Metabolic Engineering of Cancer for Immunotargeting

描述：（由申请人提供）致癌性转化与 与细胞表面糖基化模式的改变相关， 在肿瘤上表达的异常碳水化合物，称为肿瘤相关的 碳水化合物抗原（TACA）是发展 可用于癌症诊断和治疗的癌症疫苗。但 对TACA的免疫耐受问题严重阻碍了 该地区 为了解决这个问题，并开发新的，有效的癌症疫苗， 该项目将采用一种新的战略，该战略基于修改后的TACA， 癌症的代谢工程首先，TACA对癌细胞的作用将是 通过用一种人工衍生物处理它们来进行代谢修饰， 单糖，可以作为癌细胞的前体， 生物合成一种新抗原-一种人工修饰的TACA类似物。的 癌症的代谢工程利用了 碳水化合物生物合成机制的灵活性。然后，特异性单克隆 抗体（mAbs）将用于选择性靶向被标记的肿瘤细胞。 新抗原作为回报，单克隆抗体可以用合成疫苗制备， 新抗原由于人造碳水化合物制成的疫苗可能 比天然的TACA和代谢的TACA更具有免疫原性， 工程可以特异性地标记癌细胞，有效的疫苗可能是 很容易组成的修改TACA和新的战略将有可能解决 对TACA的免疫耐受问题。代谢调节靶点 这个项目是唾液酸化TACA。 采用黑色素瘤作为肿瘤模型，其细胞上的GD 3和GM 3是肿瘤细胞上的GD 3和GM 3。 具体目标。甘露糖胺和唾液酸的N-修饰的类似物将是 用作前体，然后将在黑素瘤上表达的新抗原 GD 3和GM 3的N-修饰衍生物。该项目的目标是：1） 找到黑色素瘤代谢工程的有效前体， 研究各种前体酶的生物利用度， 唾液酸TACA的生物合成和黑色素瘤细胞; 2）找到 有效的疫苗，可以激发特定的免疫反应， 通过研究各种N-修饰的GD 3和GM 3的缀合物的新抗原; 3） 为了说明通过特异性免疫靶向 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。由于过度表达 唾液酸存在于各种肿瘤中，并且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.