Inhibiting Bone Destruction by Prostate Cancer with Dual-Acting Bone-Defending Agents
Abstract
Prostate cancer (PCa) is the second most common cause of cancer related death for men living in the United States. Death results because the cancer moves out of the prostate gland and then throughout the body. These new cancer sites are referred to as metastasis. Over 90% of men with advanced PCa develop highly symptomatic metastasis to the bone. This cancer in the bone dominates the clinical management of patients; it results in pain, fracture, and spinal cord/nerve compression and leads disease burden with associated fatigue, all serving to cause symptoms that are uncomfortable and limiting and lead to early death. The current available therapy for bone metastasis has very limited clinical benefits and has many side effects. Our group is led by Dr. Bergan. He is a medical oncologist who specializes in PCa and has a long established track record of moving new forms of therapy from the bench into the clinic, where they can benefit people. This is very difficult to do. Further, our group was the first to successfully target pathways in humans that stimulate the development of cancer metastasis. We accomplished this in PCa. In our recent work, we synthesized, discovered, and patented a drug specifically designed to inhibit human PCa metastasis. That drug is called KBU2046. We found that, when given together with other drugs used to treat PCa, called bisphosphonates, the response is even better than with either drug alone. This led us to synthesize a new class of chemicals that link bisphosphonatesto-KBU2046. These dual-acting bone-defending agents (DABDs) bind bone and inhibit cell movement. DABDs stop bone cells, called osteoclasts, and PCa cells from working together to destroy bone. We show this using cells in the laboratory. Using animal models, where human PCa cells destroy bone, we demonstrate that DABDs not only stop bone destruction, they are so effective they prolong the survival of animals. In the current proposal, we seek to increase our understanding into how DABDs work as well as further evaluate their impact upon various aspects of metastatic PCa. Our goal is to use this information to move DABDs into the clinic. Who will DABDs help? It will help people whose cancer has already spread. It will help these people by stopping that cancer from further destroying the bone. By stopping bone destruction, it will stop PCa from causing pain, bone fractures, and paralysis (from damage to the spinal cord). Currently, we have not identified any risks associated with our lead DABD compound. This means that it is likely a very safe drug. We eventually plan to move DABDs into the clinic to test it on men with PCa. It takes comprehensive studies and large amounts money to do this. With funding from the Department of Defense, we will conduct a large portion of studies required by the Food and Drug Administration (FDA). Further, we intend to form a company for the purpose of raising money to move DABDs into humans. With this funding, we will conduct the toxicology studies required to submit an IND (Investigational New Drug application) to the FDA. We expect the process will take approximately 5 years, and once completed, we can move DABDs into human trials. The work defined in this proposal will directly address two Overarching Challenges: it seeks to define biology underlying lethal PCa and to develop treatments; attainment of these will address a third challenge, to improve quality of life by treating highly symptomatic bone metastasis. PCa bone metastases are highly destructive; their biology is poorly understood; and current therapy is minimally impactful. Our group has made major inroads, successfully coupling novel biological insights to a highly effective, completely new therapeutic and demonstrating its high potential for inhibiting the metastatic destruction associated with PCa. We are well poised to use this opportunity to transform how we treat and manage PCa in the clinic within
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010267
Entities
People
- Raymond Bergan
Organizations
- Oregon Health & Science University
- United States Army