This proposal describes a highly innovative approach for the treatment of cancer. One of the primary modalities for cancer treatment involves the use of chemotherapeutic agents. While useful, all of these drugs manifest substantial side effects. Thus, their use requires a tradeoff between eradicating the cancer on the one hand and causing long term cellular damage on the other. Here we propose to address the above problem using caged (inactive) drugs that can be uncaged (activated) by long wavelength light in a site-specific manner; such drugs could specifically target the tumor and spare normal tissue. This innovative strategy is based on recent developments in chemistry in the area of two photon removable protecting groups (including Bhc, BHQ and NDBF). These moieties can be removed by two-photon excitation using focused red (800 nm) light. Since long wavelength light can efficiently penetrate tissue, this uncaging strategy could be used to selectively release anti-cancer drugs within a tumor below the skin without affecting the surrounding tissue. Not only would this reduce the side effects from chemotherapy but it could also obviate the need for surgical tumor removal in some cases. However, before such an approach can be implemented, the key question that must be addressed is: At what depths can light activation (via two-photon excitation, 2PE) produce biologically useful levels of drugs? That question, in the context of application to Ras-driven cancers, is the focus of the research proposed here. Thus, in Aim 1, we will synthesize and study the properties of a caged fluorophore model and caged inhibitors of protein prenyltransferases including a caged farnesyltransferase inhibitor (FTI), a caged geranylgeranyltransferase inhibitor (GGTI) and a caged dual prenylation inhibitor (DPI) in solution and in cell culture models.
In Aim 2, a phantom tissue model will be used to evaluate the efficiency of uncaging of a fluorphore and caged inhibitors of protein prenyltransferases at different depths. Finally, in Aim 3 we will test the efficacy of site-specific uncaging of a caged FTI, a caged GGTI and a caged DPI for inhibiting H-Ras- and K-Ras-stimulated transformation and tumor formation in both a mouse skin cancer model and an in vivo xenograft model. If successful, this approach could be a revolutionary step in improving cancer therapy.
The purpose of the research described here is to evaluate whether caged (inactive) drug molecules can be activated with light in animals. If this could be accomplished, drugs could be activated in tissue only where they were needed (such as in a tumor). This could eliminate the toxic side effects manifested by a variety of drugs.
