Development of Drugs That Target Prostate Cancer

开发针对前列腺癌的药物

• 批准号: 7733081
• 负责人: William Douglas Figg
• 金额: $ 29.13万
• 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/7733081
• 关键词: Adverse effects; Affect; Age; Alendronate; Angiogenesis Pathway; Anorexia; Antineoplastic Agents; Apoptosis; BAY 43-9006; BAY 54-9085; Biological Markers; Biopsy; Bone marrow biopsy; Cancer Biology; Characteristics; Clinical; Clinical Trials; Clinical assessments; Collaborations; Collection; Correlative Study; Daily; Development; Diarrhea; Disease; Docetaxel/Ketoconazole; Dose; Drug Delivery Systems; Drug Kinetics; End Point; Enrollment; Event; Exanthema; Failure; Fatigue; Gleason Grade for Prostate Cancer; Goals; Hepatotoxicity; Hypertension; In Vitro; Institution; Investigation; Ketoconazole; Label; Laboratories; Leukocytes; MAPK14 gene; MEKs; Malignant neoplasm of prostate; Measurement; Measures; Metastatic Lesion; Metastatic to; Microarray Analysis; Microtubules; Modeling; Molecular; Molecular Target; Monitor; Nausea; Neoplasm Metastasis; New Agents; PC3 cell line; Palmar-plantar erythrodysesthesia syndrome; Patients; Perifosine; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Prior Chemotherapy; Probability; Prognostic Marker; Progression-Free Survivals; Progressive Disease; Prostate specific antigen measurement; Prostate-Specific Antigen; Protein Isoforms; Protein Microchips; Proteomics; Proto-Oncogene Protein c-kit; Proto-Oncogene Proteins c-raf; Randomized; Range; Rate; Role; Safety; Scanning; Signal Transduction; Staging; Statistically Significant; Testing; Time; Tissues; Toxic effect; Treatment Protocols; Treatment outcome; Upper arm; Vascular Endothelial Growth Factor Receptor-2; androgen independent prostate cancer; base; bone; bone imaging; computational chemistry; day; design; docetaxel; gastrointestinal; improved; inhibitor/antagonist; metastatic process; mutant; novel; programs; research study; response; tumor; tumor growth

We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents. Following previous experiments demonstrating increased efficacy of microtubule-active drugs when combined with ketoconazole in vitro, when tested in multiple prostate cancer cell lines, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with androgen independent prostate cancer (AIPC). The primary objective of this study is to determine the side effect profile and MTD. In recognition of possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. The dosing regimen was modified to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 30 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing. A randomized Phase II trial of ketoconazole plus alendronate versus ketoconazole alone has been completed with 72 patients with progressive AIPC metastatic to bone. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC. A Phase II study in AIPC has recently been completed with perifosine. Treatment with this agent was complicated by fatigue and gastrointestinal toxicity. No significant clinical activity against prostate cancer was observed. Perifosine does not merit further study in the setting of monotherapy in this population. A Phase II study of BAY 43-9006 (Sorafenib) has been initiated. is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase isoforms in vitro. In addition, this agent also inhibits p38, c-kit, VEGFR-2 and PDGFR-b affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf. At this time, over 500 patients have been treated with this drug at other institutions with tolerable side effects. The primary objective of this study is to determine if BAY 43-9006 is associated with a 50% 4 month probability of progression free survival in patients with metastatic AIPC as determined by clinical, radiographic, and PSA criteria. The secondary objectives will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible), and to determine the time to progression measured by clinical and radiographic criteria. Correlative studies will be conducted on serially obtained tissue biopsies, bone marrow biopsies, and white blood cell collections. These laboratory correlates will include elucidation of activation of components of the Raf-ERK-MEK and angiogenesis pathways using protein microarray technologies developed by the NCI/FDA clinical proteomics program. The combination of correlated clinical and laboratory endpoints with emphasis on molecular signaling will provide new information on the anti-tumor effects helping to characterize its role in the treatment of AIPC. Thirty patients have been enrolled on this ongoing study. Dr. Dahut and myself recently completed the initial phase of a clinical trial with Sorafenib. We wanted to determine if sorafenib is associated with a 4 month probability of progression free survival which is consistent with 50%, as determined by clinical, radiographic, and prostate specific antigen (PSA) criteria in patients with metastatic androgen independent prostate cancer (AIPC). Patients with progressive metastatic AIPC were enrolled in an open-label, single arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were performed every cycle while radiographic measurements were carried out every 2 cycles. Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median (range) age of 63.9 years (50-77), Gleason score of 9 (4-9.5), and PSA concentration of 53.3 ng/mL (2-1905). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as demonstrated by bone scan, even though they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included: one grade 3 hypertension and hand-foot syndrome; grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in-vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0; 12) and maximum concentration (Cmax) were 9.76 hr*mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 hrs and 0.68 to 6.43 respectively. Sorafenib is relatively well tolerated in AIPC with two patients demonstrating evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based upon these observations, further investigation using only clinical and radiographic endpoints as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

我们正在尝试开发新的药剂来改变癌症的生物学特性。为了实现这一目标，我们已经开始与一家独特的计算化学公司合作，设计能够消除癌症发生、进展和转移过程中关键分子靶点的化合物。这些研究才刚刚开始，但可以提供有价值的新药物。根据先前的实验表明，微管活性药物与酮康唑联合在体外的疗效增加，当在多种前列腺癌细胞系中进行测试时，我们启动了酮康唑联合每周多西紫杉醇治疗雄激素非依赖性前列腺癌（AIPC）患者的I期试验。本研究的主要目的是确定副作用概况和MTD。考虑到可能的药物-药物相互作用，多西他赛和酮康唑的起始剂量分别为5mg /m2和1200mg /d。多西紫杉醇剂量为10mg /m2时，观察到明显的肝毒性。给药方案改为酮康唑600 mg/d，多西他赛10 mg/m2。迄今为止，共有30名患者接受了这种联合治疗，目前正在进行药代动力学分析。一项随机II期试验已经完成了72例进展性AIPC转移到骨的患者，酮康唑联合阿仑膦酸钠与酮康唑单独使用。AIPC患者单纯KT/H与KT/H + AL治疗的有效率、无进展生存期或总生存期无统计学差异。与单独使用KT/H治疗相比，在KT/H治疗中加入AL可能会增加反应持续时间，并具有可接受的安全性。然而，AL的加入对AIPC患者的生存没有好处。最近，一项用于AIPC的II期研究已经完成。该药治疗伴有疲劳和胃肠道毒性。未观察到抗前列腺癌的显著临床活性。在这一人群中，不值得进一步的单药治疗研究。BAY 43-9006（索拉非尼）的II期研究已经启动。是野生型和突变型b-Raf和c-Raf激酶亚型的有效抑制剂。此外，该药物还抑制p38、c-kit、VEGFR-2和PDGFR-b，影响肿瘤生长，并可能通过c-Raf下游事件促进细胞凋亡。目前，已有500多名患者在其他机构接受了这种药物的治疗，副作用是可以容忍的。本研究的主要目的是通过临床、放射学和PSA标准确定BAY 43-9006是否与转移性AIPC患者4个月无进展生存率的50%概率相关。次要目标将是证明药物对患者和肿瘤的生物效应（如果可能），并确定通过临床和放射学标准测量的进展时间。将对连续获得的组织活检、骨髓活检和白细胞收集进行相关研究。这些实验室关联将包括利用NCI/FDA临床蛋白质组学项目开发的蛋白质微阵列技术，阐明Raf-ERK-MEK成分的激活和血管生成途径。结合相关的临床和实验室终点，强调分子信号传导，将提供抗肿瘤作用的新信息，有助于表征其在AIPC治疗中的作用。30名患者参加了这项正在进行的研究。Dahut博士和我最近完成了索拉非尼临床试验的初始阶段。我们想确定索拉非尼是否与转移性雄激素非依赖型前列腺癌（AIPC）患者的临床、放射学和前列腺特异性抗原（PSA）标准确定的4个月无进展生存率（50%）相关。进行性转移性AIPC患者被纳入一项开放标签、单臂II期研究。索拉非尼连续给予400毫克口服，每日两次，28天为一个周期。每周期进行临床评估和PSA测量，每2周期进行影像学测量。到目前为止，共有22名患者参加了这项研究，完成了计划中的第一阶段试验。基线患者特征包括中位（范围）年龄为63.9岁（50-77岁），Gleason评分为9 (4-9.5)，PSA浓度为53.3 ng/mL（2-1905）。59%的患者之前接受过一次化疗方案。在21例进展性疾病患者中，13例在没有临床和影像学进展证据的情况下仅根据PSA标准进展。两名患者发现骨扫描显示骨转移灶显著减少，即使他们在获得扫描时符合PSA进展标准。可能与治疗相关的毒性包括：1例3级高血压和手足综合征；1/2级毒性：疲劳、厌食、高血压、皮疹、恶心、腹泻。体外研究结果表明，PSA不是索拉非尼活性的良好标志物。几何平均暴露量（AUC0; 12）和最大浓度（Cmax）分别为9.76 hr*mg/L和1.28 mg/L。达到最大浓度的时间（tmax）和积累比（第二次给药后）分别为2 ~ 12小时和0.68 ~ 6.43小时。索拉非尼在AIPC患者中耐受性相对较好，有2例患者表现出骨转移病变改善的证据。由于x线摄影和PSA反应不一致，本研究的解释变得复杂。PSA可能不是监测索拉非尼活性的适当生物标志物。基于这些观察结果，进一步的研究仅使用临床和放射学终点作为进展标准是必要的。第二阶段试验的应计费用正在进行中。

项目成果

Lack of prognostic significance of prostate biopsies in metastatic androgen independent prostate cancer.

前列腺活检在转移性雄激素非依赖性前列腺癌中缺乏预后意义。

• DOI: 10.1111/j.1464-410x.2007.07173.x
• 发表时间: 2007
• 期刊: BJU international
• 影响因子: 4.5
• 作者: Aragon-Ching,JeannyB;Gillespie,John;Price,DouglasK;Chuaqui,Rodrigo;Rodriguez-Canales,Jaime;Steinberg,SethM;Dahut,WilliamL;Figg,WilliamD
• 通讯作者: Figg,WilliamD

Benefits of the combination of thalidomide plus cyclophosphamide in hormone refractory prostate cancer patients.

沙利度胺联合环磷酰胺对激素难治性前列腺癌患者的益处。

• DOI: 10.4161/cbt.6.3.4235
• 发表时间: 2007
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Al-Chalabi,Tania;Figg,WilliamD
• 通讯作者: Figg,WilliamD

Antitumor activity of herbal supplements in human prostate cancer xenografts implanted in immunodeficient mice.

• 发表时间: 2003-09
• 期刊: Anticancer research
• 影响因子: 2
• 作者: S. Ng;W. Figg

Temporal-mediated FGFR1 independence: implications for targeting candidate molecules in prostate cancer.

时间介导的 FGFR1 独立性：对前列腺癌候选分子的影响。

• DOI: 10.4161/cbt.7.8.6658
• 发表时间: 2008
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Miles,RobertJ;Price,DouglasK;Figg,WilliamD
• 通讯作者: Figg,WilliamD

Evaluation of human fetal bone implants in SCID mice as a model of prostate cancer bone metastasis.

SCID 小鼠中人胎儿骨植入物作为前列腺癌骨转移模型的评估。

• 发表时间: 2006
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: Singh,ArunS;Macpherson,GordonR;Price,DouglasK;Schimel,Daniel;Figg,WilliamD
• 通讯作者: Figg,WilliamD