A Novel Brachytherapy Agent for GBM

描述(由申请人提供)：尽管外科手术、化疗和放射治疗取得了进步，但多形性胶质母细胞瘤(GBM)患者的平均寿命从确诊之日算起约为15个月。整合素是一种异二聚体受体，存在于基底膜细胞和血管新生血管的表面；它们促进邻近组织的侵袭。正常脑组织不显示激活的整合素。基于整合素拮抗的基底膜治疗最具吸引力，既针对新生血管，也针对肿瘤本身。我们在这个第一阶段STTR中的方法是基于被称为去整合素的多肽。去整合素与人整合素的一个子集具有高亲和力，参与GBM和血管生成内皮细胞的侵袭，以抑制肿瘤的扩散。我们正在研究的去整合素是一种重组单链多肽，它的10个半胱氨酸残基都参与了二硫键的形成。我们已经证明，VCN在乳腺癌、卵巢癌和前列腺癌中具有强大的抗肿瘤/抗血管生成活性。VCN作为GBM治疗的优势：VCN能够扰乱细胞的运动装置(肌动蛋白细胞骨架)，并显著抑制GBM细胞和血管生成血管的侵袭；由于正常脑组织中缺乏激活的整合素表达，导致的非靶向效应极小；稳定的多肽能够更好地穿透血液-肿瘤屏障；稳健、低成本和易于扩展的独家重组生产方法；以及VCN对仅含单一酪氨酸残基(氨基酸序列中的Y51)的碘化的稳定性。由于VCN能够靶向表达在GBM内皮细胞管腔表面的整合素，131I-VCN可以通过瘤内给药(I.T.)或静脉注射(Iv)。恶性胶质瘤的近距离放射治疗传统上是通过植入脑内的侵袭性放射性探针进行的。利用131I-VCN选择性靶向血管生成肿瘤内皮细胞和胶质瘤细胞上高表达的整合素，将使一种新型的非侵袭性静脉注射成为可能。在整个肿瘤中均匀分布的给药方式。我们提出了两个具体目标：在目标1中，我们将使用静脉注射的~(131)I-VCN进行剂量-反应研究。或IT。在小鼠模型中移植到GBM。131I-VCN具有双重作用：(I)VCN整合素拮抗活性，阻断GBM和相关内皮细胞的侵袭；(Ii)131I-VCN的近距离放射治疗作用。131I-VCN与GBM细胞和相关的血管生成内皮细胞特异性结合，但不与正常脑组织结合，限制了近距离放射治疗对肿瘤的影响。我们将检测对正常大脑的毒性，以及对GBM进展的剂量反应。在目标2中，我们将研究131I-VCN(在最佳VCN和131I剂量下)与抗血管生成治疗或化疗的组合，并比较单独药物与它们的组合的疗效，使用立体植入的GBM细胞，如目标1，以存活率和肿瘤大小为终点。我们组建了一支独特的专家团队，其中包括：神经外科医生、去整合素/整合素专家、分子生物学家、放射肿瘤学家、医学物理学家、动物模型专家和生物统计学家。

DESCRIPTION (provided by applicant): Despite advances in surgery, chemotherapy, and radiation therapy, the average life span of a patient with glioblastoma multiforme (GBM) is about 15-months from time of diagnosis. Integrins are heterodimeric receptors found on the surface of GBM cells and angiogenic vasculature; they facilitate invasion into adjacent tissue. Normal brain tissue does not display activated integrins. Therapy for GBM based on integrin antagonism is most attractive, targeting both the neovasculature and the tumor itself. Our approach in this Phase I STTR is based on peptides known as disintegrins. Disintegrins bind with high affinity to a subset of human integrins involved in GBM and angiogenic endothelial cell invasion to inhibit tumor dissemination. The disintegrin we are studying, vicrostatin (VCN), is a recombinant single-chain peptide with all 10 cysteine residues involved in disulfide bond formation. We have shown that VCN has potent antitumor/antiangiogenic activity in breast, ovarian and prostate cancer. Advantages of VCN as GBM therapy: ability of VCN to disrupt the locomotor apparatus of the cell (actin cytoskeleton) and dramatically inhibit invasiveness of both GBM cells and angiogenic vasculature; minimal off-target effects due to lack of activated integrin expression in normal brain tissue; stable peptide enabling better penetration through the blood-tumor barrier; an exclusive recombinant production method that is robust, low cost and easily scalable; and stability of VCN to iodination with only a single tyrosine residue (Y51 in the amino acid sequence) iodinated. Since VCN is able to target integrins expressed on the luminal surface of GBM endothelium, 131I-VCN may be administered either intratumorally (i.t.) or intravenously (i.v.). Brachytherapy for malignant gliomas has been traditionally performed via invasive radioactive probes placed intracranially into the glioma. The use of 131I-VCN to selectively target integrins overexpressed on the angiogenic tumor endothelial cells and glioma cells will enable a novel non-invasive i.v. delivery modality with uniform distribution throughout the tumor. We propose two Specific Aims: In Aim 1 we will perform a dose-response study using 131I-VCN, delivered i.v. or i.t. to GBM in mouse models. 131I-VCN will deliver a dual effect by: (i) VCN integrin antagonistic activity, which blocks invasion of GBM and associated endothelial cells, and (ii) the brachytherapy effect from 131I. 131I- VCN binds specifically to GBM cells and associated angiogenic endothelial cells, but not to normal brain tissue, limiting the brachytherapy affect to the tumor. We will examine toxicity to normal brain, and the dose response on GBM progression. In Aim 2 we will examine combination of 131I-VCN (at optimal VCN and 131I dose) with antiangiogenic therapy or chemotherapy, and compare efficacy of the individual agents to their combination using GBM cells stereotactically implanted, as in Aim 1, with survival and tumor size as end points. We have assembled a unique team of experts including: a neurosurgeon, disintegrin/integrin specialist, molecular biologist, radiation oncologist, medical physicist, animal model specialist and biostatistician.