| Recent
Advances in Medical Applications of Synchrotron Radiation Stanford Synchrotron Radiation Laboratory March 4-5, 2002 Program Director: Edward Rubenstein |
|
Molecular
Therapeutics in Cancer
James Rubenstein, M.D., Ph.D. |
| A framework
of potential biological targets which are specific to cancer cells
has emerged and provided the opportunity for the development of new
classes of therapeutic agents. Some of these targets are the consequence
of genetic mutations while others arise from epigenetic changes in
cancer cells. These alterations are res
ponsible for each of the characteristic
features of the malignant cell phenotype: an increased drive to proliferate
and to invade tissues, the ability to build a new tumor-specific vasculature
- a process termed angiogenesis, a decreased sensitivity to undergo
programmed cell death in response to cellular damage, and the ability
to suppress the process of immunosurveillance. Mutations which directly pro mote carcinogenesis typically affect two distinct classes of genes, oncogenes and tumor suppressor genes. Mutations involving oncogenes result in the aberrant activation of the corresponding gene products, resulting in the stimulation of cell growth and survival; these mutations act dominantly and are not hereditary. Important examples of oncogenes are the bcr-abl nonreceptor tyrosine kinase which is the basis for chronic my elogenous leukemia, mutations in the ras family of GTPase signaling molecules which are commonly found in solid tumors, and the chromosomal translocation which results in the activation of bcl-2, a protein which inhibits programmed cell death, often found in non-Hodgkin's lymphoma. Mutations of tumor suppressor genes result in their inactivation; these mutations are recessive and constitute the basis for herediitary cancer s yndromes such as retinoblastoma, Li-Fraumeni syndrome or familial adenomatous polyposis. Epigenetic biological processes such as tumor angiogenesis are driven largely by cytokines whose expression is increased in tumor cells; among these, vascular endothelial growth factor (VEGF) may be the most important. Elaboration of VEGF by cancer cells may also have a role in the suppression of immunosurveillance. The molecular genetic analysis of cancer is having a significant impact on clinical practice in oncology in two ways: one, by facilitating diagnosis and two, through the translation of this information into the development of novel therapeutics which selectively target genes which are specifically expressed in cancer cells. Detailed insights into the molecular characteristics of these targets is requisite in order to develop these agents. |
