Rhenium-188 therapy of NIS-expressing breast tumors

描述（由申请人提供）： 乳腺癌仍然是妇女癌症死亡的主要原因， 发达世界。需要新的治疗方式， 化疗，激素治疗和外部放射治疗不是 有效最近，一种新的分子靶点已经在80%的 人类乳腺癌，但不存在于正常/健康乳腺组织中-乳腺癌 腺钠/碘同向转运体（mgNIS），这可能会开辟一条新的治疗途径， 放射性碘131-I治疗乳腺癌但由于没有 在表达NIS的乳腺肿瘤中131-I的生物滞留延长， 具有较短物理半衰期和优于131-I衰变上级的同位素 可以通过NIS运输的特性可以提供更好的治疗效果。 选项.我们最近发现，强大的β-发射体188-铼 （188-Re），其具有优于（188-Re）的那些的治疗上有用的发射上级。 131-I也由NIS运输， 与131-I相比，我们假设 188-Re比131-I在消除表达NIS的细胞中更有效。 小鼠乳腺肿瘤。我们还假设， 分馏/正常器官保护将增加188-Re杀肿瘤作用 同时减少对正常器官的辐射剂量。来验证这些假设 我们将开始评估188-Re和131-I对细胞杀伤的影响， 正常小鼠甲状腺组织中NIS表达细胞的变化 抑制有机化。我们将进行比较188-Re和131-I 包括剂量递增的裸鼠异种移植乳腺肿瘤的治疗 和最大耐受剂量测定。我们将采用以下组合 剂量分割/胃保护，以保护胃免受辐射。 我们还将为未来的治疗进行全面的剂量计算 表达NIS的人类乳腺癌。项目的具体目标 为： 目的1比较188-铼和131-碘对人肝癌细胞的杀伤作用， 使用健康小鼠的甲状腺作为靶器官的体内NIS表达组织。 目的2评价188-REO 4-作为抗肿瘤药物的可行性。 小鼠中表达NtS的乳腺癌肿瘤。 这项研究将为一种新型分子的相互作用提供数据。 用非碘治疗性放射性同位素的癌症靶- MgNiS及其 根除乳腺肿瘤的潜力。这项研究的长期目标是 为开发一种新的具有成本效益的放射性核素作出贡献 用于治疗乳腺癌和可能用于其它表达NIS的肿瘤的疗法 比如甲状腺癌。

DESCRIPTION (provided by applicant): Breast cancer remains the major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for those patients in whom chemotherapy, hormonal treatment and external radiation therapy are not effective. Recently a new molecular target has been identified in 80% of mammary cancers in humans but not in normal/healthy breast tissue - mammary gland sodium/iodide symporter (mgNIS) which may open a new avenue in treatment of breast cancer with radioactive iodine 131-I. However, in the absence of prolonged biological retention of 131-I in NIS-expressing mammary tumors an isotope with shorter physical half-life and superior to 131-I decay properties, which can be transported by NIS may provide a better therapeutic option. We have recently showed that the powerful beta-emitter 188-Rhenium (188-Re) which has therapeutically useful emissions superior to those of 131-I, is also transported by NIS and will deliver several times higher radiation dose to the tumor in comparison with 131-I. We hypothesize that 188-Re will be more efficient than 131-I in elimination of NIS-expressing breast tumors in mice. We also hypothesize that the combination of dose fractionation/normal organ protection will increase 188-Re tumodcidal effect while decreasing the radiation dose to normal organs. To test these hypotheses we will start with evaluation of 188-Re and 131-I cell-killing impact on NIS-expressing cells of thyroid in normal mice under the conditions of suppressed organification. We will perform comparative 188-Re and 131-I therapy of xenografted breast tumors in nude mice including dose escalation and maximum tolerated dose determination. We will employ the combination of dose fractionation/stomach protection to protect the stomach from radiation. We wilt also perform comprehensive dosimetry calculations for future therapy of NIS-expressing breast cancers in humans. The Specific Aims of the project are: Aim 1 To compare cell-killing potential of 188-Rhenium versus 131-Iodine in NIS-expressing tissue in vivo using thyroid in healthy mice as a target organ. Aim 2 To evaluate the feasibility of using 188-REO4- as a tumoricidal agent in NtS-expressing breast cancer tumors in mice. The proposed research will provide data on interaction of a novel molecular cancer target - mgNiS with non-iodine therapeutic radioisotope and on its potential to eradicate breast tumors. The long-term goal of this research is to contribute to the development of a novel cost-effective radionuclide therapy for treatment of breast cancer and, possibly, for other NIS-expressing cancers such as thyroid cancer.