Targeting Oncogenomic Function of N-Myc to Inhibit Neuroendocrine Prostate Cancer Visceral Metastasis
Abstract
Cancer cells and normal cells from the same patient have long been recognized as genetically different. Medical research has studied these differences to identify genetic vulnerabilities that are unique to cancer cells. Unfortunately, the search for new medicines to attack these genetic vulnerabilities has proven to be slow and difficult. Most existing cancer treatments are chemotherapies, and the process of finding small chemical molecules to effectively exploit a particular genetic vulnerability is technically challenging and frequently undermined by safety concerns. As a result, very few therapeutic options exist to treat the most advanced and lethal forms of prostate cancer, and additional treatment options are badly needed for patients whose cancer has spread to a critical organ such as the liver or lungs. The goal of this proposal is to develop a new treatment to attack a genetic vulnerability that is particularly found in an extremely aggressive form of prostate cancer known as neuroendocrine prostate cancer (NEPC), which frequently spreads to the liver or lungs. The ability of NEPC cancer cells to spread to the liver and lungs and survive in those locations appears to rely upon a gene known as MYCN, which encodes the N-Myc protein that belongs to a key group of molecules called transcription factors (TF). TFs can dramatically influence cellular behavior by binding to DNA itself and controlling the use of genetic information, but how N-Myc binds to DNA and controls the process of metastasis is largely unknown. This proposal describes a plan to discover in detail how N-Myc regulates the use of genetic information and enables the metastasis of NEPC cells to the liver or lungs using a combination of cutting-edge approaches, including CRISPR/Cas13d RNA-targeting technologies and high throughput genome sequencing. Traditional efforts to develop chemotherapies to inactivate TFs that promote cancer have repeatedly failed, leading to the reputation that TFs may be undruggable. We propose to develop a non-traditional form of CRISPR/Cas13d-based gene therapy to block the ability of NEPC cells to produce N-Myc. The CRISPR/Cas13 RNA therapy will be packaged into the center of tiny delivery capsules called nanoparticles that can travel through the bloodstream and deliver the therapy to prostate cancer cells that have spread to the liver or lungs. However, it will be absolutely critical to deliver the therapy directly to cancer cells in those organs, avoiding accidental delivery to nearby healthy cells or other unaffected organs. Technological breakthroughs in the nanoparticle field have now made it possible to accomplish these goals more effectively than ever before. The nanoparticles containing the CRISPR/Cas13d therapy must be surrounded with an outer coating or capsule during intravenous or oral administration to the patient. Researchers have recently discovered two modified recipes for this outer coating that can steer the nanoparticles towards either the liver or lungs, and away from other organs where therapy is not needed. At the same time, this capsule can be coated with a specially designed material that attracts them to lethal prostate cancer cells, helping them physically attach and deliver maximum therapeutic benefit to the patient, with minimal side effects. Our preliminary studies indicate that this strategy appears to be both effective and safe. Interestingly, these preliminary studies have also found that this gene therapy can sensitize NEPC cells to platinum-based chemotherapy, enhancing the effectiveness of an existing treatment. In this proposal, we propose to conduct more extensive studies to rigorously test both efficacy and safety of our gene therapy and combined gene therapy/chemotherapy in multiple laboratory models of metastatic prostate cancer. While the short-term goal is to provide a safe and effective new therapy to benefit patients with one particularly lethal form of metas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310072
Entities
People
- Qianben Wang
Organizations
- Duke University
- United States Army