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.

从临床上讲，我们试图开发改变癌症生物学的新型药物。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一种手段感兴趣。前列腺癌从潜在到侵略性形式的进展取决于血管生成表型的获取。没有血管生成，主要的前列腺肿瘤的大小仅限于1-2 mm，并且保持不变。在次生结肠的部位还需要血管生成，以使前列腺癌转移酶增殖和扩展。与患有临床疾病的男性相比，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的血管含量非常低。 Siegal及其同事报告说，在前列腺癌组织中微血管密度（MVD）明显高于相邻的增生或良性组织。已经进行了许多研究，以评估MVD在前列腺癌样本中作为预后和/或诊断标记。大多数研究表明，MVD确实有助于预测病理阶段和患者结局。 Weidner等人使用自由基前列腺切除术的标本，将原发性肿瘤标本中的血管生成与转移性疾病相关联。其他几项研究还发现，MVD可以独立预测前列腺癌患者的结果。最近的一项研究并未发现MVD对于患有临床局部前列腺癌男性的男性是有用的预后指标。 血管生成是由阳性和负调节剂的不平衡驱动的。血管生成的最有效的阳性调节因子之一是血管内皮生长因子（VEGF）。与正常的前列腺组织相比，前列腺癌细胞以非常高的浓度产生VEGF。这种升高的VEGF水平通过通过旁分泌信号传导诱导基质中的血管生成来促进前列腺癌的进展。 Balbay及其同事使用LNCAP细胞系的不同subline表明，在Anymic小鼠模型中，人前列腺癌细胞系的转移潜力与其VEGF表达相关。 VEGF的产生受正常和恶性前列腺组织中的雄激素调节。当前列腺癌细胞发展到与雄激素无关的状态时，雄激素的VEGF调节也会丢失。然后，细胞缺氧成为VEGF的主要调节剂。 VEGF作用于两个高亲和力酪氨酸激酶家族受体，即FLT-1/ VEGFR-1和FLK-1/ VEGFR-2。虽然以前被认为是内皮细胞特有的，但这些VEGF受体最近已定位在包括前列腺在内的几种类型的肿瘤中。最近的一项研究报告说，FLT-1存在于BPH和PIN中，但前列腺癌细胞和肿瘤去分化失去，这意味着该受体在前列腺转化中的作用是恶性肿瘤。 VEGF家族的另一个成员VEGF C与VEGF受体-3（VEGFR-3/ FLT-4）结合的VEGF C也由前列腺癌细胞产生，最近与淋巴结转移有关。因此，随着该领域的发展，前列腺癌进展与血管生成之间的强烈相互作用很快就被实现。我们在临床上进行评估的抗血管生成剂包括：苏拉蛋白，CAI，沙利度胺，TNP-470，COL3和躯体。目前，我们正在评估有或没有沙利度胺的多西他赛，以及在患有雄激素独立前列腺癌患者中，有或没有阿去膦酸盐（MMP抑制剂）的酮康唑。我们已经开始使用CC5013和2ME（血管生成抑制剂）进行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了临床评估。我们的实验室先前表明，细胞色素P450 2C19的一种产物（5'-OH- thalidomide）的丘里度胺的同工酶生物转化是该药物的抗血管生成活性的原因。基于该代谢产物的化学结构，我们合成了118种甲易代胺的类似物，并使用四种体外模型对它们进行了评估，以评估抑制血管生成的活性（大鼠主动脉模型，人类大静脉模型，培养的内皮细胞和管形成）。我们已经确定了其中最有效的东西，并为它们申请了专利。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。