Metabolic Engineering of Cancer for Immunotargeting

描述：(申请人提供)致癌转化密切相关 与细胞表面糖基化模式的改变有关，并与细胞表面糖基化模式的改变有关 肿瘤上表达的异常碳水化合物，称为肿瘤相关 糖类抗原(TACA)是肿瘤发生发展的重要靶点。 可用于癌症诊断和治疗的癌症疫苗。然而， 对TACA的免疫耐受问题严重阻碍了进一步的进展 这片区域。 为了解决这个问题并开发新的有效的癌症疫苗， Project将开发一种新战略，该战略基于修改的TACA和 癌症的代谢工程。首先，针对癌细胞的TACA将 通过用一种人造的衍生物处理它们来进行代谢修饰 单糖可被癌细胞作为前驱物质 生物合成一种新的抗原--一种人工修改的TACA类似物。这个 癌症的代谢工程利用显著的优势 碳水化合物生物合成机械的灵活性。然后，特定的单抗 抗体(MAbbs)将用于选择性地靶向标记的肿瘤细胞 新抗原。作为回报，单抗可以用合成疫苗制备，合成疫苗由 新抗原。因为由人造碳水化合物制成的疫苗有可能 比天然TACA和代谢产物具有更强的免疫原性 工程学可以专门标记癌细胞，有效的疫苗可能是 由修改后的TACA轻松组成，新策略可能会解决 对TACAs的免疫耐受问题。新陈代谢调节指标 这个项目是sialyl TACA。 黑色素瘤作为肿瘤模型，其细胞上的GD3和GM3是 特定的目标。甘露三胺和唾液酸的N-修饰类似物将是 作为前体，黑色素瘤上表达的新抗原将被 GD3和GM3的N-修饰衍生物。该项目的目标是：1) 寻找黑色素瘤代谢工程的有效前体 研究不同前体的生物利用度涉及的酶 唾液酸基TACA的生物合成和对黑色素瘤细胞的作用；2)发现 有效的疫苗可以激发对该病毒的特异性免疫反应 通过研究不同N修饰的GD3和GM3的偶联物来研究新的抗原；3) 通过特定的免疫靶向来说明新的策略 代谢工程黑色素瘤。这项研究最终将建立一个 前体和疫苗的适当组合。因为过度表达了 唾液酸存在于多种肿瘤中，唾液酸是肿瘤的共同特征。 许多TACA，这里建立的原则可能具有广泛的适用性。

DESCRIPTION: (provided by applicant) Oncogenic transformations are closely correlated with the change of glycosylation patterns of cell surfaces, and the aberrant carbohydrates expressed on tumors, which are called tumor-associated carbohydrate antigens (TACAs), are important targets for the development of cancer vaccines that can be used for cancer diagnosis and therapy. However, the problem of immunotolerance to TACAs has severely hindered further progress in the area. To solve this problem and to develop new, effective cancer vaccines, this project will exploit a new strategy that is based on modified TACAs and metabolic engineering of cancers. First, a TACA on cancer cells will be metabolically modified by treating them with an artificial derivative of a monosaccharide that can be taken as a precursor by cancer cells to biosynthesize a neoantigen - an artificially modified analog of the TACA. The metabolic engineering of cancer takes the advantage of the remarkable flexibility of carbohydrate biosynthetic machineries. Then, specific monoclonal antibodies (mAbs) will be used to selectively target tumor cells labeled by the neoantigen. The mAbs in return can be prepared with a synthetic vaccine made of the neoantigen. As vaccines made of artificial carbohydrates are potentially more immunogenic than those made of the natural TACAs and the metabolic engineering can specifically mark cancer cells, effective vaccines may be easily composed from modified TACAs and the new strategy will potentially solve the problem of immunotolerance to TACAs. The metabolic modifying targets of this project are sialyl TACAs. Melanoma is employed as the tumor model, and GD3 and GM3 on its cells are the specific targets. The N-modified analogs of mannosamine and sialic acid will be used as the precursors, and the neoantigens expressed on melanoma will then be the N-modified derivatives of GD3 and GM3. The aims of this project are: 1)to find the effective precursors for metabolic engineering of melanoma via studying the bioavailability of various precursors to the enzymes involved in the biosynthesis of sialyl TACAs and to melanoma cells; 2) to find the effective vaccines that can provoke specific immune responses to the neoantigens via studying the conjugates of various N-modified GD3 and GM3; 3) to illustrate the new strategy through specific immunotargeting of metabolically engineered melanoma. This research will eventually establish a proper combination of the precursor and vaccine. As the overexpression of sialic acid is found in various tumors and sialic acid is a shared feature of many TACAs, the principles established herein may be of wide applicability.