Wednesday, April 24, 2024
4/24/2024
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. 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. Employing the C-circle assay we have surveyed a variety of childhood and adult cancers and found 11 cancer histologies with ALT-positivity ranging from 10% to 74% and an additional 5 cancer histologies with 1 to 5% that are ALT+. ALT cancers have a poor clinical outcome and regardless of histology ALT+ cancer cell lines manifest high resistance to DNA damaging agents relative to telomerase+ cancers. ALT cancers have dysfunctional telomeres, which provides unique vulnerabilities that can serve as novel therapeutic targets. We have recently demonstrated high ATM kinase activation in ALT neuroblastoma leads to resistance to DNA damaging chemotherapy that can be reversed with a clinical-stage ATM inhibitor AZD0156. Based on our data we hypothesize that ALT+ cancers share both common mechanisms of resistance to standard therapies and common vulnerabilities that may be exploited for therapy. To enhance studies of ALT+ cancer biology, discovery and validation of novel therapeutic targets, and to enable comparing ALT+ cancers across a range of histologies we have assembled a large panel of ALT+ patient-derived cell lines (PDCLs) and patient-derived xenografts (PDXs) and comparator telomerase+ PDCLs and PDXs, including pediatric cancers (neuroblastoma, rhabdomyosarcoma, osteosarcoma) and adult cancers (triple negative breast cancer, colon cancer, soft tissue sarcomas). Using this unique panel of patient-derived models we will demonstrate that ATM kinase activation resulting from telomere dysfunction is a common feature of ALT+ cancers (regardless of histology). We will demonstrate that clinical-stage investigational drugs leveraging the high ATM kinase activation in ALT+ cancers (the ATM kinase inhibitor AZD1390 and the p53 activator APR-246) combined with irinotecan have significantly higher activity in ALT+ cancers relative to telomerase+ comparators. For cell lines and xenografts of selected histologies we will determine if AZD1390 can reverse resistance to irinotecan. We hypothesize that ALT+ cancers tolerate ATM activation due to dysfunctional p53, and that p53 restored to functionality by APR-246 will be activated (phosphorylated) by ATM. We will demonstrate that APR-246 (alone or in combination with irinotecan) will be selectively cytotoxic to ALT+ relative to telomerase+ cancer cell lines and xenografts. This project will demonstrate that the unique vulnerability conferred by the dependence of ALT+ cancers cells on ATM kinase is common to ALT+ cancers across a range of cancer histologies. Data from this project will inform development of histology-agnostic clinical trials seeking to enroll patients with ALT+ cancers that are readily identifiable with a robust tumor biomarker.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
