Our work, over 19 years ago, shows progressive telomere shortening in human cells during senescence, lead to the proposal that telomerase inhibition may block the growth of tumors. We followed up on this idea by generating a telomerase null mouse and over the past 12 years us, and others, have shown that indeed short telomeres limit the growth of some tumor types. In addition, we found that paradoxically, in some settings, short telomeres may initiate tumor formation. To help resolve this paradox and develop more sophisticated approaches to telomerase inhibition in cancer, we are studying the mechanism and pathways that are activated when telomeres become critically short. In this proposal we will focus on the mechanism by which short telomeres block the growth of B-cell lymphoma. We will identify the specific genes that signal from a critically short telomere, through p53 to block cell growth. We will take advantage of the powerful E-mu-myc mTR-/- G5 mice that we developed in the previous period with funding from the NCI PPG. Using this tumor model and shRNA libraries, we will identify tumor suppressor genes that may specifically respond to short telomeres. We will also examine the recombination mechanisms by which a subset of tumors with short telomeres escape and grow in the absence of telomerase.

Public Health Relevance

Understanding mechanisms that limit tumor growth will allow new approaches to cancer therapeutics. Work on the telomerase knockout mouse has shown that short telomeres can block tumor cell growth. Our studies will elucidate the specific genetic setting in which short telomeres block tumor growth. This will allow a more sophisticated and powerful approach to the use of telomerase inhibitors in cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160300-02
Application #
8296546
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2011-07-05
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$523,596
Indirect Cost
$204,330
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218