Rationale: Each year, approximately 35,000 American men die of prostate cancer, and 165,000 new cases are discovered. Though a tremendous market exists for new pharmaceutical treatments, effective cures are lacking, especially for the most aggressive types of prostate tumors. Two strategies have been used to treat human cancers, including prostate cancer. One approach uses small chemicals that can readily spread throughout the body. Because they can kill effectively any cell they come in contact with, this lack of specificity leads to the well known side effects of chemotherapeutic drugs. An alternative approach attempts to design drugs to target tumor cells directly by identifying markers that are specific for tumor cells. Though this approach works very well in the lab, where tumor cells can be grown and treated directly, these treatments often fail when applied to human patients. This is partly due to the fact that tumor cells growing in humans are not readily accessible to large drugs, even when they are injected intravenously. A tight layer of cells called the endothelium lines the blood vessels and protects the underlying tissue from blood-borne molecules and effectively hides the tumor targets from the circulating drugs. Clearly, discovering a portal across the endothelial cell barrier is the key to creating new therapies.

Objective: Each tissue, including solid tumors, appears to express a characteristic array of proteins that can act as a "zip code" to target intravenously injected agents specifically to the tumor or tissue. Agents that target domains at the cell surface called caveolae are rapidly pumped out of the blood and concentrated in the underlying tissue. The ultimate goal of this work is to develop new therapies for human prostate cancer. To do this, we will map AnnA1 expression in human prostate tumors and normal tissue to determine specificity for tumor vasculature and homogeneity of expression across stages of prostate cancer. We will use multiple cutting-edge imaging techniques to define tumor targeting and processing of AnnA1 antibodies in vivo, including IVM and SPECTCT. Finally, we will determine the efficacy of targeted radionuclides and docetaxel-loaded nanoparticles against prostate cancer in multiple preclinical models.

Ultimate Applicability: Our published work has clearly shown that antibodies against caveolar proteins are rapidly pumped into tissue, even when attached to nanoparticles. Our preliminary work shows that antibodies against tumor-induced caveolar proteins are also rapidly pumped into tumors. Here, we will determine whether caveolae can be used to pump therapeutically relevant amounts of therapeutics into prostate tumors. If successful, this could increase drug efficacy as well as decrease side effects due to two reasons: (1) Drugs will rapidly be pumped out of the blood so that they cannot interact with non-tumor tissue, and (2) most of the injected dose is concentrated in the tumor, therefore we may be able to give far smaller doses. If these antibodies can destroy prostate tumors without damaging surrounding healthy prostate tissue, this represents a paradigm shift in the way prostate cancer is treated. This work will lay the necessary preclinical groundwork to move toward human clinical trials in the next three to five years.

Likely Contributions to the Field: This proposal is responsive to one overarching challenge: develop effective therapies for advanced prostate cancer. Few effective therapies exist, especially for late-stage prostate cancer, which is resistant to standard hormone therapy. Here, we propose a novel delivery strategy that can concentrate imaging agents, radionuclides, and drugs specifically within the tumor. This proposal is also responsive to three focus areas: biomarkers, imaging, and therapy. AnnA1 is novel tumor-induced biomarker. Because AnnA1 antibodies are actively concentrated in tumors, tumors have a high signal-to-noise ratio which should greatly improve our ability to image primary prostate tumors. Finally, AnnA1 antibodies may provide a powerful new therapy by concentrating radionuclides and drugs specifically in tumors, thereby increasing efficacy and decreasing side effects. Thus, this proposal can have far reaching effects on how prostate cancer is diagnosed and treated, ultimately increasing survival and decreasing the negative impact on patients' lives.