Bladder Cancer Program

膀胱癌计划

• 批准号: 10262297
• 负责人: Andrea Apolo
• 金额: $ 61.16万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262297
• 关键词: Anchorage-Independent Growth; Angiogenesis Pathway; Automobile Driving; Basic Science; Cancer cell line; Carboplatin; Cessation of life; Cisplatin; Clinic; Clinical Trials; Collaborations; Disease; Dose; Endothelium; In Vitro; KDR gene; Laboratories; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediator of activation protein; Medical Oncologist; Muscle; Pathologist; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Property; Radiation Oncologist; Randomized Clinical Trials; Refractory; Research Personnel; Role; Serum; Signal Transduction; Testing; Transitional Cell Carcinoma; United States; Urine; Urologist; Urothelium; Vascular Endothelial Growth Factors; Visceral metastasis; Woman; Work; antiangiogenesis therapy; base; cancer cell; career; chemotherapy; cohort; design; gemcitabine; inhibitor/antagonist; lenalidomide; men; multidisciplinary; novel; phase 2 study; phase 3 study; programs; radiologist; receptor expression; response; targeted agent; targeted treatment; tumor

The focus of my work has been to develop targeted therapies for the treatment of urothelial cancer and to further our understanding of the pathways driving this disease, specifically the angiogenesis pathway. I am Principle Investigator of two first line studies for metastatic bladder cancer using lenalidomide in combination with chemotherapies. Lenalidomide possess anti-angiogenic and immunomodulating properties, making it an ideal drug to explore in urothelial carcinoma. I explored in vitro combinations of lenalidomide with cisplatin, gemcitabine and carboplatin and found the combination of lenalidomide with chemotherapy has a clear and dose-dependent enhancement of anti-proliferative activity in T24 urothelial cancer cell lines. In addition to studying the VEGF pathway, evidence derived from our group, in collaboration with Dr. Donald Botarro, supports the cooperative roles for MET and VEGFR2 in the proliferation and survival of the tumor endothelium. Inhibition of MET can amplify the effects of VEGFR blockade. In a cohort of patients with metastatic and muscle-invasive urothelial cancer from my clinic, we analyzed blood serum and urine for soluble MET levels. MET levels in the urine were significantly higher in patients with visceral metastasis and serum MET levels were higher in patients with metastatic disease. We studied cabozantinb, a dual MET and VEGFR inhibitor (among other MET inhibitors) in urothelial cancer cells and found that MET receptor expression increased at higher disease grade. Urothelial cancer cells responded to HGF stimulation with increased activation of established intracellular signaling mediators, invasion, and anchorage-independent growth. Cabozantinib reverses these HGF-driven activities. These finding provided a rational to study cabozantinib in urothelial cancer. I initiated "A Phase II Study of Cabozantinib (XL184) in Patients with Metastatic Urothelial Carcinoma." This study is ongoing and rapidly accruing patients. Based on the impressive responses we have seen to date with cabozantinib in patients with advanced, refractory urothelial cancer, I am working on designing a national phase III randomized clinical trial. This will be the first phase III study using a targeted agent in the second-line therapy of urothelial cancer in the United States.

我工作的重点是开发针对尿路上皮癌治疗的靶向疗法，并进一步了解驱动这种疾病的途径，特别是血管生成途径。我是使用列纳莱度胺与化学疗法结合使用的两项转移性膀胱癌的第一线研究的主要研究者。 Lenalidomide具有抗血管生成和免疫调节特性，使其成为尿路上皮癌探索的理想药物。我探讨了Lenalidomide与顺铂，吉西他滨和卡铂的体外组合，并发现Lenalidomide与化学疗法的组合具有明确的剂量依赖性增强T24尿路皮癌细胞中抗增殖活性的增强。除了研究VEGF途径外，与唐纳德·博塔罗（Donald Botarro）博士合作得出的证据还支持MET和VEGFR2在肿瘤内皮增殖和存活中的合作作用。 MET的抑制可以扩大VEGFR阻滞的影响。在我诊所的转移性和肌肉侵入性尿路上皮癌患者中，我们分析了血清和尿液的可溶性MET水平。内脏转移患者的尿液中MET水平明显更高，转移性疾病患者的血清MET水平较高。我们研究了Cabozantinb，这是尿路上皮癌细胞中的双重MET和VEGFR抑制剂（以及其他MET抑制剂），发现MET受体表达在较高的疾病等级时会增加。尿路上皮癌细胞对HGF刺激做出了反应，随着已建立的细胞内信号传导介质的激活，侵袭和非锚定非依赖性生长的激活。 Cabozantinib逆转了这些HGF驱动的活动。这些发现提供了研究尿路上皮癌中的cabozantinib的合理性。我启动了“ Cabozantinib（XL184）对转移性尿路上皮癌患者的II期研究”。这项研究正在进行中，并迅速累积患者。基于我们迄今为止与卡博替尼在晚期，难治性尿路上癌患者中看到的令人印象深刻的反应，我正在设计一项国家III期随机临床试验。这将是使用靶向药物在美国的二线治疗中使用靶向药物的第一阶段研究。