advancements in surgical procedures, radiation, and chemotherapy, median survival from diagnosis is only around 14 months. Upon recurrence, few effective treatment options exist. Bevacizumab, a humanized monoclonal antibody that inhibits VEGF-A, received accelerated FDA approval in May 2009 for use in recurrent GBM and quickly became the standard of care for recurrent GBM in the United States. Almost all patients receive bevacizumab at some point in their treatment.

Because bevacizumab plays such an important role in the management of GBM, the development of imaging biomarkers to improve risk stratification and predict patient benefit is highly desired. Such a biomarker would be clinically useful for identifying patients that will benefit from bevacizumab as well as scientifically useful for cohort enrichment in the next phase of combination therapies or exploratory studies aimed at high-risk patients, where conventional therapies like bevacizumab are likely to fail.

Extensive preliminary data (>7 trials in >400 patients) suggests diffusion MRI characteristics are a strong, independent predictor of anti-VEGF therapeutic efficacy in recurrent GBM, with patients exhibiting a significant survival benefit if they present with a high apparent diffusion coefficient (ADC) within contrast-enhancing tumor. Data also suggests these diffusion MR signatures may result from an elevated expression of decorin (DCN), a glycoprotein with a variety of functions.

We hypothesize that the survival advantage and imaging signatures arise from the multifaceted functions of DCN, which include anti-angiogenic characteristics and softening of the extracellular matrix, which we theorize would result in increased effectiveness of anti-VEGF therapies and an increase in ADC. The current study will explore the causal, mechanistic links between DCN expression, diffusion MRI, and anti-VEGF treatment efficacy.

First, Aim 1 will involve a deep exploration into the association between diffusion MR phenotypes and DCN expression in human GBM using image-guided biopsies. We will examine DCN protein expression using immunohistochemistry and gene expression using in-situ hybridization. The relationship between diffusion MRI, DCN expression, and corresponding genotypes using whole exome analysis, genetic subtypes using bulk RNA sequencing, cellular states using single-cell RNA sequencing, and blood plasma levels of circulating DCN will also be performed.

Concurrently, Aim 2 will establish the causal, mechanistic links between DCN expression, diffusion MRI measurements, and anti-VEGF treatment in GBM through a complex, genetically modified patient-derived orthotopic xenograft (PDX) preclinical trial. To accomplish this, a series of patient-derived cell lines will be edited to silence or overexpress DCN within PDX models using a tetracycline-controlled gene expression system. The direct role of DCN expression in changing diffusion MRI measurements and increasing survival following anti-VEGF therapy by turning on or off DCN expression using doxycycline will be determined.

Los Angeles University Of California

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]

Los Angeles, California 900244200 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $623,037 to $3,015,689.