Reducing Prostate Cancer Aggressiveness via Aptamer-Mediated Nuclear Delivery of Splice-Switching Oligonucleotides
Abstract
Rationale: Each year in the United States, more men are diagnosed with prostate cancer than any other type of cancer; the disease is so common that one out of every nine men will receive a prostate cancer diagnosis during his lifetime. Additionally, prostate cancer is the second most common cause of cancer-related death among men. Significantly, African American men are disproportionally affected by the disease. The incidence of prostate cancer is almost 60% higher among African American men than Caucasian men, and African American men are more than twice as likely to die from the disease. Despite the treatment advances seen over the past several decades, these race-related differences have remained constant. Thus, there is a significant need to develop new types of therapies designed to specifically target and treat prostate cancer in African American men and, by doing so, to address the PCRP Overarching Challenge to “reduce lethal prostate cancer in African Americans.” Additionally, as prostate cancer is dependent on hormones known as androgens, patients are generally treated with therapies designed to prevent androgen activity. However, these therapies only temporarily limit prostate cancer growth, and many patients eventually progress to a disease form known as castration-resistant prostate cancer (CRPC). Despite recent treatment advances for CRPC, the disease is often still lethal. Thus, there is also a clear need to develop new therapies to treat this lethal form of prostate cancer and, by doing so, to address the PCRP Overarching Challenge to “improve outcomes for men with lethal prostate cancer.” Both aggressive race-related prostate cancer and CRPC are promoted by what are known as “alternative splice variants,” which result in alternative forms of proteins that are known to cause aggressive disease. Small strands of ribonucleic acid (RNA), similar to small pieces of DNA known as “splice-switching oligonucleotides” or SSOs, can be used to prevent these alternative splice variants from forming and thus prevent their tumor-driving effects. However, most SSOs are not able to enter tumor cells by themselves, preventing their use as drugs. We have shown that aptamers, also small strands of RNA, can interact with a protein, known as nucleolin, found on the outside of cancer cells and that nucleolin can carry the aptamers inside the cells. Objective and Aims: Thus, we propose that nucleolin aptamers can deliver SSOs into prostate cancer cells and tumors to develop new therapies for both African American patients and patients with CRPC. We aim to characterize the nucleolin aptamers to optimize them for delivery into prostate cancer tumors, design and evaluate nucleolin aptamer-SSOs to treat CRPC, and design and evaluate nucleolin aptamer-SSOs to treat African American-derived prostate cancer. Impact: Successful completion of this project will address both the PCRP Overarching Challenges to “reduce lethal prostate cancer in African Americans” and to “improve outcomes for men with lethal prostate cancer” by developing new therapies for both African American-derived prostate cancer and for lethal CRPC. This project will include the initial stages of development of these aptamer-SSO therapies. Subsequent studies over the timeline of several additional years are expected to prepare the aptamer-SSO therapies for clinical trials. We expect that both African American and CRPC patients treated with the aptamer-SSO conjugates will have reduced tumor growth and increased survival, although there is always the risk that the therapies will not translate well to human studies, at which point we could redesign our aptamer-SSO using a different aptamer or a different SSO.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010187
Entities
People
- Bethany Gray
Organizations
- Duke University
- United States Army