New Cancer Fighting Strategy Attacks Telomere Pathway In Difficult Tumors

Lee Zou, Ph.D. Professor of Pathology, Harvard Medical School The Jim & Ann Orr MGH Research Scholar  Associate Scientific Director, MGH Cancer Interview with:
Lee Zou, Ph.D.
Professor of Pathology, Harvard Medical School
The Jim & Ann Orr MGH Research Scholar
Associate Scientific Director, MGH Cancer Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Lee Zou: Cancer cells must rely on telomerase or the alternative lengthening of telomere (ALT) pathway to maintain telomeres and bypass replicative senescence. The ALT pathway is active in about 10-15% of human cancers, and it is particularly prevalent in specific cancer types, such as osteosarcoma, glioblastoma, and neuroendocrine pancreatic tumors. ALT is a recombination-mediated process. Whether the reliance of cancer cells on  alternative lengthening of telomere can be exploited therapeutically was not known.

In our study, we discovered that the ATR kinase is a key regulator of alternative lengthening of telomere. We found that ATR inhibitors disrupt ALT effectively. Furthermore, we found that ATR inhibitors selectively kill ALT-positive cancer cells in a panel of caner cell lines. These findings have suggested the first rational therapeutic strategy for the treatment of ALT-positive cancer.

Medical Research: What should clinicians and patients take away from your report?

Dr. Lee Zou: Many of the ALT-positive cancers are difficult-to-treat cancers. Our findings have provided clinicians with a new therapeutic strategy to explore in preclinical and clinical studies. In particular, several ATR inhibitors have been recently developed and are entering clinical trials. I hope that our findings will motivate clinician to investigate the efficacy of alternative lengthening of telomere inhibitors in the treatment of ALT-positive cancers.

Our findings have provided cancer patients with new hope. However, it is important to note that further preclinical and clinical work is still needed to validate and refine this new therapeutic strategy.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Lee Zou: I hope that our findings will motivate clinicians and patients to explore this new therapeutic strategy is clinical trials.  Our work also suggest that DNA recombination could be a good therapeutic target in certain cancers. For future research, it would be interesting to identify additional cancers that are dependent on DNA recombination and to target them with ATR inhibitors.


Science. 2015 Jan 16;347(6219):273-7. doi: 10.1126/science.1257216.

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.

Flynn RL1, Cox KE2, Jeitany M3, Wakimoto H4, Bryll AR2, Ganem NJ2, Bersani F5, Pineda JR3, Suvà ML6, Benes CH7, Haber DA5, Boussin FD3, Zou L8.

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