[发明专利]靶向癌症治疗的EGFR-SGLT1相互作用

说明书

化合物可使表皮生长因子受体(EGFR)与钠/葡萄糖共转运蛋白1(SGLT 1)之间的结合相互作用不稳定。在一实施方案中，所述化合物为来源于EGFR的相互作用结构域的肽。在另一实施方案中，将所述肽施用于患者以治疗癌症。

相关申请的交叉引用：

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。

政府资助：

美国癌症学会(RSG-09-206-01)

国防部前列腺癌研究项目(W91ZSQ8334N607)

发明背景

表皮生长因子受体(EGFR)为在大多数上皮来源的癌症中高度活化/过表达的受体酪氨酸激酶(Hynes NE等, ERBB receptors and cancer: thecomplexity of targetedinhibitors, Nature Reviews Cancer, 5(5):341-354(2005))。抑制EGFR的酪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，通过受体酪氨酸激酶的小分子抑制剂靶向EGFR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％(WeissJ., First line erlotinib for NSCLC patients not selected by EGFRmutation:keep carrying the TORCH or time to let the flame die？ Transl. LungCancerRes., 1(3):219-223 (2012)；Cohen SJ等, Phase II andpharmacodynamic study ofthe farnesyltransferase inhibitor R115777 asinitial therapy in patients withmetastatic pancreatic adenocarcinoma, J.Clinical Oncology, 21(7):1301-1306(2003)；Dancey JE等, Targetingepidermal growth factor receptor—are we missingthe mark？, Lancet362(9377):62-64(2003))。换言之，存在对EGFR酪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EGFR 抑制剂(Hernes E等,Expression of the epidermal growthfactor receptor family in prostatecarcinoma before and during androgen-independence, British J. Cancer,90(2):449-454 (2004)；Pu YS等, Epidermalgrowth factor receptor inhibitor(PD168393) potentiates cytotoxic effects ofpaclitaxel againstandrogen-independent prostate cancer cells, BiochemicalPharmacology,71(6):751-760 (2006)；Sherwood ER等, Epidermal growth factor-relatedpeptides and the epidermal growth factor receptor in normal andmalignantprostate, World J. Urology, 13(5):290-296 (1995)；Zellweger T等,Expressionpatterns of potential therapeutic targets in prostate cancer,International J.Cancer, 113(4):619-628 (2005)； Canil CM等, Randomized phaseII study oftwo doses of gefitinib in hormone-refractory prostate cancer: atrial of theNational Cancer Institute of Canada-Clinical Trials Group, J.ClinicalOncology, 23(3):455-460 (2005)；Gross M等, A phase II trial ofdocetaxeland erlotinib as first-line therapy for elderly patientswithandrogen-independent prostate cancer, BMC Cancer 7:142 (2007))。