Grantee: Johns Hopkins University School of Medicine, Baltimore, MD, USA
Researcher: Gary R. Pasternack, M.D., Ph.D.
Grant Title: Induced differentiation of medulloblastoma
Program Area: Researching Brain Cancer
Grant Type: Research Award
Amount: $150,000
Year Awarded: 2002
Duration: 2 years
What if a virulent childhood brain cancer could be treated without resort to radiation and chemotherapy, with their toxic side effects? What if nearly all children could survive this brain cancer, instead of the current 40 to 50%? These are the possibilities that represent extreme success emerging from a continuum initiated by the research I propose.
How could this happen? We know that the cells of this tumor, medulloblastoma, can differentiate to become more mature brain cells, or neurons, in some children. When this occurs, those children face a more favorable prognosis. The notion underlying my proposal is that we can, in fact, induce the proliferating subset of medulloblastoma cells, the ones that grow and spread, to differentiate by manipulating the molecular machinery that controls differentiation.
My present work is focused upon a family of genes called pp32, among other names. These molecules appear to act like senior executives in the cellular corporate world. Some molecules, transcription factors, have limited authority and work as middle managers might, at more restricted tasks and programs. pp32 participates in the cellular equivalent of broad strategic decisions. The decisions, "Do I differentiate? Do I continue to proliferate?", these broad programmatic and strategic decisions are the ones that pp32 participates in. It seems to participate in regulation of the histone code, a new term for describing how broad areas of the genome are selectively activated or made quiescent. It helps determine which classes of messenger RNA are stabilized for subsequent translation into proteins, and which are degraded. And, it helps determine whether cells live or die in a specialized cell death pathway.
We have learned, empirically, that if we can manipulate pp32 at a crude level, using antisense technology, we can force cancer cells to differentiate into cells resembling neurons that no longer proliferate. And so, we dare to dream that we might, even at this level of understanding, be able to drive medulloblastoma cells into the same maturation. In our study, we will both learn more about the process, we will continue to define at a fine level of understanding exactly how pp32 acts, and we may, in fact be so fortunate as to benefit children with medulloblastoma. We may develop useful diagnostics to tell better who may survive, we may define groups that could benefit from differentiation therapy, and we could start on the road to developing the therapy itself.