Targeting CD24 Signaling for Lethal Metastatic Prostate Cancer Therapy
Abstract
Generally speaking, prostate cancer is slow-growing and relatively harmless. However, in some patients prostate cancer becomes very aggressive, turning lethal as it spreads throughout the body. Once spread of cancer occurs, chemotherapy is the only viable treatment option, but chemotherapy causes severe adverse effects and does not cure this disease. In fact, many patients opt for not treating advanced prostate cancer. For this reason, prostate cancer has become the second leading cause of cancer-related deaths in American men. Unfortunately, the mechanisms within the prostate cancer cells that lead to aggressive spreading are not completely understood. A more thorough understanding of these mechanisms and how they differ from the normal processes in healthy cells is necessary to inform the design of safe and effective treatment strategies. Recently, we discovered a protein expressed in spreading prostate cancer cells but not in normal prostate cells. Our PCRP-funded research demonstrated that this protein, CD24, can inactivate the normal functions of two genes, RCC2 and p53. These genes are responsible for keeping the prostate cancers from spreading to other areas of the body, especially if p53 is mutated, which is often the case in prostate cancer. Therefore, we can block the spread of prostate cancer cells in laboratory-based studies by deleting the portion of DNA that encodes CD24. Based on these novel observations, we hypothesize that the three genes, CD24, p53, and RCC2, regulate the spreading of prostate cancer and that targeting these genes can eliminate the aggressive, lethal spreading of prostate cancer cells. Our first goal is to determine how CD24-regulated genes control tumor metastasis in prostate cancer. We will identify the role of mutant p53 and RCC2 in CD24-mediated tumor metastasis using prostate cancer cell models and animal models. Our second goal is to develop an effective cancer cell-targeted therapy for metastatic prostate cancer by a combination of an anti-CD24 (targeting) antibody with a drug (PRIMA1) that reactivates the tumor-suppressive function of mutant p53. We will validate the ability of this novel therapy to safely and effectively eliminate metastatic prostate cancer in preclinical animal models. Our proposed work will not only help us understand how prostate cancer metastasizes, but will also build on this information to provide a new tool for eliminating metastatic prostate cancer. We have confirmed that our developed anti-CD24 antibody-PRIMA1 drug specifically targets CD24+ prostate cancer cells, but not normal human tissues (e.g., prostate, heart, liver, kidney, brain, spleen, lymph node, thyroid, stomach, small intestine, and colon), and effectively destroys prostate cancer cells by targeting both CD24 and mutant p53 in our preliminary studies. If our hypothesis is validated, then our findings will lead to the development of more effective treatment options by eliminating metastatic tumors with minimal toxicity to normal cells. This will benefit patients with metastatic prostate cancer, especially CD24+ and/or p53 mutant prostate cancer. Our results could lay the groundwork for prostate cancer clinical trials in which this anti-CD24 antibody-PRIMA1 drug is administered alone or in combination with chemotherapy. Therefore, our studies are expected to have major impacts as this new paradigm-shifting treatment strategy could be rapidly brought to the clinic for the treatment of patients with metastatic prostate cancer within 2-3 years. Ultimately, the proposed project will address the FY19 PCRP’s overarching challenges: “define the biology of lethal prostate cancer to reduce death” and “develop treatments that improve outcomes for men with lethal prostate cancer.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010426
Entities
People
- Runhua Liu
Organizations
- United States Army
- University of Alabama at Birmingham