Resistance to drugs or chemoresistance is a major limitation on the effectiveness of drug therapy for cancer, including ovarian cancer. Hallmarks of chemoresistance in ovarian cancer include the expression of genetic changes, such as the gene HER-2/neu, a so-called oncogene, and expression of various resistance mechanisms to front-line platinum and/or Taxol drugs, allowing the tumor cell to escape death. If new approaches to overcome these resistance mechanisms can be devised, significant public health improvement should be realized.
Drugs can induce tumor cell death by altering the normal balance of mechanisms within the cell enforcing or resisting death. One such drug, originally derived from a natural product, is Taxol, which has proven to have great value in the clinic against a number of tumors, including ovarian cancer. Taxol causes tumor cells to stop dividing and also causes tumor cell death. Although of great value clinically, resistance to Taxol has also been demonstrated both in the laboratory and in patients. The resistance is due to several factors; among them are genetic changes in HER-2/neu expression. Therefore, new approaches to Taxol-resistant ovarian cancer must be developed; such is the focus of this proposal.
Ovarian cancer cells attach via molecules on their cell surface to complementary molecules in their cellular environment as they leave the ovarian capsule and invade locally into the cavity in the abdomen, termed the peritoneum. One of the cell surface molecules, termed CD44, binds to a sugar polymer, hyaluronic acid, which is found widely in the peritoneum. Recent evidence indicates that patients whose ovarian cancer cells have high levels of CD44 have more aggressive disease and poorer survival. Thus, focusing the effect of chemotherapeutic drugs, like the active agent in Taxol, to cells that have high CD44 levels and aggressiveness may more selectively kill this dangerous population of cells and improve patient survival.
In this proposal, we will first test a new polymeric formulation of Taxol, which has shown promise in other systems at overcoming certain types of Taxol resistance. Of interest, it is less toxic than Taxol in rodents, and as a polymer, it localizes within tumor tissue to a much greater extent than Taxol. Determination of the ability of this formulation to circumvent the drug resistance cited above, controlled by the oncogene HER-2/neu, is a major goal of this proposal. These studies will be carried out in models of drug-resistant human ovarian tumors growing in the peritoneal cavities of immunodeficient mice. This site is clinically relevant to the progression of ovarian cancer in the majority of patients. We will also create and similarly evaluate another novel generation of these polymeric formulations designed to selectively kill ovarian cancer cells that have high levels of CD44.
If the effectiveness of this approach in these models is thereby established, further preclinical development of this approach may be strongly justified.` |
