Targeted delivery of multimodal therapy for reducing prostate cancer disparity

项目摘要 在所有种族群体中，非洲裔美国男性的前列腺癌发病率最高，他们的癌症表现为 一种更具侵略性的生物学，导致更高的死亡率。尽管已经开发了系统性治疗方法， 对于这种疾病，这些措施主要是姑息性的;需要制定其他治疗策略。主要 该拟议项目的目标是开发新的靶向治疗方法，以改善对 晚期前列腺癌，包括预后特别差的非裔美国患者， 他们的肿瘤带有更多的炎症和免疫信号。CD 24是一种细胞表面糖蛋白， 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%的非洲裔美国人前列腺癌。对于人类和小鼠，CD 24表达与 对于前列腺癌患者，CD 24的过度表达与前列腺癌转移有关。 肿瘤转移和预后差。值得注意的是，CD 24-p53轴有助于非洲裔美国人前列腺癌 差距。此外，CD 24是人类癌症中占主导地位的先天免疫检查点，并且是一种有前途的免疫检查点。 癌症免疫治疗靶点。因此，CD 24可能具有作为细胞内源性癌基因和作为细胞内分泌癌基因的双重功能。 免疫抑制因子，并且它是转移性、去势抵抗性 前列腺癌我们假设靶向CD 24-p53轴是治疗非裔美国人的有效方法。 患有转移性去势抵抗性前列腺癌在本申请中，我们提出a）合成和 表征用于靶向递送抗CD 24抗体和PRIMA 1（p53 诱导剂），B）评估靶向递送CD 24/p53靶向多模式疗法以减少前列腺癌 种族差异，以及c）确定靶向治疗的分子机制。我们的工作是 有望将CD 24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人患者。

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.