Imaging and Targeted Systemic Therapy of Prostate Cancer with Antibody to Annexin A1
Abstract
Prostate cancer remains one of the most frequently diagnosed and one of the deadliest cancers. Current treatment options are based on surgery or radiation, and recurrent disease is treated with androgen ablation (surgical or chemical castration). Unfortunately, most prostate cancer becomes castration-resistant and progresses rapidly, with a median patient survival rate of 2 to 3 years. In fact, current chemotherapy for metastatic castration-resistant prostate cancer provides no cure, with a dismally low survival benefit (2.4 months). The inefficacy of currently used prostate cancer therapeutics is, in part, related to their limited tumor-specificity and insufficient levels of delivery. Given intravenously, most of the therapeutics are diluted over the entire body, and only small amounts reach diseased tissue, with even less able to penetrate solid tumors, where they can be most effective. This leads not only to poor treatment outcomes, but also severe side effects. Besides unresponsiveness to current therapies, the high mortality of prostate cancer patients is also caused by lack of sensitive and specific diagnostic methods that can accurately localize tumors for proper treatment and management of the disease. There is an urgent critical need for more effective prostate cancer therapies and improved imaging and diagnostic agents to facilitate detection, diagnosis, and management of treatment of this serious disease. Our previous research has identified an active cellular transport pathway that can pump antibodies armed with therapeutic cargo directly into solid tumors and metastatic lesions. We also identified a specific disease biomarker that is concentrated in the tumor vasculature and is unique to this cellular pump, and we have developed the first antibody to this biomarker that is capable of penetrating deeply and specifically inside tumor tissue as the result of pumping. Armed antibodies that bind the tumor-specific target protein are rapidly pumped out of the blood into underlying tumor tissue, resulting in the highly precise and efficient delivery of attached therapeutic agents such as drugs and radiopharmaceuticals. Here, we propose to use this highly specific and unique antibody for precision delivery of select radioisotopes suitable for imaging and therapy directly into prostate tumors and metastatic lesions. Depending on the particular isotope evaluated in the study, we expect to be able to specifically visualize tumor tissue and/or deliver a therapeutic dose of radiation very selectively into the tumor to kill cancer cells while sparing normal, healthy tissue. Extending our previous work, here we will evaluate the potential of this strategy for noninvasive imaging and therapy of prostate cancer using our targeting antibody in several preclinical models, including tumors that are castration-resistant or unresponsive to conventional chemotherapy treatment. Precision delivery of radiopharmaceuticals is expected to lead to specific, rapid, and robust penetration and accumulation of radionuclides inside solid prostate tumors and spare healthy tissue from unnecessary exposure to radiation. If successful, our novel delivery strategy could significantly enhance the efficacy of radiopharmaceuticals and reduce undesirable side effects in patients suffering from prostate cancer. The preclinical research proposed here will establish a path for the development and clinical translation of a new generation of radiopharmaceuticals to treat and manage prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810364
Entities
People
- Adrian Chrastina
Organizations
- Proteogenomics Research Institute for Systems Medicine
- United States Army