PROJECT 1: Unraveling and exploiting the molecular mechanisms unique to Alternative Lengthening of Telomeres (ALT), thereby allowing therapeutic targeting of a substantial proportion of cancers. Unlimited replication is a key hallmark of cancer allowing cancer cells to evade both replicative senescence and catastrophic telomere dysfunction-induced chromosomal instability. While the majority of cancers overcome these critical barriers via upregulation of telomerase, a telomere-specific reverse transcriptase, a subset of cancers maintains telomere lengths by a telomerase-independent mechanism, termed Alternative Lengthening of Telomeres (ALT). ALT is strongly associated with recurrent, cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Although the exact mechanisms underlying ALT are still being elucidated, the current consensus is that due to telomere deprotection and altered chromatin dynamics, telomeres can be extended by an aberrant break-induced replication mechanism that involves strand invasion of telomeric sequences followed by homology-directed DNA synthesis. This underlying ALT mechanism generates unique molecular characteristics that readily distinguish ALT-positive and ALT-negative cancers. We and others, have postulated that these unique ALT-associated molecular characteristics may be exploited therapeutically. Thus, we are currently trying to identify potential cooperating ALT-suppressors, and understand mechanisms of action, to aid in the identification of optimal ALT-specific target(s).
PROJECT 2: Evaluating the translational potential of ALT as a prognostic biomarker. We previously characterized ALT across >6,000 primary cancers from over 90 different cancer subtypes. Through that comprehensive survey and others, significant fractions of ALT-positive cancers were found in some cancer types, including sarcomas, astrocytomas, pancreatic neuroendocrine tumors (PanNETs), hepatocellular carcinomas, and testicular germ cell tumors. While tumor type-dependent and context-dependent, ALT-positive cancers are generally associated with increased genomic instability and portend a poor clinical prognosis, particularly in cancer types that currently lack targeted therapies. Thus, we continue to evaluate the clinical utility of ALT, in combination with other biomarkers, as a prognostic biomarker for certain cancer types (e.g. PanNETs and gliomas).
PROJECT 3: Evaluating the translational potential for the prognostication and risk stratification of tissue-based telomere length measurements. Given that dysfunctional telomeres contribute to genomic instability and promotes tumorigenesis, we and others, have hypothesized that increased telomere shortening in cancer cells would drive the evolution of cell clones capable of invasion, extravasation, and metastasis. In these studies, we demonstrate the clinical feasibility and utility of the “telomere biomarker” – variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal (CAS) cells. These findings highlight the translational potential of the telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies in prostate cancer. In collaboration with our Pathology and Cancer Epidemiology colleagues, we are evaluating the clinical utility of the telomere biomarker in 5 key areas:
- At time of surgery (prognostication)
- At time of biopsy (risk stratification)
- Prediction of therapeutic efficacy
- Prevalence of the biomarker by race, BMI, and smoking status
- In other cancer types (breast, ovarian, pancreas)