Patyna Shem, Laird A Douglas, Mendel Dirk B, O'farrell Anne-Marie, Liang Chris, Guan Huiping, Vojkovsky Tomas, Vasile Stefan, Wang Xueyan, Chen Jeffrey, Grazzini Maren, Yang Cheng Y, Haznedar Joshua O, Sukbuntherng Juthamas, Zhong Wei-Zhu, Cherrington Julie M, Hu-Lowe Dana
Pfizer Global Research and Development, 10777 Science Center Drive, San Diego, CA 92024, USA.
Mol Cancer Ther. 2006 Jul;5(7):1774-82. doi: 10.1158/1535-7163.MCT-05-0333.
Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-beta, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies.
受体酪氨酸激酶（RTK），如血管内皮生长因子受体（VEGFR）、血小板衍生生长因子受体（PDGFR）、干细胞因子受体（KIT）和fms样酪氨酸激酶3（FLT3），在恶性组织中表达并协同作用，在血管生成、肿瘤生长和转移中发挥着多样且重要的作用。除了少数似乎由信号蛋白中的单一基因突变驱动的恶性肿瘤外，大多数肿瘤是多个异常信号通路中多个突变的产物。因此，在癌症治疗中，同时靶向抑制多个信号通路可能比抑制单一通路更有效。最近，在一些临床前和临床研究中，使用具有广泛靶点选择性的RTK抑制剂验证了这种多靶点策略。SU14813是从用于分离舒尼替尼的同一化学文库中鉴定出的小分子，通过结合并抑制VEGFR、PDGFR、KIT和FLT3具有广谱RTK抑制活性。在细胞试验中，SU14813抑制表达这些靶点的内皮细胞和/或肿瘤细胞的配体依赖性和配体非依赖性增殖、迁移和存活。SU14813以剂量和时间依赖性方式抑制异种移植肿瘤中VEGFR-2、PDGFR-β和FLT3的磷酸化。体内靶点抑制所需的血浆浓度估计为100至200 ng/mL。作为单一疗法使用时，SU14813表现出广泛而有效的抗肿瘤活性，导致源自人或大鼠肿瘤细胞系的各种已建立的异种移植瘤消退、生长停滞或生长显著减缓。与单独使用任何一种药物相比，与多西他赛联合治疗显著增强了对原发性肿瘤生长的抑制作用以及荷瘤小鼠的存活率。总之，SU14813在体内抑制靶点RTK活性，同时减少血管生成、靶点RTK介导的增殖和肿瘤细胞存活，从而产生广泛而有效的抗肿瘤疗效。这些数据支持正在进行的SU14813在晚期恶性肿瘤中的I期临床评估。
