A Novel Brachytherapy Agent for GBM

GBM 的新型近距离放射治疗剂

• 批准号: 8593066
• 负责人: THOMAS C. CHEN
• 金额: $ 29.99万
• 依托单位: APPLIED INTEGRIN SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-29 至 2015-07-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593066
• 关键词: Actins; Adverse effects; Affect; Affinity; Amino Acid Sequence; Amino Acids; Angiogenesis Inhibitors; Animal Model; Antineoplastic Agents; Apoptotic; Avastin; Binding; Blood; Blood Vessels; Bone Marrow; Brachytherapy; Brain; Cell Surface Proteins; Cells; Clinic; Clinical Trials; Combined Modality Therapy; Cysteine; Cytoskeleton; Development; Diagnosis; Dialysis procedure; Disease; Disintegrins; Dose; Endothelial Cells; Endothelium; Exhibits; Extracellular Matrix; Family; Female; Fluorescence Polarization; Glioblastoma; Glioma; Harvest; Heart; Human; Implant; Individual; Integrin Binding; Integrins; Intravenous; Invaded; Iodination reaction; Kidney; Link; Liver; Longevity; Luciferases; Lung; Malignant Glioma; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Medical; Methods; Modality; Modeling; Molecular; Monitor; Mus; Neurosurgeon; Nude Mice; Nutrient; Operative Surgical Procedures; Oral; Organ Harvestings; Oxygen; Patients; Penetration; Peptides; Phase; Phosphate Buffer; Platelet Aggregation Inhibition; Production; Pump; Radiation; Radiation Oncologist; Radiation therapy; Radioactive; Radioactivity; Recombinants; Recurrence; Repeat Surgery; Saline; Small Business Technology Transfer Research; Snake Venoms; Specialist; Surface; Technology; Therapeutic; Thyroid Gland; Time; Tissues; Topoisomerase Inhibitors; Toxic effect; Tumor Tissue; Tyrosine; U251; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Wit; angiogenesis; base; bevacizumab; brain tissue; cancer cell; chemotherapeutic agent; chemotherapy; comparative efficacy; contortrostatin; cost; disulfide bond; implantation; inhibitor/antagonist; irinotecan; male; malignant breast neoplasm; migration; mouse model; neoplastic cell; neovasculature; novel; overexpression; public health relevance; receptor; response; temozolomide; tumor; tumor growth

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.

描述（由申请人提供）：尽管手术、化疗和放射治疗取得了进步，多形性胶质母细胞瘤 (GBM) 患者的平均寿命从诊断之日起约为 15 个月。整合素是在 GBM 细胞和血管生成血管系统表面发现的异二聚体受体；它们有助于侵入邻近组织。正常脑组织不显示激活的整合素。基于整合素拮抗作用的 GBM 治疗最具吸引力，既针对新血管系统又针对肿瘤本身。我们在第一阶段 STTR 中的方法基于称为解整合素的肽。解整合素以高亲和力与参与 GBM 和血管生成内皮细胞侵袭的人类整合素子集结合，以抑制肿瘤扩散。我们正在研究的解整合素 Vicrostatin (VCN) 是一种重组单链肽，其所有 10 个半胱氨酸残基都参与二硫键的形成。我们已经证明 VCN 对乳腺癌、卵巢癌和前列腺癌具有有效的抗肿瘤/抗血管生成活性。 VCN 作为 GBM 治疗的优点：VCN 能够破坏细胞的运动装置（肌动蛋白细胞骨架）并显着抑制 GBM 细胞和血管生成血管系统的侵袭性；由于正常脑组织中缺乏激活的整合素表达，脱靶效应最小；稳定的肽能够更好地穿透血肿瘤屏障；独特的重组生产方法，稳健、低成本且易于扩展；仅单个酪氨酸残基（氨基酸序列中的 Y51）碘化的 VCN 对碘化的稳定性。由于 VCN 能够靶向 GBM 内皮细胞腔表面表达的整合素，因此 131I-VCN 可以瘤内 (i.t.) 或静脉内 (i.v.) 给药。恶性神经胶质瘤的近距离放射治疗传统上是通过颅内放置到神经胶质瘤中的侵入性放射性探针进行的。使用 131I-VCN 选择性地靶向在血管生成肿瘤内皮细胞和神经胶质瘤细胞上过度表达的整合素，将使新型非侵入性静脉注射成为可能。在整个肿瘤中均匀分布的递送方式。我们提出两个具体目标：在目标 1 中，我们将使用静脉注射的 131I-VCN 进行剂量反应研究。或者它。小鼠模型中的 GBM。 131I-VCN 将通过以下方式发挥双重作用：(i) VCN 整合素拮抗活性，阻止 GBM 和相关内皮细胞的侵袭，以及 (ii) 131I 的近距离放射治疗作用。 131I-VCN 特异性结合 GBM 细胞和相关的血管生成内皮细胞，但不结合正常脑组织，从而限制近距离放射治疗对肿瘤的影响。我们将检查对正常大脑的毒性以及对 GBM 进展的剂量反应。在目标 2 中，我们将检查 131I-VCN（最佳 VCN 和 131I 剂量）与抗血管生成治疗或化疗的组合，并比较单个药物与其使用立体定向植入的 GBM 细胞的组合的疗效，如目标 1 中那样，以及生存和肿瘤大小作为端点。我们组建了一支独特的专家团队，包括：神经外科医生、解整合素/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。