Department of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
Cancer Chemother Pharmacol. 2013 Apr;71(4):867-81. doi: 10.1007/s00280-013-2078-0. Epub 2013 Jan 25.
Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials.
We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM.
SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient-derived MM tumor cells in vivo.
Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade(®), and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies.
多项报告指出，磷酸肌醇 3 激酶（PI3K）和 AKT 信号通路在多种骨髓瘤（MM）的肿瘤存活和化疗耐药中起着重要作用。我们研究的目的是：（1）生成必要的临床前结果，以证明 SF1126 在血液恶性肿瘤包括 MM 中的 I 期临床试验的合理性；（2）开始将泛 PI3K 抑制剂与其他药物联合使用，以增强此类药物的抗肿瘤活性，为 I/II 期试验的联合治疗做准备。
我们用 16 个人 MM 细胞系来确定 SF1126 的体外活性。用人骨髓瘤（MM.1R）异种移植瘤在裸鼠中测定体内肿瘤生长抑制。此外，我们提供了 SF1126 在治疗 MM 患者方面具有药效学活性的证据。
SF1126 对所有测试的 MM 系均具有细胞毒性，并且与硼替佐米联合使用可增强其效力。SF1126 影响 MM.1R 细胞系的信号转导，抑制磷酸化 AKT、磷酸化 ERK 和 HIF1α 的缺氧稳定。肿瘤生长抑制了 94%，细胞增殖（PCNA 免疫染色）和血管生成（通过 CD31 免疫染色的肿瘤微血管密度）均明显减少。我们的临床结果表明，SF1126 在体内对原发性患者来源的 MM 肿瘤细胞的 p-AKT 具有药效学下调作用。
我们的结果确立了三个重要观点：（1）SF1126，一种泛 PI3K 抑制剂，在体外和体内对 MM 具有强大的抗肿瘤活性；（2）SF1126 与蛋白酶体抑制剂硼替佐米/万珂（Velcade）联合使用时，显示出增强的抗骨髓瘤活性；（3）SF1126 阻断 IGF-1 诱导的从 SF1126 治疗患者中分离的原发性 MM 肿瘤细胞中 AKT 的激活。这些结果支持正在进行的 MM 早期 I 期临床试验，并表明未来在血液恶性肿瘤中与硼替佐米联合进行 I 期试验。
