摘要：肺癌是全球最惡性的疾病之一，而肺癌造成死亡主要是因為轉移、抗藥性與復發。目前治療癌症的藥物大多針對分裂快速的癌細胞，然而，腫瘤並非由單一種癌細胞組成。其中的癌幹細胞可能造成癌症的生成、化療與放療抗藥性、遠端轉移與復發;我們先前研究發現細胞間的交互作用會加速癌症幹細胞的生成。找出針對癌幹細胞的標的藥物乃為當務之急。由我們先前生技醫藥國家型科技計畫的結果，我們成功地找出肺癌幹細胞標誌(CDXCSC1 與 CDXCSC2)，並建立體外模型(CSCs/CAF feeders-co-culture system)當作藥物篩選平台。而這樣的平台也適用於其他由病人萃取的細胞(CL141, CL152 等等)，發展以病人為導向的治療。藉由這樣的系統，我們已經成功的找出可以針對肺癌幹細胞的兩大類藥物，並能減少化療藥物所誘發的抗藥性與幹細胞特性(如 AE1024)。另外一類藥物則能阻斷肺癌幹細胞與癌症相關纖維母細胞之間的微環境，減少癌症幹細胞的特性(如 CHI-0107)。這兩類藥物在體外模式與動物實驗中均能減少癌症幹細胞於腫瘤中的比例，並明顯抑制肺腺癌腫瘤的生長。 這樣初步的結果對癌症治療的發展有一大進步，而我們也提出未來三年的幾個目標，希望這以癌幹細胞為標靶的藥物能針對具抗藥性的肺癌病人據治療潛力, 以進入臨床與新藥申請階段。 1. 找出癌症幹細胞旁分泌系統中的阻斷藥物 2. 透過我們的肺癌幹細胞系統與其他藥物抗藥性細胞株作為其他藥物的評估平台；並利用病人組織中得到的癌細胞於實驗動物中進行相關藥物之臨床試驗前評估 3. 利用肺癌幹細胞的標誌(CDXCSC1 與 CDXCSC2)來找出針對肺癌幹細胞的合併藥物治療方式
Abstract: Lung cancer is the most common fatal malignancy in the world; the majority of cancer-caused deaths are results from metastasis, drug-resistance and tumor recurrence. Reviews of current treatment strategies indicated that most of the interventions aimed at proliferating cancer cells; however, the solid tumor is a complex “organ” with heterogeneous cell population. Our previous study indicated that the complicated cell–cell interactions that form the tumor microenvironment (or niche) could facilitate cancer stem/initiating cells (CSCs), which may contribute to carcinogenesis, chemo- or radio-resistance, metastasis, and recurrence. Targeting on CSCs has been suggested as one of the key issues to cure cancer. Based on our previous NRPB project (2010-2014), we have successfully identified the lung CSCs markers (CDXCSC1 and CDXCSC2) and established an in vitro model (CSCs/CAF feeders-co-culture system) for anti-CSCs drug screening system. This system can also be applied to the other primary cultured lung cancer cells (CL141, CL152, …etc) for the personalized drug-screening system. Focusing on targeting lung CSCs, we have identified at least two categories of leading compounds, one can directly target on CSCs to overcome the chemotherapy-induced drug resistance and cancer stemness (e.g., AE1024); another one can block the paracrine interactions between the CSCs and the micro-environmental supporting feeder cells, CAFs; which can also limit the cancer stemness (e.g., CHI-0107). Both of these two compounds have been validated on the ability of reducing lung CSCs populations and significantly inhibit tumor growth in lung adenocarcinoma both in vitro model, as well as, in the xenograft NOD/SCID mice model. According to these preliminary results, we believe that our novel finding should have great impacts on anti-cancer therapy and thus we propose the following three specific aims for the coming three years on promoting the development of new drug targeting on lung CSCs or the niche for the pre-clinical trials and IND application focusing on the lung cancer patients with drug resistances. (1) To discover and optimize the drugs targeting on the cancer stemness paracrine system. Leads (AE1024 & CHI-0107) optimization and design combination therapy for pre-clinical trials. (2) Using the established CSC/CAFs model and other primary cultured drug-resistant lung adenocarcinoma cell lines for further validation; and may process the pre-clinical trial using the patient-derived xenograft (PDX) NSG mice. (3) The combination multiple-targeting therapy with lung CSCs markers (CDXCSC1 and CDXCSC2) for specific targeting on CSCs.