Highly selective targeted theranostics for prostate cancers

前列腺癌的高选择性靶向治疗诊断

• 批准号: 10296947
• 负责人: James Peter Basilion
• 金额: $ 56.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296947
• 关键词: Adverse event; Affinity; Androgens; Animal Model; Animals; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; Antineoplastic Agents; Binding; Biochemical; Biological Markers; Blood group antigen S; Cancer Etiology; Canis familiaris; Carcinoma; Cell Death; Cessation of life; Chemicals; Chemoresistance; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Companions; Complex; Cytotoxic agent; Data; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Synergism; Drug resistance; Drug toxicity; Effectiveness; Exhibits; FOLH1 gene; Future; Generations; Genetic; Goals; Hematologic Neoplasms; Hormones; Human; Immune response; Immunocompetent; Immunologics; Implant; Ligands; Light; Local Therapy; Localized Disease; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Methodology; Methods; Microtubules; Modification; Molecular Weight; Movement; Mus; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; PUVA Photochemotherapy; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Photosensitizing Agents; Physiology; Prodrugs; Prostate Cancer therapy; Prostate carcinoma; Radiation therapy; Radical Prostatectomy; Reactive Oxygen Species; Recurrence; Refractory; Relapse; Reporting; Resistance; Risk; Site; Solid Neoplasm; Structure of base of prostate; Systemic Therapy; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Toxicology; Translations; Trastuzumab; United States; Weight; cancer biomarkers; cancer cell; cancer heterogeneity; cancer therapy; cell killing; chemotherapy; clinical application; clinical efficacy; clinical translation; combat; cost efficient; design; disorder risk; drug clearance; drug development; drug efficacy; efficacy evaluation; efficacy study; efficacy trial; high risk; human model; humanized antibody; improved; irradiation; men; minimally invasive; mouse model; multimodality; novel; novel therapeutics; overexpression; phthalocyanine; prevent; prostate cancer model; response; screening; serum PSA; side effect; small molecule; systemic toxicity; targeted delivery; targeted imaging; targeted treatment; theranostics; treatment strategy; tumor; virtual

Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that considers the use of a multimodal approach and that includes both local and systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain clinical conditions, have changed the natural course of some of these diseases. While effective, due to their intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin (SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less complex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT) agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs will substantially encourage clinical translation of the developed agent.

抽象的。前列腺癌是最常见的恶性肿瘤，也是第二大致癌原因。 美国男性死亡人数。尽管手术和放射治疗在低风险疾病患者中出现 适当和有效，那些有高风险局部疾病的人几乎总是变得激素抵抗和 然后迅速进步。高危局限性前列腺患者迫切需要新的治疗策略 癌症，尤其是一种考虑使用多模式方法的方法，包括局部和局部 和系统性治疗。 细胞毒性药物被广泛用于治疗血液系统恶性肿瘤和实体肿瘤，在某些情况下 临床情况，改变了其中一些疾病的自然病程。虽然有效，但由于他们的 固有的行动模式，它们还可能引起重大的非目标不良事件，从而可能阻止其完全 临床疗效，可能导致提前停药，从而增加发病风险 肿瘤复发或复发。两种维持化疗效果的替代方法 药物和最大限度地减少全身毒性包括将细胞毒剂与人源化抗体(也 称为抗体药物结合物(ADC)。布妥昔单抗的持久临床疗效报告 (SGN-35：西雅图遗传学/武田)和曲妥珠单抗emtansine(T-DM1；罗氏与 最近获得了监管部门的批准，这深刻地改变了ADC的前景 癌症治疗。这些方法虽然显示出很大的潜力，但非常昂贵，而且成本更低 需要复杂和更具成本效益的方法。 在这里，我们描述了一种新的前列腺特异性膜抗原(PSMA)配体的用途，PSMA是一种生物标记物 用于前列腺癌)靶向一种有效的微管抑制剂MMAE和光动力疗法(PDT) 试剂IR700选择性地治疗前列腺癌。这种新药分子的设计利用了前药的方法。 同时选择性地提供两种治疗前列腺癌的药物。通过选择性地给药两种药物 针对肿瘤细胞不同的治疗机制，有望在提高抗肿瘤活性的同时降低毒副作用。这个 由于预期的药物协同作用(需要较低的药物剂量)，预计毒性将会降低，具体地点 前药激活，并快速清除药物分子，防止偏离目标给药。这个分子会 使用两种前列腺癌动物模型，小鼠异位人前列腺癌和 伴犬的自发性前列腺癌。已经注意到MMAE和IR700疗法都能刺激 对癌症的免疫反应，我们将在免疫能力强的伴犬身上初步测试这一点。 狗的前列腺癌的病理和生理学与人类非常相似，狗经常被用在 药物开发试验。由于在小鼠身上进行的疗效试验不能预测人类的效果，所以在狗身上进行的功效研究 将极大地鼓励已开发试剂的临床翻译。