Telomeres cap the ends of linear chromosomes and provide a molecular barrier for the human genome. Following each cell division, progressive telomere shortening erodes that barrier and threatens the stability of the genome. Critically short, or dysfunctional telomeres induce replicative senescence and/or cell death and ultimately, lead to cellular aging. Cancer cells, however, overcome the replicative senescence associated with critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme telomerase, or activation of the Alternative Lengthening of Telomeres (ALT) pathway, account for cellular immortalization in the majority of human cancers. Telomere lengthening mechanisms are active in the majority of all cancer cells, however, they are absent or ineffective, in normal somatic cells making them ideal candidates for targeted cancer therapies. Currently, clinical trials are underway to test the efficacy of telomerase inhibitors in the treatment of cancer, however, there are no treatments for cancers that rely on the ALT pathway for telomere maintenance. These efforts have been limited, in part, by an incomplete understanding of the molecular mechanisms regulating the ALT pathway. Recently, we demonstrated that the ataxia telangiectasia and Rad3-related (ATR) DNA damage response kinase was a critical regulator of the ALT pathway. Inhibition of ATR kinase activity not only decreased telomeric recombination, but also led to significant and selective lethality in ALT positive cancer cells. While these studies were the first to demonstrate a functional requirement for ATR in maintenance of the ALT pathway, exactly how ATR regulates ALT activity and whether ATR can be targeted therapeutically in the context of ALT cancers, remains unclear. Therefore, the goal of this proposal is to tease apart the function of ATR within the ALT pathway, validate the therapeutic efficacy of ATR inhibition in ALT positive cancers, and continue to define the molecular mechanisms regulating ALT activity.

Public Health Relevance

Reactivation of the enzyme telomerase, or activation of the Alternative Lengthening of Telomeres (ALT) pathway promote telomere elongation and consequently, cellular immortalization, in the majority of human cancers. Therefore, investigating how these pathways are activated and/or maintained during cellular transformation is pivotal to our understanding of cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA201446-03
Application #
9523254
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Witkin, Keren L
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Mason-Osann, Emily; Dai, Anqi; Floro, Jess et al. (2018) Identification of a novel gene fusion in ALT positive osteosarcoma. Oncotarget 9:32868-32880