Ligand-Targeted miRNA Delivery for Prostate Cancer Therapy
Abstract
Scientific Objective and Rationale: MicroRNAs (miRNAs) are small RNAs that have the ability to target multiple genes at the same time, and they work by turning gene expression off. Therefore, miRNAs that inhibit tumor growth by targeting multiple cancer genes, such as miR-34a, have the potential for cancer therapy. Although attempts have been made to deliver miR-34a to tumor, it leads to undesirable toxic effects due to the vehicle used for delivery. To eliminate the vehicle-associated toxicity, we previously developed a vehicle-free miRNA delivery approach. In this approach, the miRNA is directly conjugated to folate, a specific and high-affinity ligand for the folate receptor. Folate receptors are overexpressed on cancer cells, and this approach allows targeted delivery of miR-34a to cancer cells. However, prostate cancers do not overexpress folate receptor, but they do overexpress prostate-specific membrane antigen (PSMA) receptor. So, in Aim 1, we plan to use a high-affinity ligand of PSMA, called DUPA, conjugate it to miR-34a (DUPA-miR-34a), and test its delivery to prostate cancer cells in vitro as well as in mice. Secondly, another challenge associated with miRNA delivery is its low stability in the blood circulation and potential immune response. To address this, in Aim 2, we plan to enhance the stability and activity of miR-34a by introducing chemical modifications in its backbone and in sugar moieties. These chemical modifications have been previously shown to enhance the stability and activity and reduce immune effects in another class of small RNAs, called siRNAs. Applicability of the Research: PSMA is overexpressed on prostate cancer cells, especially metastatic prostate cancer, and is currently used to detect metastatic tumors. The DUPA-miR-34a approach allows targeted delivery of this miRNA to PSMA-expressing prostate cancer cells, hence concentrating the miRNA in these aggressive cancer cells without any vehicle-associated toxicity. As PSMA is overexpressed on metastatic prostate cancer, this approach will allow effective treatment of these lethal forms and improve overall survival. Moreover, our second aim will enable further enhancement of the stability and efficacy of DUPA-miR-34a that will prolong the effect of the therapeutic dose or reduce the required dose. We plan to test DUPA-miR-34a in immune-deficient mice in this proposal; future work will test these in immunocompetent mice as well as canine models. Upon successful completion of the proposed and future studies in large animals, we expect DUPA-miR-34a to undergo human clinical trials in 3-6 years. PI’s Career Goals: While several treatment strategies are available for prostate cancer treatment such as surgery, radiation, and androgen deprivation therapy, they are associated with resistance and recurrence of an aggressive cancer phenotype. My long-term career goal is to develop more effective and targeted therapies that ensure better management and prevent recurrence of prostate cancer. MiRNAs can target multiple cancer genes at the same time, and the ligand-conjugated approach proposed here aims to improve upon the non-specific and invasive nature of currently available therapies by enhancing specificity and reducing toxicity of the cancer therapeutic (miR-34a). Although my Ph.D. was in nanotoxicology research, as a postdoctoral trainee in Dr. Kasinski’s laboratory, I have developed a comprehensive plan that will help me succeed as an independent prostate cancer researcher. I am capitalizing on the laboratory’s existing expertise in developing similar miRNA-based therapies in lung and breast cancer, as well as more than six decades of combined experience of my co-Mentors in prostate cancer research. The cross-disciplinary mentorship of Dr. Philip Low, Dr. Timothy Ratliff, and Dr. Andrea L. Kasinski throughout the study and the core research facilities available at Purdue University will ensure my development as an ind
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110181
Entities
People
- Ikjot Singh Sohal
Organizations
- Purdue University
- United States Army