Development of Angiogenesis Inhibitors

血管生成抑制剂的开发

• 批准号: 6756271
• 负责人: William Douglas Figg
• 金额: --
• 依托单位: DIVISION OF CLINICAL 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/6756271
• 关键词: alendronate; androgen inhibitor; androgen receptor; angiogenesis inhibitors; antineoplastics; butyrates; clinical trial phase I; drug design /synthesis /production; gene mutation; genetic regulation; human subject; human therapy evaluation; ketoconazole; metastasis; neoplasm /cancer chemotherapy; paclitaxel; patient oriented research; phenylacetates; phenylcarboxylate; prostate neoplasms; receptor binding; suramin; thalidomide; tissue /cell culture; tissue inhibitor of metalloproteinases; vascular endothelial growth factors

Clinically we have attempted to develop novel agents that alter the biology of the cancer. Specifically, we have been interested for many years in inhibiting angiogenesis as a means to treat prostate cancer. The progression of prostate cancer from a latent to an aggressive form depends on the acquisition of the angiogenic phenotype. Without angiogenesis, the primary prostate tumor is confined to 1-2 mm in size, and remains indolent. Angiogenesis is also required at sites of secondary colonizations in order for prostate cancer metastases to proliferate and expand. Prostate tumors found in autopsy specimens from men without clinical prostate cancer have very low blood vessel content, compared to prostate cancer specimens from men with clinically-evident disease. Siegal and colleagues reported that microvessel density (MVD) was significantly higher in prostate cancer tissue, than in adjacent hyperplastic or benign tissue. Numerous studies have been conducted to evaluate the use of MVD in prostate cancer samples as a prognostic and/or diagnostic marker. Most studies have demonstrated that MVD does help predict pathological stage and patient outcome. Using specimens from radical prostatectomies, Weidner et al., correlated increased angiogenesis in primary tumor specimens with metastatic disease. Several other studies also found MVD to independently predict the outcome of patients with prostate cancer. A recent study did not find MVD to be a useful prognostic indicator for men with clinically localized prostate cancer. Angiogenesis is driven by an imbalance of positive and negative regulators. One of the most potent positive regulators of angiogenesis is the vascular endothelial growth factor (VEGF). Prostate cancer cells produce VEGF at very high concentrations compared to normal prostate tissue. Such elevated levels of VEGF contribute to prostate cancer progression by inducing angiogenesis in the stroma via paracrine signalling. Using different sublines of LNCap cell lines, Balbay and colleagues demonstrated that the metastatic potential of human prostate cancer cell lines in an athymic mice model correlated with their VEGF expression. VEGF production is regulated by androgens in both normal and malignant prostate tissues. When prostate cancer cells progress to an androgen-independent state, VEGF regulation by androgens is also lost. Cellular hypoxia then becomes the main regulator of VEGF. VEGF acts upon two high affinity tyrosine kinase family receptors, Flt-1/ VEGFR-1 and Flk-1/ VEGFR-2. While previously believed to be specific to endothelial cells, these VEGF receptors have recently been localized to several types of tumors, including prostate. A recent study reports that Flt-1 is present in BPH and PIN, but lost in prostate cancer cells and with tumor dedifferentiation, implicating a role for this receptor in prostatic transformation to malignancy. Another member of the VEGF family, VEGF C, which binds to VEGF receptor-3 (VEGFR-3/ Flt-4) is also produced by prostate cancer cells and has recently been implicated in lymph node metastasis. Thus, the strong interplay between prostate cancer progression and angiogenesis are quickly being realized as this field unfolds. Antiangiogenic agents which we have clinically evaluated include: suramin, CAI, thalidomide, TNP-470, COL3, and somatuline. Currently, we are assessing docetaxel with or without thalidomide, and ketoconazole with or without alendronate (an MMP inhibitor) in patients with androgen indepedent prostate cancer. We have initiated a phase I clinical trial with CC5013 and 2ME (angiogenesis inhibitors). The angiogenic property of thalidomide reported by D'Amato and colleagues has prompted its clinical evaluation in various solid tumors including prostate cancer. Our laboratory previously showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide, 5'-OH-thalidomide, is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite, we have synthesized 118 analogs of thalidomide and have evaluated them using four in vitro models to assess activity in the inhibition of angiogenesis (rat aorta model, human saphenous vein model, cultured endothelial cells, and tube formationassay). We have identified the most potent of these and have patented them. We are continuing to develop these compounds. These compounds appear have minimal side effects in initial preclinical toxicology studies.

在临床上，我们试图开发新的药物，改变癌症的生物学。具体来说，我们多年来一直对抑制血管生成作为治疗前列腺癌的手段感兴趣。前列腺癌从潜伏型到侵袭型的进展取决于血管生成表型的获得。如果没有血管生成，原发性前列腺肿瘤的大小仅限于1-2 mm，并且保持惰性。在继发性定植部位也需要血管生成，以使前列腺癌转移增殖和扩展。与来自具有临床明显疾病的男性的前列腺癌标本相比，在来自没有临床前列腺癌的男性的尸检标本中发现的前列腺肿瘤具有非常低的血管含量。Siegal及其同事报告称，前列腺癌组织中的微血管密度（MVD）显着高于邻近的增生或良性组织。已经进行了许多研究来评估MVD在前列腺癌样品中作为预后和/或诊断标志物的用途。大多数研究表明，MVD确实有助于预测病理分期和患者预后。使用根治性前列腺切除术的标本，原发性肿瘤标本中血管生成增加与转移性疾病相关。其他几项研究也发现MVD可以独立预测前列腺癌患者的预后。最近的一项研究没有发现MVD是临床局限性前列腺癌男性的有用预后指标。 血管生成是由正负调节因子的不平衡驱动的。血管生成的最有效的正调节因子之一是血管内皮生长因子（VEGF）。与正常前列腺组织相比，前列腺癌细胞以非常高的浓度产生VEGF。这种VEGF水平的升高通过旁分泌信号传导诱导基质中的血管生成而促进前列腺癌进展。使用LNCap细胞系的不同亚系，Balbay及其同事证明了人前列腺癌细胞系在无胸腺小鼠模型中的转移潜力与其VEGF表达相关。在正常和恶性前列腺组织中，VEGF的产生受雄激素的调节。当前列腺癌细胞进展到雄激素非依赖性状态时，雄激素对VEGF的调节也丧失。然后细胞缺氧成为VEGF的主要调节因子。VEGF作用于两种高亲和力酪氨酸激酶家族受体Flt-1/ VEGFR-1和Flk-1/ VEGFR-2。虽然以前认为是特异性的内皮细胞，这些VEGF受体最近被定位于几种类型的肿瘤，包括前列腺。最近的一项研究报道，Flt-1存在于BPH和PIN中，但在前列腺癌细胞和肿瘤去分化中丢失，暗示该受体在前列腺转化为恶性肿瘤中的作用。VEGF家族的另一个成员VEGF C与VEGF受体-3（VEGFR-3/ Flt-4）结合，也由前列腺癌细胞产生，并且最近与淋巴结转移有关。因此，随着这一领域的发展，前列腺癌进展和血管生成之间的强烈相互作用正在迅速实现。我们已经临床评估的抗血管生成剂包括：苏拉明、CAI、沙利度胺、TNP-470、COL 3和生长抑素。目前，我们正在评估多西他赛联合或不联合沙利度胺，酮康唑联合或不联合阿仑膦酸钠（一种MMP抑制剂）治疗雄激素依赖性前列腺癌的疗效。我们已经启动了CC 5013和2 ME（血管生成抑制剂）的I期临床试验。 D 'Amato及其同事报道的沙利度胺的血管生成特性促使其在包括前列腺癌在内的各种实体瘤中进行临床评价。本实验室先前研究表明，沙利度胺的细胞色素P450 2C 19同工酶生物转化产物之一，5 '-OH-沙利度胺，负责药物的抗血管生成活性。基于这种代谢产物的化学结构，我们合成了118种沙利度胺类似物，并使用四种体外模型（大鼠主动脉模型、人隐静脉模型、培养的内皮细胞和管形成试验）评估了它们抑制血管生成的活性。我们已经确定了其中最有效的，并已获得专利。我们正在继续开发这些化合物。这些化合物在最初的临床前毒理学研究中似乎具有最小的副作用。