Therapeutic Targeting of Nox2 to Target Bone Metastatic Prostate Cancer Progression and Immune Evasion
Abstract
The American Cancer Society has projected that approximately 33,000 men, including Service Members and Veterans, will die from prostate cancer (PCa) in 2020. This is largely due to skeletal related complications from prostate cancer spread to the bone. Men with bone metastatic prostate cancer experience severe pain, increased risk of fractures, and often succumb to the disease within 2-3 years after detection of bone metastasis. Current bone-targeting therapies have been unsuccessful at eliminating PCa growth in bone. Understanding the mechanisms that contribute to prostate cancer progression in bone will be valuable for finding a cure. The Cook laboratory recently discovered that neutrophils, innate immune cells that comprise ~50- 60% of cells in bone marrow, mobilize to prostate cancer in bone and directly kill the cancer cells through unknown mechanisms. However, inevitably, the tumor becomes resistant to neutrophil killing and also suppresses neutrophil function. We now have preliminary evidence that metastatic prostate cancer cells produce abundant amounts of reactive oxygen species (ROS), which are molecules that promote cell death of normal cells but promotes growth and spread of cancer cells. Our preliminary data showed that, in response to neutrophils, metastatic prostate cancer cells increase their expression of NADPH oxidase 2 (NOX2), an enzyme important for producing ROS. When we treated metastatic cancer cells with a NOX2 inhibitor, ~70-80% of the cancer cells were killed and nearly ~100% when neutrophils were added in addition to the NOX2 inhibitor. In addition, metastatic cancer cells that are resistant to neutrophils became sensitized to neutrophil killing when treated with the NOX2 inhibitor. Thus, we hypothesize that NOX2 and ROS promote PCa progression and resistance to neutrophil immune response. This proposal aims (1) to define the role of NOX2 in bone metastatic prostate cancer progression and resistance to neutrophil killing and (2) to determine the therapeutic potential of targeting NOX2 for preventing prostate cancer growth in bone. The main objective of these studies is to identify the importance of NOX2 in cancer progression and develop a novel therapeutic strategy for curing bone metastatic prostate cancer. We will contribute to the Overarching Challenges to (1) define the biology of lethal prostate cancer and (2) develop novel therapies for treating lethal prostate cancer. Ultimate Applicability of the Research: 1. This research will help patients with lethal prostate cancer, including but not limited to metastatic prostate cancer and treatment-resistant disease. Our findings can be applied to other lethal PCa such as neuroendocrine PCa and high-risk localized PCa. 2. In the long term, the proposed research will address each of the Overarching Challenges; in the short term, we will define the biology of lethal prostate cancer to reduce death. 3. Although not immediately ready for clinical application, these studies will characterize NOX2 as a therapeutic candidate for treating lethal prostate cancer. We will follow these studies with further optimization of NOX2 in vivo with the goal of development of NOX2 candidate inhibitors for further in vivo testing (5-10 years after the proposed studies).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110917
Entities
People
- Leah M Cook
Organizations
- United States Army
- University of Nebraska Medical Center