TWI798532B - Ｋｄｍ５ａ基因和ａｔｒｘ基因的應用 - Google Patents
Ｋｄｍ５ａ基因和ａｔｒｘ基因的應用 Download PDFInfo
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Abstract
本發明涉及藥物技術領域，公開了KDM5A基因和ATRX基因的應用。本發明通過以患者的無進展生存期(progression-free survival，PFS)和客觀緩解率(Objective Response Rate，ORR)作為療效指標，驗證了KDM5A基因和ATRX基因變異與西奧羅尼療效的關聯性，對KDM5A基因和ATRX基因突變資訊的檢測，可以指導西奧羅尼的臨床用藥和評價其對小細胞肺癌的療效。
Description
本發明涉及藥物技術領域，具體涉及KDM5A基因和ATRX基因的應用。
本發明要求於2019年3月25日提交中國專利局、申請號為201910228411.9、發明名稱為“KDM5A基因和ATRX基因的應用”的中國專利申請的優先權，其全部內容通過引用結合在本發明中。
肺癌發病率及死亡率均高居惡性腫瘤第一位，小細胞肺癌(small cell lung cancer，SCLC)占肺癌總數的10%~15%，其臨床特點和生物學行為異於其他類型肺癌，表現為倍增時間短，早期易發生轉移，惡性程度極高。未接受治療的患者常在2~4個月內死亡，儘管初治患者對化療較敏感，但很容易產生耐藥性和復發，且對二線化療藥物相對不敏感，預後較差。確診30%~40%的患者處於局限期，60%~70%的患者處於廣泛期。局限期長期生存率在20%，廣泛期則在2%。
依託泊苷/順鉑(EP)方案是目前SCLC主要化療方案，III期臨床研究結果顯示，在局限期SCLC患者中，EP方案的2年和5年生存率優於環磷醯胺/表阿黴素/長春新鹼方案(25%比10%，8%比3%)；對於廣泛期SCLC患者，EP方案同樣可以帶來生存獲益。後續的一系列研究亦證實了EP方案的有效性，因此EP方案成為SCLC的標準一線化療。
伊立替康/順鉑(CPT-11/DDP，IP)方案組和EP方案組，結果顯示，兩組患者的客觀緩解率(ORR)分別為84.4%、67.5%(P=0.02)，中位生存期分別為12.8個月、9.4個月(P=0.002)。拓撲替康聯合最佳支持治療組總生存期、生活品質及症狀的改善均明顯優於單用最佳支持治療組，拓撲替康也成為SCLC的二線化療藥物。總體而言，SCLC缺乏有效的
治療手段，在常規EP或IP方案失敗後，二線可選方案較少(如拓撲替康、紫杉醇等)，且二線治療失敗後，NCCN等指南只推薦支援治療或臨床研究。因此小細胞肺癌，需要探尋更高療效的治療方案。
有鑑於此，本發明的目的在於提供KDM5A基因和/或ATRX基因作為生物標誌物在評價西奧羅尼療效或指導西奧羅尼用藥中的應用。
中文通用名為西奧羅尼的化合物目前處於臨床試驗階段，其化學名為N-(2-氨基苯基)-6-(7-甲氧基喹啉-4-氧)-1-萘醯胺，其結構式如式(I)所示：
本發明以西奧羅尼膠囊針對復發難治的小細胞肺癌進行Ib期臨床試驗，通過對血漿游離腫瘤DNA(circulating tumor DNA，ctDNA)的檢測分析，對548個腫瘤相關基因進行了療效相關生物標誌物的伴隨研究。所有患者在入組前均提取血液樣品，對腫瘤相關基因的基因序列檢測，包括基因突變和拷貝數異常。檢測結果選取了所有突變發生率0.4%以上的基因，以患者的無進展生存期(PFS)和客觀緩解率(ORR)作為療效指標，分析腫瘤相關基因異常與西奧羅尼療效的關聯性。結果顯示，在548個腫瘤相關基因中，只有KDM5A基因和ATRX基因與西奧羅尼療效有顯著的關聯性。
具體試驗結果表明，KDM5A基因和ATRX基因的變異分別與西奧羅尼在小細胞肺癌患者中的PFS和ORR存在顯著相關性。其中，中位PFS在KDM5A基因突變患者中為145天，野生型患者中為27.5天，P值為0.0087；在以客觀緩解(PR，partial response)和非緩解(SD+PD)作為療效評價指標時，ATRX基因突變患者的療效評價顯著優於野生型患者，P值為0.0031。
根據上述技術效果，本發明還對應提出了檢測KDM5A基因和/或ATRX基因變異的產品在製備評價西奧羅尼療效或指導西奧羅尼用藥的產品中的應用；以及KDM5A基因和/或ATRX基因在製備評價西奧羅尼療效或指導西奧羅尼用藥的生物標誌物中的應用。
此外，本發明還提供一種評價西奧羅尼療效或指導西奧羅尼用藥的方法，對小細胞肺癌腫瘤組織進行基因突變的檢測，若KDM5A基因或ATRX基因存在基因突變，則西奧羅尼的療效較佳。
在本發明具體實施方式中，以小細胞肺癌腫瘤組織ctDNA為檢測樣品，採用二代測序技術檢測；基因突變的檢測手段有多種，並不局限於具體實施中對ctDNA的二代測序技術檢測，對腫瘤組織、腫瘤迴圈細胞或人體其它來源的樣品，採用基因測序、PCR(Polymerase chainreaction，聚合酶連鎖反應)、FISH(螢光染色體原位雜交技術，Fluorescence in situ hybridization)、免疫組化等其它檢測手段，均可實現對基因突變的檢測。
由以上技術方案可知，本發明通過以患者的無進展生存期(PFS)和客觀緩解率(ORR)作為療效指標，驗證了KDM5A基因和ATRX基因變異與西奧羅尼療效的關聯性，對KDM5A基因和ATRX基因突變資訊的檢測，可以指導西奧羅尼的臨床用藥和評價其對小細胞肺癌的療效，特別適用於難治、復發的小細胞肺癌。
本發明公開了KDM5A基因和ATRX基因的應用，本領域技術人員可以借鑒本文內容，適當改進工藝參數實現。特別需要指出的是，所有類似的替換和改動對本領域技術人員來說是顯而易見的，它們都被視為包括在本發明。本發明所述應用已經通過較佳實施例進行了描述，相關人員明顯能在不脫離本發明內容、精神和範圍內對本文所述應用進行改動或適當變更與組合，來實現和應用本發明技術。
以下就本發明所提供的KDM5A基因和ATRX基因的應用做進一步說明。
實施例1：西奧羅尼單藥治療復發難治的小細胞肺癌的Ib期臨床試驗
試驗藥物：西奧羅尼膠囊，規格：5mg、25mg。由深圳微芯生物科技股份有限公司生產。
給藥方案：西奧羅尼膠囊按50mg/天、QD給藥(對體重或體表面積不做調整)。每天上午空腹服用，用水送服，完整吞服整粒膠囊。
連續給藥28天為1個治療週期，每個治療周期間無間隔。
病例數：入組25例。
入選標準：
1、年齡
18歲，
75歲，性別不限；
2、組織學或細胞學證實的小細胞肺癌；
3、既往至少接受過2種不同的系統化療方案(其中包括含鉑化療方案)後均出現疾病進展或復發；
4、根據RECIST1.1標準，至少有一個可測量的靶病灶，放療或局部區域治療的病灶必須有疾病進展的影像學證據方可視為靶病灶；
5、ECOG體力評分0-1分；
6、主要器官功能符合以下標準：
血常規：中性粒細胞絕對值
1.5×109/L，血小板
75×109/L，血紅蛋白
80g/L；
血生化：總膽紅素
正常值上限的1.5倍，AST/ALT
正常值上限的2.5倍(若肝轉移，則
正常值上限的5倍)，血清肌酐
正常值上限的1.5倍；
凝血功能：凝血酶原時間-國際標準化比率(PT-INR)<1.5。
7、預期生存時間
3個月；
8、自願簽署書面知情同意書。
治療計畫：
試驗受試者每天口服西奧羅尼膠囊50mg一次，每28天為一個治療週期，治療周期間無停藥間隔期。整個試驗期間，所有受試者均持續治療直至出現以下任一情況(以先發生者為準)：疾病進展、不能耐受的毒性反應、死亡、撤回知情同意或失訪。
療效評估：根據RECIST1.1標準，分別在基線期以及治療後第4週末評估一次，後續每8周重複進行，直到疾病進展。腫瘤影像學檢查包括頸部、胸部、全腹、盆腔CT或MRI(magnetic resonance imaging，磁共振成像)，其他部位檢查根據臨床指徵，有需要時進行，病灶基線和後續評估測量應採用同樣的技術和方法。
安全性評估：包括體格檢查、生命體徵、ECOG體能評分、血常規、尿常規、12導聯ECG、血生化、電解質、凝血功能、心肌酶、肌鈣蛋白、TSH(Thyroid-stimulating hormone，促甲狀腺激素)、FT3、FT4、澱粉酶、超聲心動圖、24小時尿蛋白定量(必要時)、不良事件。
生物標誌物研究：
在受試者首次服用西奧羅尼前和疾病進展時取外周血10毫升，對血漿游離腫瘤DNA(ctDNA)和白細胞提取DNA(對照)進行基因序列的檢測，共包括548個腫瘤相關基因，檢測結果包括基因突變和拷貝數異常，以及對腫瘤突變負荷(tumor mutational burden，TMB)的分析。
臨床試驗結果：
入組患者25例，有療效評價的患者20例，其中有4例患者的最佳療效評價為部分緩解(partial response，PR)，ORR為20%，獲益率60%。結果顯示西奧羅尼單藥治療小細胞肺癌有效。
對已評價患者血漿游離腫瘤DNA(ctDNA)檢測分析，對548個腫瘤相關基因進行了療效相關生物標誌物的伴隨研究。檢測結果選取了所有突變發生率0.4%以上的基因，以患者的無進展生存期(PFS)和客觀緩解(PR)作為療效指標，分析腫瘤相關基因異常與西奧羅尼療效的關聯性。結果顯示，在548個腫瘤相關基因中，只有KDM5A基因和ATRX基因與西奧羅尼療效有顯著的關聯性。
KDM5A基因與患者無進展生存期(PFS)獲益存在顯著相關性，結果見表1。
表1結果顯示，以患者的無進展生存期(PFS)作為療效評價指標，KDM5A基因突變與患者PFS獲益存在顯著相關性。KDM5A基因野生型患者共12例，中位PFS為27.5天；KDM5A基因突變型患者共8例，中位PFS為145天。KDM5A基因突變患者和野生型患者無進展生存期存在顯著統計學差異，P值為0.0087。表明KDM5A基因突變型患者在西奧羅尼治療中能獲得更好的獲益。
ATRX基因與患者客觀緩解(PR)獲益存在顯著相關性，結果見表2。
表2結果顯示，在以客觀緩解(PR)和非緩解(SD+PD)作為療效評價指標時，ATRX基因突變患者共6例，其中出現客觀緩解評價病例4例，占全部突變患者的66.7%，ATRX基因野生型患者共14例，出現客觀緩解評價病例0例，占全部野生型患者的0%。ATRX基因突變患者和野生型患者客觀緩解情況存在顯著統計學差異，P值為0.0031。以上結果表明ATRX基因突變型患者在西奧羅尼治療中能獲得更好的客觀緩解獲益。
以上所述僅是本發明的優選實施方式，應當指出，對於本技術領域的普通技術人員來說，在不脫離本發明原理的前提下，還可以做出若干改進和潤飾，這些改進和潤飾也應視為本發明的保護範圍。
Claims (6)
- 一種KDM5A基因和/或ATRX基因作為生物標誌物在評價西奧羅尼療效或指導西奧羅尼用藥中的應用；所述西奧羅尼療效為西奧羅尼對小細胞肺癌的療效，所述西奧羅尼用藥為對小細胞肺癌患者施用西奧羅尼。
- 一種檢測KDM5A基因和/或ATRX基因變異的製劑在製備評價西奧羅尼療效或指導西奧羅尼用藥的產品中的應用，所述西奧羅尼療效為西奧羅尼對小細胞肺癌的療效，所述西奧羅尼用藥為對小細胞肺癌患者施用西奧羅尼。
- 一種評價西奧羅尼療效或指導西奧羅尼用藥的方法，包括，對小細胞肺癌腫瘤組織進行基因突變的體外檢測，若KDM5A基因或ATRX基因存在基因突變，則西奧羅尼的療效較佳。
- 如請求項3所述方法，其中，所述體外檢測以ctDNA、腫瘤組織、腫瘤迴圈細胞(Circulating Tumor Cell,CTC)或人體其它來源的組織為檢測樣品。
- 如請求項3所述方法，其中，所述體外檢測以基因測序、PCR、FISH、免疫組化(Immunohistochemistry,IHC)、ELISA、Western或流式細胞技術為檢測方法。
- 一種西奧羅尼在製備用於治療KDM5A基因或ATRX基因存在基因突變的小細胞肺癌患者的藥物中的用途。
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| MM4A | Annulment or lapse of patent due to non-payment of fees |