Here we propose that a long non-coding RNA PVT1 can provide a solution for developing effective therapy against multiple human cancers. We have recently identified the mechanistic basis of 8q24 amplification, one of the most common mutations present in almost all kinds of cancer. We have identified a long noncoding RNA, PVT1, which is a part of the 8q24 amplicon, as a major oncogene. We have found that PVT1 can regulate the stability of MYC, one of the most important drivers in cancer. We hypothesize that the dependence of MYC on PVT1 can be exploited to target MYC, otherwise a notoriously undruggable candidate. In this proposal we propose to dissect the mechanism through which PVT1 regulates MYC protein levels in cancer. We also investigate the role of PVT1 in cancers without supernumerary 8q4. Finally, we will examine the therapeutic potential of PVT1 specific antisense oligonucleotides in vivo and in xenograft models. We propose that our new findings will enable the cancer community to develop new therapeutic strategies for cancer patients in near future.

Public Health Relevance

Despite remarkable advances in our understanding of cancer in the last few decades, the disease still has a devastating impact on affected families in particular and society in general. American Cancer Society predicts 1,658,370 Americans to be diagnosed with cancer and 589,430 cancer related death in 2015, or 1,620 deaths per day. Thus there is an urgent need to develop more effective therapies that can positively impact the life and health of the cancer patients. One of the prominent genes that play a critical role in causing and advancing cancer is MYC. It is a very attractive drug candidate, and it is generally accepted that a therapeutic intervention that can inhibit MYC-driven tumor growth will be a breakthrough in cancer treatment. However, drugging MYC has remained a challenge. We have recently identified a long noncoding RNA PVT1 as a key regulator of MYC stability, particularly in cancers with gain of 8q24, a prominent mutation present in ~ 19% of all cancers. In this project, we investigate the mechanism by which PVT1 contributes to MYC stability in these cancers, expand our understanding of the role of PVT1 in other cancers where 8q24 is not gained, and finally determine the therapeutic potential of inhibiting PVT1 as a strategy to target MYC-driven cancers. Successful completion of this project will help us to develop new ways to find cure for cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mietz, Judy
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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