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，我们尝试开发改变癌症生物学的新药物。具体来说，多年来我们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 毫米，并且保持惰性。为了前列腺癌转移的增殖和扩展，二次定植部位也需要血管生成。与患有临床明显疾病的男性的前列腺癌标本相比，在没有临床前列腺癌的男性尸检标本中发现的前列腺肿瘤的血管含量非常低。 Siegal 及其同事报告说，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。已经进行了大量研究来评估 MVD 在前列腺癌样本中作为预后和/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阶段和患者结果。 Weidner 等人使用根治性前列腺切除术的标本，将原发性肿瘤标本中血管生成的增加与转移性疾病相关联。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。最近的一项研究并未发现 MVD 对于患有临床局限性前列腺癌的男性来说是一个有用的预后指标。 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，前列腺癌细胞产生的 VEGF 浓度非常高。 VEGF 水平的升高通过旁分泌信号诱导基质中的血管生成，从而促进前列腺癌的进展。 Balbay 及其同事使用 LNCap 细胞系的不同亚系证明，无胸腺小鼠模型中人类前列腺癌细胞系的转移潜力与其 VEGF 表达相关。正常和恶性前列腺组织中 VEGF 的产生均受到雄激素的调节。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 的调节也随之消失。细胞缺氧则成为VEGF的主要调节者。 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。虽然以前认为这些 VEGF 受体对内皮细胞具有特异性，但最近已定位于几种类型的肿瘤，包括前列腺。最近的一项研究报告称，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，表明该受体在前列腺癌转化为恶性肿瘤中发挥作用。 VEGF 家族的另一个成员 VEGF C 与 VEGF 受体 3 (VEGFR-3/Flt-4) 结合，也是由前列腺癌细胞产生，最近被认为与淋巴结转移有关。因此，随着这一领域的展开，前列腺癌进展和血管生成之间的强烈相互作用很快就被认识到。我们临床评估过的抗血管生成药物包括：苏拉明、CAI、沙利度胺、TNP-470、COL3 和 somatuline。目前，我们正在评估多西紫杉醇联合或不联合沙利度胺，以及酮康唑联合或不联合阿仑膦酸盐（一种 MMP 抑制剂）治疗雄激素独立型前列腺癌患者的情况。我们已经启动了 CC5013 和 2ME（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进了其在包括前列腺癌在内的各种实体瘤中的临床评估。我们实验室此前表明，沙利度胺的细胞色素P450 2C19同工酶生物转化的产物之一5'-OH-沙利度胺负责该药物的抗血管生成活性。根据该代谢物的化学结构，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一项，并已为其申请了专利。我们正在继续开发这些化合物。在最初的临床前毒理学研究中，这些化合物似乎具有最小的副作用。