Oncogenic Disruption of Circadian Rhythm and Chronotherapy

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Project Summary Long Term Goals: The first objective of this proposal is to identify Myc as a disrupter of circadian rhythm in cancer and explore the implications of this finding for tumor cell growth and the development of new therapy approaches. The second objective is to train Brian Altman, PhD under the mentorship of Dr. Chi Dang at the University of Pennsylvania. Brian will be trained in the fields of cancer metabolism and circadian rhythm through acquisition of new research skills, presentations, discussions with labmates and professors, seminars on responsible research conduct, teaching experience, attendance at conferences, and preparation of manuscripts. These will prepare Brian to transition to a career as an independent academic investigator. Background: Circadian rhythms in mammals are 24 hour cycles regulated by a series of molecular feedback loops. While many cancers have disrupted circadian rhythms, there is currently no molecular basis to identify which cancers have altered or absent rhythms, and the implications of disrupted circadian rhythm on cancer cell growth and survival are not well understood. Identifying an oncogene as being associated with circadian disruption would greatly aid in developing future strategies to target these cancers with chronotherapy, or timed administration of cancer treatment to increase effectiveness and reduce toxicity. Myc is an oncogenic transcription factor translocated or amplified in a variety of blood cancers and solid tumors. We have already shown that Myc specifically disrupts circadian rhythm in cancer cell cultures by binding to the same promoters used by circadian-associated proteins and altering circadian gene expression. Therefore, we hypothesize that circadian rhythms in cancers are disrupted by oncogenic overexpression of Myc, that this disruption provides a specific growth advantage to cells, and that we can take advantage of this pathway to treat cancers in a chronotherapeutic manner by specifically targeting the apoptotic pathway. Specific Aims / Study Design: (1) To determine the effect of Myc overexpression on circadian rhythm in mice. (2) To study the role the novel Myc target Rev-erb¿ on tumor cell and xenograft growth. (3) To study the importance of oscillation of apoptotic genes and pharmacologically target the apoptotic pathway in a circadian-dependent manner. To carry out these aims, circadian gene expression and oscillation will be measured in a Myc-driven mouse model of liver cancer compared to normal liver tissue by real-time luminescent circadian monitoring. Next, I will use cell lines representing at least three kinds of cancer as well as xenografts to study the role of upregulated Rev-erb¿ in Myc driven cancers by looking at cell / tumor growth, alterations in gene expression, and specific metabolic pathways that Rev-erb¿ controls. Finally, I will study oscillation of the apoptotic pathway using genetic and protein analysis in tumor cell lines and mouse tumors as well as a functional sensitivity assay to help me determine how we can best use Myc-disruption of circadian rhythm to time specific therapy to tumors based on oscillating sensitivity to apoptosis.