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Edward Prochownik, MD, PhD
Program(s): Cancer Biology
Contact:
Children's Hospital of Pittsburgh of UPMC
4401 Penn Avenue Rangos Research Center, Rm. 5124
Pittsburgh PA
Phone: 412-692-9110
Research Interests and Keywords:
  • c-Myc, glycolysis, oxidative phosphorylation, mitochondria, metabolism, TCA cycle, electron transport chain
Summary
Research in our laboratory is focused on two major areas concerning the c-Myc (Myc) oncoprotein: Project 1: The role of Myc in promoting metabolic reprogramming Project 2: Identification and characterization of small molecule Myc inhibitors Background: Myc is among the most commonly de-regulated oncoproteins in human cancer with up to 70% of all tumors showing evidence of Myc over-expression. Myc plays a role in many of the functions that are know to be aberrant in cancer including cell cycle, proliferation, translation, survival, differentiation and metabolism. We have recently begun to focus on how Myc contributes to the metabolic re-programming that is required to supply the necessary metabolic precursors needed for rapid proliferation (Project 1). Myc is a bHLH-ZIP transcription factor. It binds to canonical sequences in the promoters of many genes and recruits many other transcriptional co-regulators to aid in the fine-tuning of gene expression. DNA binding by Myc requires that it associate with another bHLH-ZIP protein, Max. Myc-Max interaction is required for all known biological functions of Myc, and the prevention of this heterodimeric association abrogates all Myc activity. We are interested in developing small molecule inhibitors that prevent the Myc-Max association and that can potentially be developed into actual anti-neoplastic drugs. Because Myc is such a central oncogenic player in cancer, its therapeutic targeting could potentially allow such drugs to be used against a wide variety of cancers (Project 2). Project 1: We have previously shown that Myc is essential for maintaining normal levels of glycolysis, oxidative phosphorylation (Oxphos) and ATP. We have shown that Myc supports the normal structural and functional integrity of mitochondria, including the normal maintenance and function of the TCA cycle and electron transport chain (ETC). We are currently employing state-of-the-art proteomic and genomic technologies to study how the conditional loss of Myc or its over-expression in liver is associated with mitochondrial and glycolytic re-programming and dysfunction. One example of this approach involves the conditional deletion of Myc in the liver of mice at the time of birth and then studying metabolic changes that occur either subsequent to this or following the imposition of a proliferative stress. The latter involves the transplantation of wild-type or knockout hepatocytes into recipient mice that are genetically engineered to destroy their own liver. In this way, we are able to test how well the two types of hepatocytes can reconstitute a normal liver, respond to a significant metabolic stress and properly regulate their metabolism. To measure these responses, we are employing mass spectroscopy to compare metabolites and the mitochondrial proteomes of these mice and RNA seq to compare their transcriptional profiles. Similar studies are being performed in mice following conditional over-expression of Myc in the liver that leads to hypertrophy and eventual tumorigenesis as well as subsequent tumor regression when Myc is silenced. Project 2: We have identified a number of small, drug-like molecules that inhibit Myc-Max binding to DNA and Myc function in cells. Using a variety of biophysical techniques such as circular dichroism, NMR and surface plasmon resonance, we have shown that most of these molecules function by binding to Myc's bHLH-ZIP domain and altering its structure in ways that render it incapable of binding Max. We are collaborating with several groups to examine these compounds in several different cancer models in vivo and to construct novel analogs with increased potency and improved pharmacologic behaviors. New assays that allow the function of these molecules to be assessed in live cells and in vivo are also being developed.
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