The c-Myc proto-oncogene is a key factor in both B-cell homeostasis and B-lymphomagenesis. Its transforming potential is based largely on its ability to drive cell proliferation. At the same time, Myc can also induce apoptosis, either throug induction of p53 or in a p53-independent manner. Yet the goal of channeling the pro-apoptotic activity of Myc toward anti-cancer therapies has so far proven elusive, primarily because methods to transiently increased Myc levels didn't exist. Our recent research showed that boosting Myc expression elevates p53 and increases sensitivity to bortezomib. One limitation of that study was the reliance on the p53 pathway, which is frequently lost in human B-lymphomas. To determine how Myc contributes to p53-independent apoptosis in a bona fide therapeutic setting (CHOP therapy), we now used cells isolated from bone marrows of p53ERTAM knock-in mice and subsequently transduced with a Myc-expressing retrovirus. This inducible system allowed us to distinguish between p53-dependent (cells treated with tamoxifen) and independent (no tamoxifen given) cell deaths. Additionally, very recent data from our lab show that GSK-3? is actively involved in the regulation of Myc protein degradation in B-cells, and that inhibition of GSK-3? with CHIR99021 sharply increases Myc levels. Using these reagents, we observed that pharmacological stabilization of Myc with GSK-3? inhibitors strongly enhanced p53-independent doxorubicin-induced apoptosis. Most importantly, even in p53-mutated Ramos Burkitt's lymphoma cells, Myc stabilization resulted in increased responses to doxorubicin. These results fully support our innovative hypothesis that transient up-regulation of Myc could be a viable adjuvant therapy for Myc-driven tumors even with p53 loss or MDM2 amplification. We will pursue this hypothesis in the following two aims. 1) To investigate Myc-dependent and - independent events that drive p53-independent apoptosis in response to doxorubicin+GSK3? inhibitors. Specifically, we will determine whether genetic or pharmacological inhibition of Myc abolishes pro- apoptotic effects of CHIR99021 or whether other GSK-3? targets such as BCL2L12 contribute to chemosensitization. 2) To investigate how GSK3? inhibition affects Burkitt's lymphoma response to doxorubicin in acute and chronic treatment models. On the strength of our in vitro data, we will test if GSK-3? inhibition potentiates doxorubicin-based chemotherapy against murine syngeneic grafts and human xenografts, resulting in a more robust apoptotic response (acute model) and prolonged event- free survival (chronic model). Upon completion of this work we will have a better understanding of the apoptotic pathways regulated by GSK3? and its targets such as Myc and BCL2L12. Also, we will validate GSK3? inhibitors as adjuvant therapeutics to treat Myc-driven B cell lymphomas with mutant p53 or MDM2 amplification.

Public Health Relevance

Our key observation is that transient pharmacological stabilization of the Myc oncoprotein with GSK-3 inhibitors strongly enhances p53-independent doxorubicin-induced apoptosis. Thus; it could be a viable adjuvant therapy for Myc-driven tumors even with p53 loss or MDM2 amplification. Also; one of the better known inhibitor of GSK-3 is lithium; which is an FDA-approved drug for mental disorders and could be easily repurposed for anit-cancer therapies; without the need for lengthy Phase I/II trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RPRB-M (O1))
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Arya, Suresh
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Children's Hospital of Philadelphia
United States
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