Bladder Cancer Program

膀胱癌计划

• 批准号: 8157786
• 负责人: Andrea Apolo
• 金额: $ 21.19万
• 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/8157786
• 关键词: Malignant neoplasm of urinary bladder; programs

I want to test the clinical hypothesis that angiogenesis is an important target in bladder cancer. One of the clinical trials I am currently developing is a phase II study of TRC105 in patients with advanced/metastatic urothelial carcinoma. The median survival of patients with metastatic disease that has progressed after first line chemotherapy is 6 to 9 months. There is no FDA-approved drug for this setting and no standard conventional chemotherapy agent(s) have demonstrated a survival benefit in this patient population. This highlights the need for the development of novel therapies for these patients. Multiple lines of evidence support targeting angiogenesis in bladder cancer. Microvessel density, a histological measure of angiogenesis, has been correlated with stage, recurrence, and survival. Several reports have described increased expression of vascular endothelial growth factor (VEGF), a mediator of angiogenesis, in the tissue, serum, and urine of patients with bladder cancer and correlated these markers with stage and prognosis. Inhibitors of angiogenesis have shown activity in preclinical models of bladder cancer. A functional autocrine loop involving VEGF/VEGFR2 may be important in the pathogenesis of some bladder cancers. In a recent non-clinical study, 6 of 13 bladder tumor cell lines examined expressed VEGFR2 (Flk-1). Further analysis of the T24 bladder tumor cell line revealed a functional autocrine loop involving VEGF and VEGFR2. TRC105 is a genetically engineered human/murine chimeric monoclonal antibody, that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition and apoptosis. TRC105 is directed against human CD105 (endoglin), an angiogenic membrane protein that is highly expressed on proliferating vasculature in solid tumors including bladder tumors. Inhibitors of angiogenesis either alone or in combination with chemotherapy have demonstrated antitumor efficacy in patients with metastatic bladder cancer. This is a Phase II study of TRC105 in patients with metastatic urothelial carcinoma that have progressed despite treatment with prior cytotoxic chemotherapy. The primary objective of the study will be to determine the activity of TRC105 as determined by Response Evaluation Criteria in Solid Tumors (RECIST). TRC105 will be administered at a dose of 10mg/kg intravenously every two weeks, on days 1 and 15 of each 28 day cycle. Patients may continue on study as long as they are tolerating therapy and are free of disease progression. This trial is currently under review by the NCI Medical Oncology Branch (MOB) office of protocol administration. A second trial I am developing is a phase II study of gemcitabine, carboplatin and lenalidomide (GCL) as first line therapy for the treatment of patients with advanced/metastatic urothelial carcinoma. Cisplatin-based combination chemotherapy is considered the standard of care for patients with metastatic bladder cancer. However greater than 40% of patients are ineligible for such treatment based on renal function or disease/functional status. This has led many oncologists to utilize non-cisplatin-based therapy such as gemcitabine plus carboplatin in patients with advanced bladder cancer. This alternative combination is well tolerated with a comparable response rate of 36-58% compared to the response rate of gemcitabine and cisplatin of 45-64%. This regimen has become a community standard for patients with advanced bladder cancer in polls of community oncologists, carboplatin-based therapy is utilized in approximately 66% of patients with advanced/metastatic bladder cancer. Lenalidomide has both immunomodulatory and anti-angiogenic properties. The anti-angiogenic activity of lenalidomide is mediated through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation. In addition, lenalidomide has a variety of immunomodulatory effects, including stimulation of T cell proliferation, and production of IL-2, IL-10 and IFN-gamma, inhibition of IL-1 beta and IL-6 and modulation of IL-12 production. The drug has gained interest in solid tumors because of its anti-angiogenic properties, anti-neoplastic properties and favorable toxicity profile. Preliminary evaluation of an ongoing study in metastatic prostate cancer patients has demonstrated significant activity of lenalidomide in combination with bevacizumab and docetaxel with the first 14 patients enrolled having a 100% PSA response (decline greater than or equal to 50%) for patients receiving greater than or equal to 2 cycles. Lenalidomide which target different angiogenic factors, and has immunomodulation properties in combination with an active chemotherapy regimen of gemcitabine and carboplatin is a promising regimen in patient with metastatic bladder cancer who are in great need for better therapies. This is a single-stage Phase II study for patients with metastatic bladder cancer who are ineligible for cisplatin therapy. Gemcitabine 1000 mg/m2 will be administered intravenously on day 1 and 8 and carboplatin AUC 4.5 on day 1 with treatment re-cycled every 21 days. Lenalidomide will be administered at 10 mg orally once daily day 1 through 14 every 21 days. This trial is currently under review by the NCI MOB office of protocol administration. I will be the principle investigator of these two trials. A third trial I will be running at the NCI is a phase II study of gemcitabine, cisplatin, and sunitinib (GCS) as neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. Muscle invasive bladder cancer is a prevalent health care problem, despite surgery with curative intent (radical cystectomy and a bilateral pelvic lymph node dissection), approximately 50% of patients will develop distant metastases and succumb to their disease. A survival benefit with neoadjuvant cisplatin-based combination chemotherapy has been confirmed in two randomized clinical trials and a meta-analysis of over 3000 patients. Unfortunately, despite the use of conventional combined modality therapy, a large proportion of patients remain uncured, and novel neo-adjuvant chemotherapy regimens are needed to improve outcomes. The addition of sunitinib a vascular endothelial growth factor (VEGF) inhibitor to neoadjuvant gemcitabine and cisplatin has the potential to increase the rate of a pathologic complete response and therefore the rate of survival in patients with muscle-invasive bladder cancer. I developed this protocol at the ASCO/AACR Methods in Clinical Cancer Research Workshop during my fellowship at Memorial Sloan-Kettering Cancer Center (MSKCC). We are currently working to open this trial at the NCI. A secondary objective is to test alternative imaging modalities for restaging and assessing response to treatment in bladder cancer. I have established collaboration with the Molecular Imaging Program within the Center for Cancer Research at the NCI and am currently the lead investigator in a pilot study of F-18 sodium fluoride PET/CT for metastatic burden quantification in prostate cancer. I plan to conduct a prospective study of FDG PET/CT to evaluate treatment response in patients with advance bladder cancer. Advancing the treatments available for patients with bladder cancer with a focus on anti-angiogenic targeted agents is my primary goal. Along the way, I want to get many other scientist and clinicians at the NCI interested in learning more about the biology of bladder cancer. It is my hope that these efforts will help advance our understanding of the mechanisms of tumor development and find much needed novel therapies for the treatment of this aggressive and deadly malignancy.

我想检验临床假设，即血管生成是膀胱癌的重要靶点。我目前正在开发的临床试验之一是对晚期/转移性尿路癌患者的TRC105的II期研究。一线化疗后发生转移性疾病患者的中位生存期为6至9个月。在这种情况下没有FDA批准的药物，并且没有标准的常规化学疗法剂在该患者人群中表现出生存益处。这凸显了为这些患者开发新疗法的需求。多种证据支持靶向膀胱癌的血管生成。微血管密度是一种血管生成的组织学测量，与阶段，复发和存活有关。几份报道描述了血管内皮生长因子（VEGF）的表达增加，这是膀胱癌患者的组织，血清和尿液中血管生成的介体，并将这些标记物与阶段和预后相关联。血管生成的抑制剂已显示出在膀胱癌的临床前模型中的活性。涉及VEGF/VEGFR2的功能性自分泌环在某些膀胱癌的发病机理中可能很重要。在最近的非临床研究中，检查了13个膀胱肿瘤细胞系中的6个表达VEGFR2（FLK-1）。对T24膀胱肿瘤细胞系的进一步分析显示，涉及VEGF和VEGFR2的功能性自分泌环。 TRC105是一种基因设计的人/鼠嵌合单克隆抗体，可通过内皮细胞生长抑制和凋亡抑制血管生成和肿瘤生长。 TRC105针对人CD105（内尾），这是一种血管生成膜蛋白，在包括膀胱肿瘤在内的实体肿瘤中高度表达的血管蛋白。单独或与化学疗法结合使用血管生成的抑制剂在转移性膀胱癌患者中表现出抗肿瘤功效。这是一项TRC105的II期研究，尽管先前的细胞毒性化学疗法治疗了转移性尿路上皮癌患者。该研究的主要目的是确定TRC105的活性，如实体瘤中的响应评估标准确定（Recist）。 TRC105将在每28天周期的第1天和第15天静脉内以10mg/kg的剂量施用。只要患者耐受治疗并且没有疾病进展，就可以继续进行研究。 NCI医学肿瘤科（MOB）协议管理办公室目前正在审查该试验。 我正在开发的第二次试验是对吉西他滨，卡泊肽和那纳利度胺（GCL）的II期研究，作为治疗晚期/转移性尿路上皮癌患者的第一线治疗。基于顺铂的组合化疗被认为是转移性膀胱癌患者的护理标准。但是，基于肾功能或疾病/功能状况，超过40％的患者不符合资格进行此类治疗。这导致许多肿瘤学家利用非甲铂的治疗，例如吉西他滨加上膀胱蛋白的膀胱癌患者。与吉西他滨和顺铂的反应率为45-64％相比，这种替代组合的耐受性良好，可比的响应率为36-58％。在社区肿瘤学家的民意测验中，该方案已成为患有晚期膀胱癌患者的社区标准，在大约66％的晚期/转移性膀胱癌患者中使用了基于卡铂的治疗。 Lenalidomide具有免疫调节和抗血管生成特性。 Lenalidomide的抗血管生成活性是通过抑制BFGF，VEGF和TNF-Alpha诱导的内皮细胞迁移的介导的，至少部分是由于抑制AKT磷酸化。此外，Lenalidomide具有多种免疫调节作用，包括刺激T细胞增殖，以及IL-2，IL-10和IFN-GAMMA的产生，抑制IL-1β和IL-6的抑制以及IL-12的调节。由于其抗血管生成特性，抗塑性特性和有利的毒性特征，该药物已经对实体瘤引起了兴趣。对正在进行的前列腺癌患者的一项正在进行的研究的初步评估表明，Lenalidomide与Bevacizumab和多西他赛的结合具有显着的活性，而前14例患者的PSA反应（下降大于或等于50％）的前14名患者接受了大于或等于2个周期。靶向不同的血管生成因子，并具有免疫调节特性以及吉西他滨和卡泊铂的主动化学疗法方案是一种有希望的方案，在转移性膀胱癌患者中非常有希望的方案，他们非常需要更好地疗法。这是一项单阶段II研究，针对不符合顺铂治疗的转移性膀胱癌患者。吉西他滨1000 mg/m2将在第1和第8天静脉内给药，第1天的卡泊素AUC 4.5每21天重新捕获治疗。周期为10 mg，每天第1天至14天以10 mg口服。 NCI暴民协议管理办公室目前正在审查此试验。我将成为这两个试验的主要研究者。第三次试验将在NCI上进行，是对肌肉侵入性膀胱癌患者的新辅助化学疗法的吉西他滨，顺铂和舒尼替尼（GCS）的II期研究。肌肉浸润性膀胱癌是一个普遍的医疗保健问题，尽管手术具有治愈性（自由基膀胱切除术和双侧骨盆淋巴结清扫术），但大约50％的患者仍会发展远处转移并屈服于其疾病。在两项随机临床试验和3000多名患者的荟萃分析中已经证实了基于新辅助顺铂的结合化疗的生存益处已得到证实。不幸的是，尽管使用了常规的合并方式疗法，但仍有很大一部分患者尚未释放出来，并且需要新的新辅助化疗方案来改善预后。舒尼替尼向新辅助吉西他滨和顺铂添加了一种血管内皮生长因子（VEGF）抑制剂，有可能提高病理完全反应的率，因此肌肉侵入性膀胱癌患者的生存率。我在纪念斯隆 - 凯特林癌症中心（MSKCC）奖学金期间，在临床癌症研究研讨会的ASCO/AACR方法中开发了该方案。我们目前正在NCI开放此试验。 次要目标是测试替代成像方式，以重新恢复和评估膀胱癌治疗的反应。我已经与NCI癌症研究中心的分子成像计划建立了合作，目前是F-18 Fluoride PET/CT的试点研究中的主要研究员，用于前列腺癌的转移负担负担定量。我计划对FDG PET/CT进行前瞻性研究，以评估膀胱癌患者的治疗反应。 我的主要目标是推进膀胱癌患者可用的治疗方法，重点是抗血管生成剂。在此过程中，我想让NCI的许多其他科学家和临床医生有兴趣了解有关膀胱癌生物学的更多信息。我希望这些努力将有助于提高我们对肿瘤发育机制的理解，并为治疗这种侵略性和致命的恶性肿瘤找到急需的新疗法。