A Novel Brachytherapy Agent for GBM

描述（由申请人提供）：尽管在手术、化疗和放疗方面取得了进展，但多形性胶质母细胞瘤（GBM）患者的平均寿命从诊断起约为15个月。整合素是在GBM细胞和血管生成系统表面发现的异二聚体受体；它们易于侵入邻近组织。正常脑组织不显示激活的整合素。基于整合素拮抗剂的GBM治疗是最有吸引力的，既针对新血管系统，也针对肿瘤本身。我们在I期STTR中的方法是基于被称为分解素的肽。崩解整合素与一组参与GBM和血管生成内皮细胞侵袭的人整合素高亲和力结合，抑制肿瘤扩散。我们正在研究的分解素vicrostatin （VCN）是一种重组单链肽，所有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有效的抗肿瘤/抗血管生成活性。VCN作为GBM治疗的优势：VCN能够破坏细胞的运动器官（肌动蛋白细胞骨架），并显著抑制GBM细胞和血管生成系统的侵袭；正常脑组织中缺乏激活的整合素表达导致的最小脱靶效应；稳定的肽，能够更好地穿透血液-肿瘤屏障；一种独特的重组生产方法，稳健，低成本，易于扩展；仅一个酪氨酸残基（氨基酸序列中的Y51）碘化时，VCN对碘化的稳定性。由于VCN能够靶向表达在GBM内皮腔表面的整合素，131I-VCN可以通过瘤内（i.t）或静脉（i.v）给药。恶性胶质瘤的近距离放射治疗传统上是通过侵入性放射性探针置入脑内胶质瘤进行的。使用131I-VCN选择性靶向血管生成肿瘤内皮细胞和胶质瘤细胞上过表达的整合素，将实现一种新的非侵入性静脉给药方式，在整个肿瘤中均匀分布。我们提出了两个具体目标：在目标1中，我们将使用131I-VCN进行剂量反应研究，在小鼠模型中静脉或静脉给药GBM。131I-VCN将提供双重效果：(i) VCN整合素拮抗活性，阻断GBM和相关内皮细胞的侵袭；（ii） 131I的近距离治疗效果。131I- VCN与GBM细胞和相关血管内皮细胞特异性结合，但不与正常脑组织结合，限制了近距离治疗对肿瘤的影响。我们将检查对正常大脑的毒性，以及对GBM进展的剂量反应。在Aim 2中，我们将检查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，并比较单个药物与使用立体定向植入GBM细胞的组合的疗效，如在Aim 1中，以生存和肿瘤大小为终点。我们组建了一支独特的专家团队，包括：神经外科医生、崩解素/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.