生物谷Bioon.net 訊 賓夕法尼亞大學(xué)醫(yī)學(xué)院的研究人員開發(fā)了一種新穎的方法可攻擊含有BRCA1或BRCA2基因變異的乳癌患者的腫瘤,，能夠減緩85%乳癌晚期患者的腫瘤生長,，這項(xiàng)研究結(jié)果發(fā)布在7月6日的The Lancet雜志上。
這項(xiàng)研究的參與者Domchek教授表示,，這是他們首次利用患者的遺傳學(xué)原因，并將其作為靶標(biāo)開發(fā)療法。通常情況下研究會觀察腫瘤本身的發(fā)展,，然后嘗試?yán)斫馊绾伟邢蚨ㄎ荒[瘤。在這項(xiàng)研究中,，所有的患者都繼承了BRCA1基因或BRCA2基因的變異,，因此研究人員能夠利用這一特點(diǎn)開發(fā)療法,，這種療法或能減少對患者造成的副作用。提示：生物谷啟用新域名www.bioon.net
所開發(fā)的新作用劑olaparib能夠抑制一種叫PARP的蛋白,。PARP和BRCA蛋白都參與DNA修復(fù),。細(xì)胞能夠完成DNA修復(fù)只需其中的一個(gè)蛋白，然而當(dāng)抑制缺乏BRCA基因的腫瘤中的PARP蛋白對于細(xì)胞來說很難承受,，會致其死亡,。
Domchek解釋說："如果給一個(gè)癌細(xì)胞施加太多的壓力，它將不能承受并最終滅亡,。因?yàn)槔^承有BRCA變異的患者中的非腫瘤細(xì)胞仍然保留BRCA基因的一個(gè)正?？截悾韵鄬碚f他們不會受PARP抑制的影響,。這類藥物可能對腫瘤細(xì)胞具有強(qiáng)大殺傷力,，且對正常細(xì)胞毒性更小，這對于癌癥治療來說是很重要的,。
這項(xiàng)研究涉及54個(gè)患者,，她們被平均分成兩組。第一組27人每天兩次每次均口服400毫克olaparib,，第二組患者每天兩次每次均口服100毫克olaparib,。結(jié)果表明高劑量抑制劑似乎更具抵抗疾病的威力，在高劑量組中1位患者（4%）的腫瘤出現(xiàn)完全消退,，10位患者（37%）表現(xiàn)出腫瘤明顯減小,，另外的12位患者（44%）表現(xiàn)出疾病穩(wěn)定或腫瘤部分減小。在低劑量的一組,，6位患者（22%）表現(xiàn)出明顯腫瘤減小,，12位患者（44%）腫瘤部分減小或保持穩(wěn)定。
這項(xiàng)研究結(jié)果是令人興奮的,，但是在olaparib或其他PARP抑制劑進(jìn)入常規(guī)使用前還需要進(jìn)行一系列必要的臨床研究,。對于患者來說參加這些臨床測試也是很重要的，可以確定更好的藥物使用方式,，即單獨(dú)或聯(lián)合用藥,，此外也需要最終確立這種抑制劑效果好于其他藥物。
PARP抑制劑是癌癥藥物開發(fā)的重要變革,，這是一種與眾不同的癌癥療法,。從腫瘤學(xué)角度來講，這確實(shí)是首次在遺傳易感性的基礎(chǔ)上開發(fā)藥物,，這或?qū)㈤_辟一種藥物開發(fā)的全新方式,。(生物谷Bioon.net)
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生 物 谷推薦原文出處：
The Lancet doi:10.1016/S0140-6736(10)60892-6
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
Dr Andrew Tutt PhD a , Mark Robson MD b, Judy E Garber MD c, Susan M Domchek MD d, M William Audeh MD e, Prof Jeffrey N Weitzel MD f, Prof Michael Friedlander PhD g, Prof Banu Arun MD h, Niklas Loman MD i, Prof Rita K Schmutzler MD j, Andrew Wardley MD k, Gillian Mitchell MD l, Helena Earl PhD m, Mark Wickens BSc n, Prof James Carmichael MD n
Background
Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.
Methods
Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234.
Findings
Patients had been given a median of three previous chemotherapy regimens (range 1—5 in cohort 1, and 2—4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25—59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11—41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).
Interpretation
The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.
