Wednesday, February 5, 2025
2/5/2025
All cancers must solve the problem of elongating telomeres to achieve replicative immortality. Roughly 90% of all cancers accomplish this task by reactivating the expression of the telomerase reverse transcriptase (TERT) gene, and a large fraction of them achieve this transcriptional dysregulation by mutating regulatory sequences in the TERT promoter. In the previous two funding segments, we have discovered that the molecular function of these highly recurrent mutations is to recruit specifically the transcription factor (TF) GABP to TERT promoter. Understanding and targeting the regulatory network of GABP thus provides an unprecedented opportunity to develop effective strategies for treating numerous cancer types. Despite the clear significance of this opportunity, however, there still remain several urgent questions surrounding the TERT promoter mutations and GABP function, partial answers to which we have recently uncovered. This renewal application thus seeks to integrate rigorous computational and experimental analyses to initiate a novel framework for dissecting the transcriptional regulation of telomere-associated genes and for circumventing potential resistance mechanisms against precision therapies targeting the GABP network. The long-term goal of our research program is to establish a rigorous computational framework for understanding aberrant transcriptional and epigenetic networks in cancers and to apply the resulting knowledge to develop effective therapeutic interventions that can a priori predict and avoid potential resistance mechanisms. The objective of the current renewal application is to initiate a new direction in this endeavor and develop rigorous approaches for dissecting the co-regulation of several hallmarks of cancer by TF modules involving GABP. We will accomplish our objective by pursuing the following aims: (1) develop and apply predictive models for distinguishing specific ETS factor binding patterns; (2) identify key transcriptional regulators of telomere- associated genes; (3) dissect the genome-wide co-localization and regulatory patterns of GABP and its cooperating factors; and, (4) develop and apply methods for predicting the transcriptional regulators of immune- checkpoint genes coordinated with telomere maintenance. The results of our research will establish a hitherto-unrecognized integration and coordination of mutant TERT promoter function, telomere maintenance, and immunotherapy resistance mediated through GABP and its interacting TFs.
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).