(三軍 查岱龍) GW5074 ( targeting C-Raf ) + sorafenib 強化癌症治療

三總找出抗癌藥新組合 可望治8成癌症 發稿時間：2016/06/02（中央社記者張茗喧台北2日電）癌症用藥新突破，三總團隊研究5年發現，把兩種特定抗癌藥物並用竟能消滅癌細胞，不僅能解決抗藥性問題，劑量只要原本的1/10，更重要的是，對8成癌症都有效。三軍總醫院外科部主任查岱龍自2007年帶領研究團隊，耗時5年找出創新藥物組合，包含2種小分子藥物臨床抗癌藥物「Sorafenib」及純化合物「GW5074」，只要原藥物1/10劑量，就能發揮比原先更好的抗癌效果，研究成果已發表於知名癌症研究雜誌「Cancer Research」。查岱龍說，目前治療癌症的標靶藥物多半透過抑制蛋白活性，達到減輕癌症症狀效果，患者服藥初期可能有效，但過了半年到1年，癌細胞就會突變產生抗藥性，不僅原藥物失效、癌症還可能復發得更嚴重。這次新發現的藥物組合，則是改變蛋白結構，服用後可破壞癌細胞粒線體，彷彿「把癌細胞發電機關掉，再用轟炸機轟炸」，直接消滅癌細胞，克服抗藥性難題。研究團隊在小鼠實驗中，將腎臟癌細胞植入小鼠腎臟，並等到癌細胞轉移到全身才開始給藥治療，使用傳統藥物的小鼠4至6週就全數死亡，而使用組合藥物的小鼠有7、8成存活，且幾乎康復。查岱龍指出，新藥組合不但副作用少，不易產生抗藥性，對已有抗藥性的患者也有效，而且只需原藥物1/10劑量，是癌症精準醫學的一大突破。更重要的是，多達8成癌症都適用這項藥物組合，針對肺癌、大腸癌、乳癌、黑色素細胞癌效果特別好，三總團隊正著手研究檢測方法，未來患者只要抽血就能知道是否適用這項療法。查岱龍表示，這項組合治療案已成功在台灣及美國專利申請，並逐步在其他國家專利申請中，目前也已技轉生技公司進行動物毒性及臨床一期人體試驗。1050602

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy  Cancer Res; 75(17); 3568–82.  2015 AACR. Mitochondria are the powerhouses of cells. Mitochondrial CRaf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its Nterminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-RafS338) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPKS308), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEFC-Raf /  or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPKS308, this drug–target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-RafS338 and pDAPKS308 translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPKS308 to DAPK. PP2A then dissociated from the C-Raf–DAPK complex and induced profound cancer cell death. Increased pDAPKS308 modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPKS308 may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation.