Development of Tethered Hsp90 Inhibitors Carrying Radioiodinated Probes to Specifically Descriminate and Kill Malignant Breast Tumor Cells
Abstract
Breast cancer, like other types of cancer, varies widely in its characteristics among patients with this disease. One of the most important features determining the success of different cancer therapies is the nature and concentration of oncogenic signaling molecules in a particular patient. Hsp90 is an oncogenic molecule that is expressed at high levels in 70% of breast cancers, and whose presence is associated with poor outcome. However, Hsp90 is also expressed in many normal tissues, complicating its use as a molecular target for imaging and treating breast cancer. Recently, we developed a novel class of drugs called tethered Hsp90 inhibitors that bind tightly and selectively to Hsp90 molecules on breast cancer, which are on the cell surface, but not to Hsp90 molecules on normal tissues, which are inside the cell. The goal of this research is to take advantage of the exquisite tumor specificity of tethered Hsp90 inhibitors to first identify those cancer patients whose tumors express Hsp90 and then be able to treat them with targeted radiation specifically delivered to their cancer cells by these tethered inhibitors. Our first objective will be to synthesize diagnostic probes derived from tethered Hsp90 inhibitors that will permit visualization and quantification of Hsp90 levels noninvasively by positron emission tomography (PET). Because there are novel cancer therapies already in clinical trial designed to target the Hsp90 molecule, PET imaging of Hsp90 levels with these labeled, tethered Hsp90 inhibitors will allow selection of patients most likely to respond to such treatments, and those not likely to benefit from such treatments, so as to avoid unnecessary side effects and expense. It might also be possible to use these PET probes to determine if a lesion is malignant or benign in patients being evaluated for breast cancer recurrence. The second objective of this research is to use our tethered Hsp90 molecules that bind specifically to Hsp90 on breast cancers as a means to selectively deliver therapeutic radionuclides to breast cancers, with the expectation of delivering tumor ablative levels of radiation while avoiding side effects in normal tissues. The work plan proposed in this project is exclusively preclinical, focusing on the synthesis of optimized tethered Hsp90 inhibitors and their evaluation in appropriate animal models of human breast cancer. Nonetheless, we have enlisted the aid of a patient advocate and a breast cancer oncologist at the beginning of this project in order to insure that the new approaches that are developed are likely to have patient acceptance and a meaningful impact on the management of patients with breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510072
Entities
People
- Timothy A. Haystead
Organizations
- Duke University
- United States Army