Telomere dysfunction is a major determinant of aging, degenerative diseases and cancer. In cancer, the telomeres and telomerase have been shown to play critical roles in the initiation and progression of malignancy. Telomere dysfunction, coupled with deactivated p53 checkpoints, enables genome instability and the development and progression of cancer, including metastasis. Significant effort in the current grant has been elucidating the wiring of the p53-dependent telomere checkpoint response and how p53 downstream targets promote degenerative conditions and enable malignant progression. Building on our ongoing work, this renewal will address two important areas of study. First area focuses on two critical targets of the p53 pathway. Work from current funding period from my laboratory has identified a profound deficiency in mitochondria biogenesis and function in telomere dysfunctional mice which results from p53-directed repression of PGC11/2 transcriptional coactivators, the master regulators of mitochondrial biogenesis and p53-directed activation of Quaking (QK), a RNA binding protein which we show is a potent tumor suppressor and regulator of microRNA-directed control of the key mitochondrial regulator, PPARa. These observations have led to the hypothesis that mitochondriopathy and associated energy loss is the primary cause of age related maladies in telomere dysfunctional mice and may dictate certain metabolic responses in cancer cells. The objectives of this competitive renewal will be to genetically assess the telomere-mitochondria link in aging and cancer. The specific efforts focus on (i) the use of an inducible telomerase model (TERT-ER) to assess the regenerative impact on mitochondrial biology and degenerative phenotypes in stem cells and diverse post-mitotic organ systems in aged telomere dysfunction mice;(ii) to genetically define the importance of the PGC11/2 and QK targets as critical mediators of the telomere checkpoint response with respect to mitochondria biology, degenerative aging, and the genesis and progression of cancer and cancer genomic changes. Second area speaks to translation of the concept of anti-telomerase therapy. Our previous work has suggested that anti-telomerase therapy should preferentially avoid patients with p53-deficient tumors. In this renewal, we will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms on the genomic and metabolic levels to anti-telomerase therapy. The identification of these mechanisms should lead to new drugs that may synergize with anti-telomerase therapy.

Public Health Relevance

Telomere dysfunction is one of the hallmark of aging, degenerative diseases and cancer. We will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms which should lead to new drugs that may synergize with anti-telomerase therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA084628-19
Application #
8014948
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2000-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
19
Fiscal Year
2011
Total Cost
$648,194
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Colla, Simona; Ong, Derrick Sek Tong; Ogoti, Yamini et al. (2015) Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27:644-57
Zhang, Yuqing; Shin, Sandra J; Liu, Debra et al. (2013) ZNF365 promotes stability of fragile sites and telomeres. Cancer Discov 3:798-811
Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy et al. (2013) Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nat Cell Biol 15:895-904
Sahin, Ergun; DePinho, Ronald A (2012) Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 13:397-404
Moslehi, Javid; DePinho, Ronald A; Sahin, Ergun (2012) Telomeres and mitochondria in the aging heart. Circ Res 110:1226-37
Ding, Zhihu; Wu, Chang-Jiun; Jaskelioff, Mariela et al. (2012) Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148:896-907
Hu, Jian; Hwang, Soyoon Sarah; Liesa, Marc et al. (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148:651-63
Martin, Neil E; Mucci, Lorelei A; Loda, Massimo et al. (2011) Prognostic determinants in prostate cancer. Cancer J 17:429-37
Jaskelioff, Mariela; Muller, Florian L; Paik, Ji-Hye et al. (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469:102-6
Sahin, Ergün; Colla, Simona; Liesa, Marc et al. (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359-65

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