Reprogramming the Cancer Genome
Human development from the egg to the fully-grown adult is an epigenetic process. That is, with few exceptions, development does not involve changes to the structure of the gene (or DNA sequence). Importantly, epigenetic processes are reversible as shown by the ability to de-differentiate a mature adult cell back to an early embryonic cell. De-differentiation has now been accomplished by several mechanisms including somatic cell nuclear transfer (SCNT), fusion of adult cells to embryonic cells, and the transduction of virally expressed factors. All of these methods of de-differentiatiton turn back the clock, epigenetically speaking, from an adult cell to that of an embryonic cell.
Epigenetics also plays an important role in disease. For example, there is good evidence that deviant epigenetic modifications promote and maintain cancers. Therefore, it may be possible suppress cancer by reversing these modifications. Support for this comes from the success of ongoing clinical trials using drugs that can suppress proteins that direct these modifications. Furthermore we have used SCNT to globally reset the epigenetics of tumor cells, analogous to resetting the state of the mature adult to the embryonic stem cell. Amazingly, following SCNT, the nucleus from the former cancer cell was able to produce functional adult tissues. This finding strongly suggests that resetting the epigenetic state of tumor cells can partially, if not fully suppress further tumor growth.
There were two limitations to the SCNT studies. First, the work was limited to the mouse model system. Second, it remained unclear which of the many epigenetic modifications that were reset by SCNT were originally responsible for supporting growth of the cancer. In this grant, we propose to address these two limitations by extending our work to humans and by following the epigenetic events at a more detailed level. We will first optimize SCNT in rhesus macaques, a nonhuman primate model. Next we propose to translate our experience with the rhesus macaque SCNT to human SCNT. We also propose alternative techniques to SCNT in case we find SCNT infeasible. We will use these techniques to reprogram the epigenetics of human cancers. We will then evaluate how this resetting of epigenetics influences cancer growth. Finally, we will aim to identify which are the sentinel epigenetic events supporting tumor growth.
The tools we develop should be broadly applicable to the study of epigenetics in human disease. Furthermore, identification of the sentinel epigenetic modifications in cancer should identify excellent targets for cancer therapeutics.
This grant proposes to develop methods for reprogramming cancer cells into embryonic stem cells. The techniques developed through these experiments should be broadly applicable to the production of disease specific embryonic stem cell lines. The production of such lines will provide an unlimited source of cells to study the biology, genetics, and epigenetics of disease. Furthermore the cells could be used in drug screens for identification of novel therapeutics.
This grant also proposes to identify and follow epigenetic aberrations that lead to tumor formation and maintenance. Knowledge of such aberrations would provide targets that are reversible by nature and hence potentially very promising drug targets for therapeutic development.
Such advances could have a significant impact on the public health and the economy of the State of California. For example, the development of drugs that specifically target aberrant epigenetic events could alter tumor growth without the harmful side effects associated with most current cancer therapeutics. Such a drug would be a dramatic improvement in the care of the cancer, the second leading cause of death in the United States.