Development of a combination therapy for the treatment of prostate cancer

开发治疗前列腺癌的联合疗法

• 批准号: 7326445
• 负责人: FRANCIS S MARKLAND
• 金额: $ 24.99万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-13 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326445
• 关键词: Ablation; Address; Adjuvant Therapy; Affinity; American; American Cancer Society; Androgens; Angiogenesis Inhibitors; Animal Model; Animals; Antineoplastic Agents; Biological; Cancer Etiology; Cause of Death; Cell Line; Cessation of life; Characteristics; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collection; Combined Modality Therapy; Condition; Cyclic GMP; Data; Dependence; Development; Diagnosis; Disease; Disintegrins; Drug Formulations; Drug Kinetics; Effectiveness; Endothelial Cells; Gene Mutation; Goals; Half-Life; Human; Immune; In Vitro; Integrins; Intravenous; Language; Lesion; Liposomes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Methods; Modality; Modeling; Mus; Names; Neoplasm Metastasis; Nude Mice; Numbers; Operative Surgical Procedures; Organ; PC3 cell line; Pathway interactions; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Preparation; Process; Production; Property; Prostate; Prostate Adenocarcinoma; Prostate Cancer therapy; Proteins; Public Health; Recombinant Proteins; Recombinants; Resistance; Rodent; Rodent Model; Site; Skeleton; Skin Cancer; Small Business Technology Transfer Research; Snake Venoms; Source; Structure; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxic effect; Toxicology; Translations; Treatment Efficacy; Treatment Protocols; United States; United States Food and Drug Administration; Variant; Vascular Endothelial Cell; Xenograft Model; Xenograft procedure; angiogenesis; anticancer activity; base; bone; cancer cell; chemotherapeutic agent; chemotherapy; clinical application; contortrostatin; cytotoxic; design; docetaxel; end of life; in vivo; male; men; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; prevent; research clinical testing; scale up; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): Prostate cancer (PC) is the second most common form of cancer in American males, second only to skin cancer. In addition, it trails only lung cancer as a cause of death from cancer. The American Cancer Society estimated that 234,460 new cases of PC would be diagnosed in the United States and 27,350 men would die from PC in 2006. Most deaths from prostate cancer are still caused by spread of the cancer cells to remote tissue or organs, most frequently to the skeleton, which are resistant to conventional therapies. It is imperative, therefore, that new treatment modalities be developed for this devastating disease. This Phase I application proposes studies that will aid in the development of and clinical translation of a novel therapeutic regimen which combines conventional chemotherapeutics with the antiangiogenic agent, vicrostatin (VN), which possesses potent antitumor activity against prostate cancer. Our recent studies have shown that we can produce a recombinant version of CN (since the recombinant protein contains features found both in CN as well as other disintegrins, the recombinant protein we produce has been given the name vicrostatin, VN, a combination of viper and croatalid disintegrin sequences) that is as active as the native protein both in vitro and in vivo. In this Phase I proposal we will demonstrate that a liposomal formulation of VN (LVN) can be prepared in a form suitable for clinical use. Further, we will show that intravenous (IV) delivery of this formulation in a mouse model of prostate cancer produces effective control of tumor growth, angiogenesis and metastasis. We hypothesize that: (i) VN can be produced in a bacterial expression system at levels that will be suitable for clinical trials; (ii) LVN can be prepared by a technology that will provide sufficient material for clinical use; and (iii) LVN will demonstrate impressive anticancer efficacy and pharmacological and toxicological properties suitable for clinical translation. The following specific aims and milestones are established for the successful completion of these Phase I studies: Specific aim #1: Prepare a modified version of VN (that has full biological activity and enhanced affinity for integrin ?5¿1) in sufficient quantity for clinical application (Milestone 1, months 0-6), and prepare a liposomal formulation of VN (LVN) with appropriate stability characteristics and in amounts suitable for clinical application (Milestone 2, months 0-12). Specific Aim #2: Examine initial toxicologic properties of LVN (Milestone 3, months 6-12). Specific Aim #3: Examine efficacy of VN combined with chemotherapy in rodent models of human prostate cancer (PCA). In view of the realization that in the clinic antiangiogenic drugs will need to be used in combination with chemotherapeutic agents or antiangiogenic agents with a different mechanism of action, we will examine effectiveness of the combination of VN with a chemotherapeutic agent used for treatment of PCA, such as docetaxel. For these studies we will employ human PCA subcutaneous and orthotopic xenograft models in vivo. As part of the rodent model studies we will test the activity of LVN +/- androgen ablation +/- chemotherapy against androgen-dependent PCA. We will determine whether there is enhanced antitumor/antiangiogenic efficacy with combination therapy (Milestone 4, months 9-12). Specific Aim #4: Determine if LVN has activity against bone metastases from PCA in rodent models. A major end-of-life issue in PCA is the devastating effect of bone metastases. We will establish rodent models of prostate cancer bone metastases with a luminescent PC cell line which will allow us to determine the efficacy of LVN in combination with androgen ablation+/-chemotherapy in treating existing bone metastases and preventing new bone lesions (Milestone 5, months 6-12). New approaches for the treatment of prostate cancer are needed. Angiogenesis is a critical step for tumor growth and metastasis. The milestones delineated in this application will demonstrate the therapeutic efficacy of LVN alone and in combination with other chemotherapeutic agents in xenograft and bone metastasis rodent models of human prostate cancer. We expect that the proposed studies will identify VN as an anti-cancer agent that may be suitable for further clinical studies in prostate cancer. Lay Language: Prostate cancer is the second leading cause of cancer death of men in the United States. We have identified a natural protein that possesses potent anti- cancer activities. In the development of more effective prostate cancer therapies we have produced a recombinant variant of the natural protein. In this proposal we will show that the recombinant protein has activity equivalent to the natural protein and is amenable to therapeutic use in prostate cancer. We will examine the anti-tumor efficacy of this protein alone and in combination with current prostate cancer therapeutics as well as evaluate the toxicologic properties of the protein. These studies will advance the clinical potential of this novel anticancer protein.

描述（由申请人提供）：美国癌症协会称，前列腺癌 (PC) 是美国男性第二常见的癌症，仅次于皮肤癌。据估计，2006 年美国将诊断出 234,460 例 PC 新病例，27,350 名男性将死于 PC。大多数前列腺癌死亡仍然是由于癌细胞扩散到远处组织或器官造成的，最常见的是对传统疗法有抵抗力的骨骼，因此，必须为这种破坏性疾病开发新的治疗方式，该一期申请提出的研究将有助于新型治疗方法的开发和临床转化。该方案将传统化疗药物与抗血管生成药物维克他汀 (VN) 相结合，该药物对前列腺癌具有有效的抗肿瘤活性。我们最近的研究表明，我们可以生产重组版本的 CN（因为重组蛋白含有）。由于 CN 以及其他解整合素中都存在这些特征，我们生产的重组蛋白被命名为 vicrostatin (VN，viper 和 croatalid 解整合素序列的组合)，其在体外和体内与天然蛋白一样活跃。在这一第一阶段提案中，我们将证明 VN (LVN) 的脂质体制剂可以制备成适合临床使用的形式。此外，我们将证明该制剂的静脉 (IV) 递送。在前列腺癌小鼠模型中，我们发现：(i) VN 可以在细菌表达系统中产生，其水平适合临床试验；所制备的技术将为临床使用提供足够的材料；(iii) LVN 将表现出令人印象深刻的抗癌功效以及适合临床转化的药理学和毒理学特性，为成功完成这些 I 期研究制定了以下具体目标和里程碑。 ：具体目标#1：制备足够数量的 VN 修饰版本（具有完整的生物活性和增强的整合素 ?5¿1 亲和力）以供临床应用（里程碑 1，第 0-6 个月），并制备 VN 的脂质体制剂（LVN ）具有适当的稳定性特征和适合临床应用的量（里程碑 2，第 0-12 个月）。 具体目标 #2：检查 LVN 的初始毒理学特性（里程碑 3，几个月）。 6-12）具体目标#3：检查 VN 联合化疗在人类前列腺癌 (PCA) 啮齿动物模型中的疗效，鉴于临床上抗血管生成药物需要与化疗药物或化疗药物联合使用。对于具有不同作用机制的抗血管生成药物，我们将检查 VN 与用于治疗 PCA 的化疗药物（例如多西紫杉醇）联合使用的有效性。在这些研究中，我们将采用人 PCA 皮下注射和注射。作为啮齿动物模型研究的一部分，我们将测试 LVN +/- 雄激素消融 +/- 化疗对雄激素依赖性 PCA 的活性，我们将确定联合治疗是否具有增强的抗肿瘤/抗血管生成功效。里程碑 4，第 9-12 个月）具体目标#4：确定 LVN 是否具有针对 A Major 啮齿动物模型中 PCA 骨转移的活性。 PCA 的临终问题是骨转移的破坏性影响，我们将使用发光 PC 细胞系建立前列腺癌骨转移的啮齿动物模型，这将使​​我们能够确定 LVN 与雄激素消融+/-化疗相结合的疗效。现有治疗骨转移和预防新骨病变（里程碑 5，第 6-12 个月）需要治疗前列腺癌的新方法。血管生成是肿瘤生长和预防的关键步骤。本申请中描述的里程碑将证明 LVN 单独使用以及与其他化疗药物联合使用在人类前列腺癌的异种移植和骨转移啮齿动物模型中的治疗效果，我们预计所提出的研究将确定 VN 作为抗癌药物。可能适合前列腺癌的进一步临床研究。 外行语言：前列腺癌是美国男性癌症死亡的第二大原因。我们已经鉴定出一种具有有效抗癌活性的天然蛋白质。在开发更有效的前列腺癌疗法中，我们生产了天然蛋白质的重组变体，在本提案中，我们将证明重组蛋白质具有与天然蛋白质相当的活性，并且适合于前列腺癌的治疗用途。该蛋白质单独使用以及与目前的前列腺癌疗法联合使用的抗肿瘤功效，以及评估该蛋白质的毒理学特性，这些研究将推进这种新型抗癌蛋白质的临床潜力。