靶向癌症治疗的egfr-sglt1相互作用
【专利说明】革田向癌症治疗的EGFR-SGLT1相互作用
[0001] 相关申请的否叉引用：
[0002] 本申请要求于2013年5月8日提交的美国临时申请号61/821，028的优先权，所 述申请通过引用整体并入本文。
[0003] 政府變助:
[0004] 美国癌症学会巧SG-09-206-01)
[O(K)日]国防部前列腺癌研究项目（W91ZSQ8334N607)
[000引 发明背景
[0007] 表皮生长因子受体巧GFR)为在大多数上皮来源的癌症中高度活化/过表达 的受体酷氨酸激酶（Hynes NE 等，ERBB receptors and cancer:化 e complexity of targeted inMbitors，Na 化 re Reviews Cancer，5 巧）：341-354巧00巧）D 抑制 EGF民的 酷氨酸激酶活性已经成为基于EGFR的癌症疗法的主要策略。然而，通过受体酷氨酸 激酶的小分子抑制剂靴向￡6!^并未产生令人满意的治疗功效。各种人恶性肿瘤的总 体应答率为 10-20 % (Weiss J.，First line erlotin;Lb for NSCLC patients not selected by EGF民 mutation:keep carrying the TO民CH or time to let the flame die ? Transl. Lung Cancer Res. ,1 (3):219-223口012) ;Cohen SJ 等，Phase II and pharmacodynamic study of the farnesyItransferase inhibitor 民115777as initial therapy in patients with metastatic pancreatic adenocarcinoma, J. Clinical Oncology, 21 (7):1301-1306 (2003) ;Dancey JE 等，Targeting epidermal growth factor receptor-are we missing the mark ? ，Lancet362 (9377):62-64(2003))。 换言之，存在对EGFR酷氨酸激酶抑制剂无应答的较多癌症患者群体。例如，虽然EGFR 在超过80 %的晚期前列腺癌中过表达并与预后负相关，但前列腺癌耐受EGK?抑制 剂（Hernes E 等,Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence,British J.Cancer,9〇 (2):449_454(2〇04) ;Pu YS 等，Epidermal growth factor receptor inhibitor (PD168393)potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells,Biochemical Pharmacolo gy, 71 (6) :751-760 (2006) ;Sherwood ER 等，Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate,World J. Urology, 13 (5) :290-296 (1995) ;Zellweger T 等，E邱ression patterns of poteotisl therapeutic targets i打 prostate c过打cer, Ioterostioosl J.Cancer, 113 (4):619-628 (2005) ;Canil CM 等，Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer:a trial of the National Cancer Institute of Canada-Clinical Trials Group, J. Clinical Oncology, 23(3):455-460(2005) ;Gross M 等，A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer, BMC Cancer 7:142 (2007))〇
[0008] 证据表明EGFR具有独立的酷氨酸激酶功能。例如，敲除EGK?的动物在出生后很 个夹死亡(Threadgill DW 等，Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype, Science, 269巧221):230-234 (19%))D 然 而，具有严重受损的EGK?酷氨酸激酶活性的小赢完全能够存活并仅显示出一些上皮缺 陷（Luetteke NC,等，The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase,Genes&Development, 8 (4):399-413(1994))。 作为另一实例，野生型和激酶死亡的EGFR增强EGFR阴性32D造血细胞的存活率（Ewald JA 等,Ligand-and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells. Experimental Cell Research 282(2):121-131 (2003))。同样已经发现EGFR通过与不依赖于EGFR酷氨酸激 酶活性的钢-葡萄糖共转运蛋白I(SGLTl)相互作用并使其稳定来参与维持癌细胞的细胞 内葡萄糖基础水平（Weihua Z等，Survival of cancer cells is maintained by EGF民 independent of its kinase activity, Cancer Cell,13巧）：385-393(2008))D
[0009] S化Tl为主动的葡萄糖转运蛋白，其依靠细胞外钢浓度将葡萄糖转运至细 胞而不依赖于葡萄糖浓度（Wri組t EM,等，Biology of human sodium glucose transporters, Physiological Reviews, 91 (2) :733-794 (2011) D SGLTl 在体内的葡萄 糖吸收和保留中起关键作用（Castaneda-Sceppa C等，Sodium-d邱endent glucose transporter protein as a potential therapeutic target for improving glycemic control in diabetes, Nutrition Reviews, 69(12):720-729(2011)) D 癌症的其中 一个标志为癌细胞显示出改变的能量代谢，即癌细胞消耗的营养物和能量底物的量 大大高于其正常对应物（Hanahan D 等，Hallmarks of cancer:化e next generat ion，Cell，144(5) :646-674(2011)。该增强的能量消耗要求高比率的营养物摄取，这 通过过表达质膜转运蛋白来实现（Ganapathy V，等，Nutrient transporters in cancerirelevance to Warburg hypothesis and beyond, Pharmacology&Therapeutic S 121(l):29-40(2009)。研究已经发现SGLTl在不同类型的癌症中过表达，所述癌症包 括卵巢癌、口腔鱗状细胞癌、结直肠癌、膜腺癌和前列腺癌化ai B等，Overexpression of SGLTl is correlated with tumor development and poor prognosis of ovarian carcinoma. Archives of Gynecology and Obstetrics,285 (5):1455-1461 (2012); Hanabata Y 等，Coexpression of SGLTl and EGF民 is associated with tumor differentiation in oral squamous cell carcinoma，Odontology/the Society of 化e Nippon Dental University, 100(2):156-163(2012);加O GF 等，Overe邱ression of SGLTland EGF民 in colorectal cancer showing a correlation with the prognosis, Medical Oncology 28 Suppl 1:8197-203 (2011) ；Casneuf VF 等,Expression of SGLTl, Bcl-2 and p53 in primary pancreatic cancer related to survival，Cancer Investigation 26(8):852-859(2008) ;Blessing A 等，Sodium/ Glucose Co-transporter I Expression Increases in Human Diseased Prostate, J. Cancer Sci. Ther. 4 (9) : 306-312 (2012))。作为例子，晚期前列腺癌表达升高水 平的EGFR并摄取大量的葡萄糖Glernes E等，Expression of化e邱idermal growth factor recep