U01CA263988

Robust assays to define telomere maintenance mechanisms as cancer biomarkers.

Abstract:
Telomeres are nucleoproteins with TTAGGG DNA repeats at the ends of chromosomes that protect coding DNA from erosion and detection as DNA damage. Telomere maintenance is necessary for cancer cells to have unlimited proliferation capacity.

Most cancers maintain their telomeres via activation of the ribonucleoprotein telomerase containing a catalytic subunit encoded by the TERT gene and an RNA template encoded by the TERC gene. Cancers with low or no telomerase activity often use another mechanism to extend their telomeres, the alternative lengthening of telomeres (ALT) in which telomeres are maintained via homologous telomeric-DNA recombination, but the mechanism is still poorly understood.

ALT tumors contain extra-chromosomal telomeric DNA C-circles, which (detected with a unique PCR assay) provides a specific and sensitive ALT biomarker. We have shown that quantifying TERT mRNA expression together with telomeric DNA C-circles enables classifying cancers into 3 groups based on telomere maintenance mechanism (TMM); telomerase-positive (high TERT), ALT-positive (C-circle+), and TMM-negative.

Classifying the childhood cancer neuroblastoma by TMM provides prognostic information that overrides currently employed clinical and biological prognostic markers, and our preliminary data suggest this is possible for other cancer types.

ALT cancers are consistently difficult to treat but have dysfunctional telomeres, creating unique vulnerabilities that can provide novel therapeutic targets. For example, we have recently demonstrated high ATM kinase activation at telomeres in ALT neuroblastoma leads to resistance to DNA damaging chemotherapy that can be reversed with a clinical-stage ATM inhibitor AZD0156.

Biomarkers of TMM provide both prognostic information and the C-circle assay can potentially serve as a companion diagnostic assay to identify patients with tumors that are likely to be more responsive to novel ALT-targeted therapies.

Thus, it is important to define parameters that impact accurate TMM assessment of cancers, i.e. accurate quantitation of TERT mRNA and DNA C-circles. We will define the impact of collection and storage conditions and the minimum amounts of tissue and amounts, and quality of nucleic acids needed for the assays.

Identifying ALT patients from a blood sample would have clinical utility, and our preliminary data suggest that C-circles can be detected in plasma containing circulating tumor DNA. Thus, we also propose to develop and validate a plasma C-circle assay as a novel approach to identifying patients with ALT cancers.

Finally, to ensure that these assays can be used for clinical risk stratification, and as companion diagnostics for selection of therapy, we propose to carry out studies necessary for CAP/CLIA certification of TERT mRNA qPCR and the telomeric DNA C-circle assay.

To accomplish our aims, we are integrating sample collection from adult and pediatric cancers together with a team of experts in telomere biology and molecular pathology. This project will provide important information on analyzing cancer TMM phenotype that will be of value to both research and clinical labs and will enable completion of regulatory requirements necessary for clinical implementation of the assays.

Texas Tech University Health Sciences Center

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. 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.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Lubbock, Texas 794309445 United States

Single Zip Code

Integrating Biospecimen Science Approaches into Clinical Assay Development (U01 Clinical Trial Not Allowed) (PAR-18-947)

Amendment Since initial award the total obligations have increased 256% from $412,718 to $1,468,125.