Cancer Prevention-Interception Against MGUS Progression

项目摘要 未确定意义的单克隆性伽马病(MGUS)是一种癌前状态，在这种情况下 血液中一种异常免疫球蛋白(Ig)水平适度升高(称为M蛋白)。 MGUS患者患癌症的风险是对照人群的6.5倍。MGUS可能会进展到 多发性骨髓瘤(MM)、Waldenström巨球蛋白血症(WM)、非霍奇金淋巴瘤(NHL)、慢性 淋巴细胞白血病(CLL)、淀粉样轻链淀粉样变性(AL)或浆细胞瘤。嗯，WM，一大份 非霍奇金淋巴瘤和AL淀粉样变性是不治之症。慢性淋巴细胞性白血病和浆细胞瘤很少治愈。它的意义 MGUS呼吁建立一个癌症预防-拦截U54专门中心，专门针对这一癌前病变 病情MGUS影响约1%的人口，MGUS进展为癌症或其他相关血液 疾病以每年~1%的速度持续存在，从MGUS进展的~90%的癌症/疾病是 不治之症。所有患有MGUS的患者都是癌症预防和拦截的潜在候选者。我们 假设致癌分子和促进MGUS的骨髓微环境 进展是精准癌症预防和拦截的合适靶点。我们建议设立 癌症预防-阻止MGUS进展为癌症(CAP-MGUS)中心作为一个灵活和 致力于防止MGUS进展的有效网络基础设施。该中心将承担 专注于免疫和化学靶向的预防或拦截药物的合作研究 MGUS或阴燃疾病患者的致癌过程。我们提出了三个目标来实现 CAP-MGUS中心的首要目标。在目标1中，我们将从功能上验证肿瘤中的几个肿瘤靶点 开始和进展为浸润性癌症，并确定它们是否适合于有针对性的干预策略。 在目标2中，我们将通过体外发现创新的免疫和化学预防和拦截药物。 并进行体内疗效评价。在目标3中，我们将通过确定癌症的新靶点来开发新的项目- 针对MGUS进展的预防性或拦截性干预。总体而言，我们希望获得 用于进一步开发或早期临床试验的化学预防和免疫预防药物。

Project Summary Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition in which a person has moderately elevated levels of an abnormal immunoglobulin (Ig) protein (called M protein) in the blood. MGUS patients have a cancer risk ~6.5 times as high as the control population. MGUS may progress to multiple myeloma (MM), Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), amyloid light-chain (AL) amyloidosis, or plasmacytoma. MM, WM, a large portion of NHL, and AL amyloidosis are incurable diseases. CLL and plasmacytoma are rarely cured. The significance of MGUS calls for a cancer prevention-interception U54 Specialized Center dedicated to this precancerous condition  MGUS affects ~1% of the population, MGUS progresses to cancer or other associated blood disorders persistently at a rate of ~1% per year, and ~90% cancer/disorder that progressed from MGUS are incurable. All patients with MGUS are potential candidates for cancer prevention and interception. We hypothesize that cancer-driving molecules and the bone marrow microenvironment promoting MGUS progression are suitable targets for precision cancer prevention and interception. We propose to establish the Cancer Prevention-Interception against MGUS Progression to Cancer (CAP-MGUS) Center as an agile and effective network infrastructure dedicated to preventing MGUS progression. This Center will undertake collaborative research focusing on immunologically and chemically targeted agents that prevent or intercept the oncogenic process in patients with MGUS or smoldering diseases. We propose three aims to achieve the CAP-MGUS Center’s overarching goal. In Aim 1, we will functionally validate several oncotargets in tumor initiation and progression to invasive cancer and ascertain their suitability for targeted intervention strategies. In Aim 2, we will discover innovative immuno- and chemo-prevention and interception agents through in vitro and in vivo efficacy evaluation. In Aim 3, we will develop new projects by identifying novel targets for cancer- preventive or interceptive interventions against MGUS progression. Collectively, we expect to obtain chemoprevention and immunoprevention agents for further development or earlier phase clinical trials.