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Targeted delivery of multimodal therapy for reducing prostate cancer disparity

靶向多模式治疗减少前列腺癌差异

基本信息

批准号：
10538635
负责人：
Runhua Runa Liu
金额：
$ 37.15万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538635
关键词：
Ablation Acceleration African American African American population American Antibodies Biology Cancer Biology Cancer Etiology Cancer Patient Cell Communication Cell Line Cell membrane Cell model Cells Cessation of life Clinical Combined Modality Therapy Data Data Set Death Rate Development Diagnosis Disease Ectopic Expression Epithelial Cells European Exhibits Genes Genetic Glycolates Goals Human Immune Immune Evasion Immune response Immunosuppressive Agents Inflammatory Macrophage Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Membrane Glycoproteins Messenger RNA Metastatic Prostate Cancer Molecular Monoclonal Antibodies Mus Mutation Neoplasm Metastasis Oncogenes Oncogenic Outcome Oxidation-Reduction Patients Phagocytosis Pharmaceutical Preparations Phosphatidylinositols Polymers Prognosis Prostate Repression Resources Role Sampling TP53 gene Testing Therapeutic Tumor-associated macrophages United States Work Xenograft Model Xenograft procedure advanced prostate cancer antibody conjugate cancer health disparity cancer immunotherapy cancer type castration resistant prostate cancer effective therapy high risk improved improved outcome in vivo inducible gene expression innate immune checkpoint knock-down malignant breast neoplasm men mouse model mutant nanoparticle nanopolymer neoplastic cell new therapeutic target novel therapeutics overexpression palliative prostate cancer cell prostate cancer metastasis racial disparity racial population sialic acid binding Ig-like lectin small molecule systemic toxicity targeted delivery targeted treatment therapeutic target treatment strategy tumor

项目摘要

Project Summary Among all racial groups, African American men have the highest rate of prostate cancer, and their cancers exhibit a more aggressive biology, leading to higher rates of death. Although systemic treatments have been developed for this disease, these are primarily palliative; additional treatment strategies need to be developed. The major objective of this proposed project is to develop new targeted therapeutics to improve treatment of patients with advanced prostate cancer, including African American patients who have a particularly worse prognosis and whose tumors harbor more of an inflammatory and immune signature. CD24, a cell-surface glycoprotein, is not expressed in normal prostate epithelial cells but is expressed in approximately 50% of prostate cancers and in 60-66% of African American prostate cancers. For humans and mice, CD24 expression is associated with prostate cancer metastasis, and for patients with prostate cancer, over-expression of CD24 is associated with tumor metastasis and poor prognosis. Notably, a CD24-p53 axis contributes to African American prostate cancer disparities. In addition, CD24 is the dominant innate immune checkpoint in human cancers and is a promising target for cancer immunotherapy. Thus, CD24 may have dual functions as a cell-intrinsic oncogene and an immune suppressor, and it is a potential therapeutic target for patients with metastatic, castration-resistant prostate cancers. We hypothesize that targeting the CD24-p53 axis is an effective therapy for African Americans with metastatic castration-resistant prostate cancer. In this application, we propose a) to synthesize and characterize multifunctional nanoparticles for targeted delivery of anti-CD24 antibody and PRIMA1 (a p53 inducer), b) to evaluate targeted delivery of CD24/p53 targeted multimodal therapy to reduce prostate cancer racial disparities, and c) to determine the molecular mechanisms of the targeted therapy. Our proposed work is expected to establish CD24 as a new therapeutic target and to demonstrate a new therapy that meets the needs of African American patients with metastatic castration-resistant prostate cancer.

项目概要在所有种族群体中，非洲裔美国男性患前列腺癌的比例最高，而且他们的癌症表现出更具攻击性的生物学特性，导致更高的死亡率。尽管已经开发出系统治疗方法对于这种疾病，这些主要是姑息治疗；需要制定额外的治疗策略。主要该拟议项目的目标是开发新的靶向疗法，以改善患有以下疾病的患者的治疗晚期前列腺癌，包括预后特别差的非裔美国患者，他们的肿瘤具有更多的炎症和免疫特征。 CD24 是一种细胞表面糖蛋白，不是在正常前列腺上皮细胞中表达，但在大约 50% 的前列腺癌和 60-66% 的非洲裔美国人患有前列腺癌。对于人类和小鼠，CD24 表达与前列腺癌转移，对于前列腺癌患者来说，CD24 的过度表达与肿瘤转移，预后不良。值得注意的是，CD24-p53 轴导致非裔美国人前列腺癌差异。此外，CD24是人类癌症中占主导地位的先天免疫检查点，是一种很有前途的免疫检查点。癌症免疫治疗的靶点。因此，CD24可能具有作为细胞内在癌基因和细胞内癌基因的双重功能。免疫抑制剂，是转移性去势抵抗患者的潜在治疗靶点前列腺癌。我们假设针对 CD24-p53 轴是非裔美国人的有效疗法患有转移性去势抵抗性前列腺癌。在此应用中，我们建议a）合成和表征用于靶向递送抗 CD24 抗体和 PRIMA1（p53 诱导剂），b）评估 CD24/p53 靶向多模式疗法的靶向递送以减少前列腺癌种族差异，c) 确定靶向治疗的分子机制。我们建议的工作是有望将CD24确立为新的治疗靶点，并展示满足需求的新疗法患有转移性去势抵抗性前列腺癌的非裔美国患者。