乳腺癌患者福音:新药奥拉帕尼获批上市,针对乳腺癌基因突变!

新闻乳腺癌患者福音:新药奥拉帕尼获批上市,针对乳腺癌基因突变!

美国食品和药物管理局批准了乳腺癌新药,旨在治疗与BRCA基因突变有关的乳腺癌。 这些突变基因,BRCA1和BRCA2,在2013年间首次崭露头角,当时女演员兼导演安吉莉娜·朱莉宣布她进行了预防性双乳房切除术。因为朱莉携带了BRCA1基因,这大大提高了女性患乳腺癌和卵巢癌的几率。 现在,FDA正在扩大批准lynparza(奥拉帕尼),针对与BRCA相关的乳腺癌。Lynparza是一组强大的新癌症药物,被称为PARP抑制剂,它是这类药物中第一个被批准用于预防乳腺癌的药物。PARP抑制剂已经被用来治疗晚期,BRCA突变的卵巢癌,现在治疗BRCA突变的特定类型的乳腺癌的疗效。 “这项研究证实了当前开发药物的范例,这种药物针对的是癌症的潜在遗传病因,通常是癌症类型”。根据FDA,BRCA基因突变是乳腺癌的遗传因素。该机构称,这些异常基因也与非遗传性乳腺肿瘤有关。 当功能正常时,BRCA实际上有助于修复受损细胞的DNA,防止肿瘤,但是当BRCA1和BRCA2出错时就会促进乳腺癌的形成。PARP抑制剂的药物如Lynparza可以干扰突变的BRCA乳腺细胞的功能,导致他们死亡,或者停止复制,从而减慢肿瘤生长。详情>>

2018-01-17 00:00:00
结直肠癌的新生物标记物

新闻结直肠癌的新生物标记物

Researchers from the University of Luxembourg found a new biomarker for colorectal cancer (CRC) that might improve therapy and survival rates of patients. Biomarkers are measurable biological indicators for a specific disease, such as changes in the amounts of certain proteins that occur in combination with certain illnesses. Such biomarkers help physicians to diagnose a condition, identify the disease stage, and determine a patient's risk for recurrence of the disease. This supports the doctor in choosing the best-fitting treatment plan. For colorectal cancer (CRC), early detection and classification is especially important, as, for example, not all Stage II patients benefit from chemotherapy. Especially identifying patients at risk for recurrence during the early course of the disease might help clinicians. However, there are still too few prognostic markers for colorectal cancer known so that too many patients still suffer needlessly from side effects of the chemotherapy without having real benefits. In a study supported by the Fondation Cancer and the Luxembourg National Research Fund (FNR), an interdisciplinary team composed of experimental and computational scientists from the Molecular Disease Mechanisms (MDM) group at the Life Sciences Research Unit of the University of Luxembourg has recently discovered a new promising biomarker for colorectal cancer. Especially in early stages, such markers might allow to classify patients into "high" and "low" risk group. Such a classification may help oncologists choosing the adequate treatment regimens for a given patient. "The strength of the study lies in the concerted effort and the interdisciplinary approaches, involving bioinformatics and state-of-the-art experimental techniques. Especially the financial support from the Fondation Cancer has been crucial for the successful completion of our biomarker projects," explains Dr. Elisabeth Letellier, principal investigator in the MDM group. Using a previously established meta-analysis of publicly available gene expression data, the research team identified the protein family "Myosin" and especially the protein "MYO5B" as potential prognostic marker in the context of CRC. Members of this family are recognised to play a major role in cellular trafficking and polarisation of cells and have recently been reported to be closely associated with several types of cancer. The meta-analysis as well as an independent patient cohort study revealed that the concentration of "MYO5B" decreases as the disease progresses. CRC patients with low "MYO5B" expression had significantly lower chances of disease- and metastasis-free survival. Altogether, the data collected from the Molecular Disease Mechanisms (MDM) group identify MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy. LSRU-team identifies new prognostic biomarkers for CRC "Together with our partners, we have been able to set up a high-quality tissue collection from colon cancer patients here in Luxembourg. Only the close collaboration with the Integrated Biobank of Luxembourg (IBBL), the Laboratoire National de Santé (LNS), the Centre d'Investigation et d'Épidémiologie Clinique (CIEC) and local hospitals, primarily the Centre Hospitalier Emile Mayrisch (CHEM), has allowed us to establish these important foundations for further colon cancer projects," says Prof. Dr. Serge Haan, Head of the MDM group. In this research project, the MDM group has analysed the value of a biomarker in a Luxembourgish colorectal cancer (CRC) collection. Indeed, they have established a CRC collection that includes tissue samples from patients. This collection is of high value as it allows, for example, the identification of new prognostic biomarkers for CRC as highlighted in the present project.详情>>

2018-01-15 00:00:00
科学家发现脑癌进展和药物反应的生物标志物

新闻科学家发现脑癌进展和药物反应的生物标志物

Scientists at the Icahn School of Medicine at Mount Sinai, Sema4, and collaborating institutions including Colorado State University and Fred Hutchinson Cancer Center reported results today from a glioblastoma study in which they validated a biomarker indicative of a patient's prognosis and likely response to specific therapies. The article appeared in the October 15 issue of Cancer Research. Glioblastoma is a highly aggressive and heterogeneous form of brain cancer, with a median survival time from diagnosis of just one year. Previous efforts to classify glioblastoma tumors into molecular subtypes for precision treatment have been largely unsuccessful. In this study, scientists developed an innovative computational method to classify tumors based on their dependency on a molecule, known as BUB1B, that some glioblastomas need to survive. The project revealed new tumor subtypes and found that BUB1B-sensitive tumors had significantly worse prognosis but were more likely to respond to many drugs already in clinical use. "It was truly remarkable to see our predictive model yield a new set of molecular subtypes, which appear to be far more indicative of prognosis and therapeutic response than existing subtypes," said Jun Zhu, PhD, Head of Data Sciences at Sema4, Professor of Genetics and Genomic Sciences at Mount Sinai, and senior author of the paper. "For patients who receive the grim diagnosis of glioblastoma, this signals new hope for tailored treatment more likely to be effective against their cancer." "This research is an outstanding example of how theoreticians working with complex datasets, and clinicians on the frontlines of patient care, can collaborate to uncover new insights into cancer biology that will directly impact clinical decision-making," said Raymund Yong, MD, Assistant Professor of Neurosurgery and Assistant Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, who made a significant contribution to tumor samples, glioma stem cells, and in vitro experiments in the paper. Eric Schadt, PhD, Sema4 CEO and Dean for Precision Medicine at Mount Sinai, added: "These findings underscore the significant potential we see to improve patient outcomes by investing in predictive modeling of even the most complex types of cancer. We look forward to building on this collaborative project and moving toward development of a diagnostic test that could help physicians better understand and treat their patients' glioblastoma cases."详情>>

2017-10-20 00:00:00
生物标记物如何帮助早期临床试验设计

新闻生物标记物如何帮助早期临床试验设计

Biomarkers could be a boon for a new era of medicine. Finding the best method to hone in on certain genes, cells, or molecules associated with tumors could give physicians more flexibility in identifying the drugs that will deliver the best therapy for their patients. Clinical investigators have incorporated these markers into the later stages of clinical trials to assist in reducing sample size and refining the patient population to get a better sense of the drug’s efficacy. However, the traditional clinical trial design does not accommodate the biomarker-oriented approach within the earlier stages of the experiment. Scott Marshall, Ph.D., Managing Director, Translational Informatics & Diagnostics at Precision for Medicine believes there are opportunities to incorporate these metrics into early-phase trials. His company is the, “first precision medicine research organization,” where they focus on biomarker driven clinical research to support life science companies. Marshall’s background in biostatistics and formal training in statistical genetics and genomics has driven his career in translational research. He has analyzed the integration of biomarker data in clinical study contexts where the goal is often to answer questions related to drug development, such as how to characterize the mechanism of action associated with certain therapeutics for purposes of drug target identification and stratifying patient populations. Marshall shared his insights with Drug Discovery & Development regarding the benefit these biomarkers could yield in early-stage trials. DD&D: What are some types of biomarkers that could be beneficial in the early stages of clinical trials? Marshall: A variety of biomarkers could be considered in the early stages of clinical trials and in large part the type of biomarker may be driven by the scientific objective. For example, is a biomarker being used to support dosing or to drive patient selection strategies and clinical trial design? Investigators could use biomarkers like immunohistochemistry (IHC) or genetic mutations to stratify patients to support various biomarker-guided adaptive designs and development of companion diagnostics. However, to me, the key is to look at a variety of types of biological variation, and evaluate it all in the context of the clinical outcomes. We have been amazed at the new “multi-omic” signatures that we have uncovered. This approach of biomarker data management and informatics is where we see the true promise of biomarkers on display. DD&D: Is there a specific disease research area where investigators could harness this approach? Marshall: Where we have seen the most success has been in the oncology space where there is a much better understanding of the biology of the disease and what type of biological variation is underlying treatment response, non-response and acquired resistance. However, it is hard to imagine any trial without a biomarker approach, say, five years from now. The cost of therapeutic development is so significant, biomarker driven approaches is a clear way to reduce cost and timelines from discovery to approval to reimbursement. DD&D: Do you see challenges or opportunities in other areas where a focus on biomarkers could work with trial design? Marshall: An area such as central nervous system disorders presents challenges due to the heterogeneity of the diseases; however, we are seeing progress being made in terms of developing targeted therapeutics. And it seems like there may be opportunities within the autoimmune disease space or immunological conditions, as well as in rare and orphan diseases. DD&D: What type of study designs could benefit from incorporating diagnosis based on biomarkers? Marshall: There are various biomarker-guided (adaptive) study designs, leveraging both Bayesian and Frequentist methodologies. However, one particular design gaining significant traction and proving to be successful is the basket study type design. This is especially useful when exploring rare mutations and for selecting patients independent of tumor histology. DD&D: What are the overall benefits of incorporating biomarkers into the first phase of clinical development? Marshall: Incorporating biomarkers into earlier phases of clinical development can serve multiple purposes, ranging from helping to guide dose selection, to characterization of mechanism of action, to providing a strategy to inform patient stratification or selection. Additionally, the traditional stepwise march from Phase I to Phase II to Phase III has dramatically changed. Today, we see basket studies and adaptive designs, starting in Phase I with protocols that are amended to evolve directly into a pivotal study. So, this idea of early phase clinical development is changing. Biomarkers are the driver of these changes, and are significantly lowering the time and costs of clinical development. Ultimately, our goal is to support the development of safe and effective therapies for patients in a more streamlined and efficient manner. Biomarkers can help us do this, and I am excited to work with a passionate team every day to help make this happen.详情>>

2017-10-17 00:00:00
一个接一个地编辑大肠癌细胞基因组的基因,揭示新的靶标

新闻一个接一个地编辑大肠癌细胞基因组的基因,揭示新的靶标

Cancers driven by mutations in the KRAS gene are among the most deadly. For decades, researchers have tried unsuccessfully to directly target mutant KRAS proteins as a means to treat tumors. Instead of targeting mutant KRAS itself, researchers at University of California San Diego School of Medicine are now looking for other genes or molecules that, when inhibited, kill cancer cells only when KRAS is also mutated. The team used the CRISPR-Cas9 gene editing technique to systematically inactivate every gene in the genome of human colorectal cancer cells with and without mutant KRAS. They found that growth of KRAS-mutant colorectal cancer cells in mice was reduced by approximately 50 percent when two genes that encode metabolic enzymes — NADK and KHK — were also inactivated. The study, published September 27 in Cancer Research, provides potential new drug targets for KRAS-driven cancers. “We did not get these same results with cancer cells grown in the lab — the growth inhibition we saw when the NADK and KHK genes were inactivated only occurs in tumors in a mammalian system, in a more realistic microenvironment where the tumor has to survive,” said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “That suggests that the metabolic dependencies of tumor cells growing in a laboratory dish may differ dramatically compared to the same cells growing in a living system, underscoring potential limitations of standard laboratory-based cancer cell growth tests.” Approximately 20 to 30 percent of all human cancers have mutations in the KRAS gene. KRAS mutations occur in many of the most lethal and most difficult to treat cancers, including lung, pancreatic and colorectal cancer. KRAS mutant cancer cells are able to rewire their metabolism in a way that gives them a growth advantage compared to normal cells. Rana’s approach to treating KRAS-driven cancers — inhibiting other genes or molecules in addition to KRAS — is called “synthetic lethality” because the intervention is only lethal to the mutated cells. In a previous study, Rana’s team used a library of microRNAs, small pieces of genetic material, to systematically block protein production and look for those inhibitions that are synthetic lethal in combination with KRAS mutations. In their latest study, Rana’s team used CRISPR-Cas9 to systematically inactivate genes in two human colorectal cancer cell lines — one with normal KRAS and one with a mutant KRAS. They then tested the ability of each of these cell lines to grow as tumors in mice. They found that inactivating two metabolic enzymes, NADK and KHK, reduced the growth of KRAS-mutant tumors by approximately 50 percent, but had no effect on normal KRAS tumors. They also blocked these same enzymes with commercially available small molecule inhibitors and saw significant reduction in tumor growth in mice only in tumor cells with mutant KRAS. Rana and team also identified several new genes that, when inactivated, had the opposite effect — they increased KRAS-mutant tumor growth, but not the growth of normal KRAS tumors. These types of genes are known as “tumor suppressors” because they normally keep cancer cell growth in check. “One of the most surprising findings from our study is how performing this type of genetic screen directly in a mammalian microenvironment revealed not only new synthetic lethal interactions, but also new tumor suppressor genes that are dependent on KRAS mutations,” said first author Edwin Yau, MD, PhD, a hematology/oncology and Cancer Therapeutics Training Program fellow in Rana’s lab. One of these new tumor suppressor genes encodes INO80C, a large multi-subunit protein that, among other things, stabilizes the genome. Rana, Yau and colleagues are now taking steps to carry their findings forward, with the ultimate goal of better understanding how KRAS-mutant cancers develop and translating these insights into developing new therapies to stop them.详情>>

2017-09-30 00:00:00
CSCO 2017 肺癌精准治疗2.0时代 看强效精准药物为肺癌患者带来的获益

新闻CSCO 2017 肺癌精准治疗2.0时代 看强效精准药物为肺癌患者带来的获益

    非小细胞肺癌(NSCLC)自表皮生长因子受体(EGFR)突变的发现和验证开始可谓打开了精准治疗时代的大门近年来这一领域获得突飞猛进的发展。并且EGFR-酪氨酸激酶抑制剂(TKI)类药物的发现与发展一直在引领着肺癌精准医学之路的前进方向。从一代以吉非替尼为代表的EGFR-TKI药物确定地位到当前第三代EGFR-TKI奥希替尼所带来的强效、精准的令人叹服的治疗疗效与发展速度并且通过进入医保更新目录的助推让NSCLC诊疗进入了崭新的2.0时代。为此本版回顾EGFR-TKI药物发展历史、描绘当前NSCLC诊疗2.0时代并进一步梳理EGFR-TKI耐药相关机制、药物策略的探索、明确耐药后行二次活检的临床意义,从而全方位地为广大读者呈现当前肺癌诊疗领域的先进理念,提高我国肺癌诊疗水平,进而为NSCLC患者带来获益。 纵观发展历史肺癌精准医学步入2.0新时代 肺癌精准医学1.0时代开启开创经典诊疗模式     近年来肺癌诊疗领域的发展从单病种到根据组织分期指导下的放化疗治疗再到当前根据分子分型决定治疗方案可谓进入了肺癌精准治疗的时代。最早自IDEAL研究首次提示了EGFR-TKI疗效可能与种族相关,使得EGFR-TKI得以问世。2009年公布的IPASS研究为全球首个确定了优势人群靶向治疗的研究开启了肺癌精准医学1.0时代。此后多项研究以突变状态选择人群证实在相对的人群中靶向治疗获益明显。直至今日,EGFR-TKI的地位已不容质疑。在这一学术发展历程当中,EGFR突变的发现和不断验证可谓开启了晚期NSCLC精准治疗的时代且EFGR-TKI的发现与发展一直在引领着肺癌精准医学之路的前进方向。 1.0时代之下持续创新、勇往直前     在EGFR通路上的药物与治疗决策的创新并未止步。研究者们不断地优化治疗策略旨在尽可能地延长EGFR突变NSCLC患者的生存。 思考如何进一步提高一线治疗疗效     首先对于EGFR-TKI与其他药物联合治疗是否能够优化一线治疗这一命题展开探索。有研究分别对EGFR-TKI联合化疗、联合抗血管生成治疗的疗效予以验证。另一方面为提高疗效着力研发第二、三代EGFR-TKI药物。阿法替尼、达克替尼都与一代EGFR-TKI进行了疗效和安全性的对比但一线治疗选择需要综合考虑疗效及安全性二代TKI安全性上的劣势极大地限制其成为一线新标准。 EGFR-TKI成为无症状脑转移患者的新标准治疗     我国学者开展的多中心BRAIN(CTONG1201)研究显示埃克替尼能够改善EGFR突变脑转移NSCLC患者的无进展生存期(PFS),埃克替尼组客观缓解率(ORR)和疾病控制率(DCR)优于WBR±化疗,TKI药物可被用于晚期EGFR突变脑转移NSCLC患者一线治疗。 寻求EGFR-TKI耐药后策略,奥希替尼强势逆袭     发生EGFRT790M突变的耐药患者中由AURA系列研究尤其是Ⅲ期AURA3研究(图1~2)充分证实在T790M突变患者中带来的生存获益确立了奥希替尼的标准治疗地位同时也为NSCLC脑转移患者带来新希望深刻地改变了NSCLC患者的临床实践。 图1 AURA3研究中两组患者的PFS的KM曲线 图2 AURA3研究CNS亚组患者PFS的KM曲线 迈向新的2.0时代开创肺癌精准医学新未来 EGFR-TKI进入医保,得以帮助更多患者     自今年吉非替尼(易瑞沙)等EGFR-TKI药物被列入国家乙类医保名录同时进行了国家药品价格谈判吉非替尼的治疗费用仅为几千元已经不同于往日动辄上万元的药物费用是当前患者用得起的进口EGFR-TKI。 EGFR-TKI拓展应用于早期肺癌领域     ADJUVANT研究探索了EGFR-TKI在早期肺癌辅助治疗中的应用。结果达到主要研究终点(图3),吉非替尼疗效显着优于标准化疗方案中位无病生存期(DFS)为28.7个月对18.0个月风险比(HR)0.60,P=0.005;3年DFS率分别为34%和27%。吉非替尼的不良事件(AE)与既往报道一致未出现间质性肺病,证实吉非替尼2年的辅助治疗时间是合理安全的吉非替尼辅助治疗或可成为可切除N1/N2的EGFR突变NSCLC患者的首选辅助治疗方案。 图3 ADJUVANT研究中患者DFS的KM曲线图 奥希替尼有望成为新时代EGFR突变患者一线新标准     在刚刚落幕的2017欧洲肿瘤内科学会(ESMO)年会上让人期待已久的FLAURA研究正式亮相。显示对比EGFR-TKI标准治疗药物奥希替尼在局部晚期或转移性EGFR阳性NSCLC中一线治疗显着延长患者PFS达到18.9个月(图4~5),降低了54%的疾病进展风险或将就此改变EGFR突变阳性晚期NSCLC患者的一线治疗策略。综上肺癌精准治疗2.0时代基于分子分型的肺癌全程管理理念,TKI成为EGFR突变患者全程管理中不可或缺的部分。展望肺癌精准医学时代的未来必将更加精彩 ! 图4 FLAURA研究两组患者PFS的KM曲线 图5 FLAURA研究两组患者OS的KM曲线 探究TKI耐药患者治疗的规范与艺术     随着NSCLC诊疗进入精准治疗时代,NSCLC的治疗因EGFR-TKI的发展而不断改变。但EGFR-TKI的获得性耐药仍是临床诊疗当中不可避免的难题,为此需要思考如何优化EGFR-TKI耐药患者的生存? 探讨最佳干预时机     对于NSCLC患者来讲耐药进程从早到晚分别表现为①从发病机制引发分子耐药的产生;②进一步发现影像学异常发生影像学耐药;③临床表现出临床耐药。其中临床耐药是判断耐药的线索和征象影像学耐药是判断耐药的基础和标准而分子耐药能明确具体的耐药机制、更好地指导后续治疗。那么最佳的干预时机是在什么时候?通过既往研究结果显示目前影像学耐药阶段予以T790M耐药干预的时机似乎是目前的金标准。因此在患者发生影像学进展时即进行T790M检测如果结果为阳性患者即应首选奥希替尼治疗。 最佳的血液检测平台     ctDNA常见的检测方法包括聚合酶链式反应(PCR)为基础的多种方法和第二代测序(NGS)法。因ctDNA检测需要较为敏感的方法研究显示数字PCR及NGS等高敏感的检测方法对ctDNA中T790M的检出率更高。两种平台的敏感性和特异性需要更多研究验证如世界肺癌大会(WCLC)上公布的ADELOS研究数据以期获得标准的答案。 明确优势人群,提高药物获益程度     中枢神经系统(CNS)转移是晚期NSCLC患者中常见的情况因为缺乏有效的治疗手段,往往导致预后较差。AURA3研究亚组分析显示(图2),CNS亚组PFS获益与总人群一致接受奥希替尼治疗具有更高的ORR。此外奥希替尼在伴有软脑膜转移患者中疗效也颇为喜人。一项基于RANO-LM1评分的独立的影像学检查回顾性分析表明基线时奥希替尼组中软脑膜转移患者占CNS转移患者的7/116。7例软脑膜转移患者中的4例软脑膜病灶得到缓解其中2例完全缓解(CR),2例部分缓解(PR)。软脑膜病灶得到缓解的患者中同样观察到CNS及系统性病灶有获益。 从一代TKI耐药看耐药后活检(二次活检)的意义 探寻克服肿瘤获得性耐药方法强化T790M突变检测     肿瘤治疗的演变是一场从组织分型到分子分型的变革其中EGFR-TKI大幅改善EGFR突变患者的生存。然而靶向治疗会不可避免地出现耐药问题,EGFR-TKI获得性耐药的生物学机制包括药物靶点本身变异、其他信号传导通路激活等其中T790M突变是第一、二代EGFR-TKI产生获得性耐药最常见的机制。为了有效解决患者耐药问题研究者针对耐药机制研发新型药物经过大型临床研证实奥希替尼成为T790M突变患者治疗的标准方案显着延长无疾病生存时间达化疗的2倍(10.1个月对4.4个月),疾病进展风险显着降低70%,P<0.001(图1)。因此EGFR-TKI耐药患者必须进行T790M突变检测从而为T790M突变患者提供奥希替尼这一有效治疗药物。同时国内外权威指南均强调EGFR-TKI耐药后应进行T790M突变检测。美国国家癌症综合网络(NCCN)2017版NSCLC指南指出在二线治疗前推荐二次活检或血液检查以明确EGFR-TKI耐药机制因为目前研究发现EGFR-TKI有多重耐药机制其中T790M突变是最常见的类型。中国原发性肺癌诊治专家共识(2016版)推荐所有NSCLC患者都应进行EGFR基因突变检测对EGFR-TKI治疗失败后的NSCLC患者应再次检测明确T790M、MET、HER2等基因的状态。 T790M突变检测的相关问题探讨 T790M突变检测的标本类型     包括组织活检、细胞学标本和血液标本。组织学、细胞学标本可使用ARMS方法进行检测血液学标本应使用dPCR或NGS等高灵敏度方法。以组织检测为参照不同血浆检测法的敏感性和特异性不同。相对于ARMS平台数字PCR对于血浆T790M突变检测敏感性较高。多项国际领域权威指南均一致推荐耐药患者应先行组织活检血液检测可作为有效补充。 二次活检的临床可行性     活检的部位可以选择原有病灶增大(肺部病灶、转移的淋巴结或新增的转移灶(颅脑、骨、肾上腺、肝、肺、胸膜、心包、腹膜、皮肤。选择合适的技术方面考虑技术的可获得性、安全性、标本的类型和可用于检测的细胞数量等。一项回顾性评估二次活检临床可行性的Ⅱ期临床研究显示约70%耐药患者可接受二次活检。另一项来自日本的晚期NSCLC患者二次活检现状的回顾性分析显示二次活检的成功率为79.5%,其中经皮肺穿刺二次活检成功率略高于经支气管二次活检。美国克利夫兰诊所对晚期肺癌患者组织再活检的临床经验进行总结肺癌患者重复活检并发症发生率随活检次数增加反而逐渐降低。以上临床经验显示组织再活检可行性高安全可控获益风险比较高。由此掌握组织活检技能的意义就是精确地指导患者用药。望今后我国学者开展更多组织再活检的多学科协作真正为我国NSCLC的精准治疗助力 !详情>>

2017-09-28 00:00:00
约翰霍普金斯医学院院长:使用21世纪的信息数据使患者获益

新闻约翰霍普金斯医学院院长:使用21世纪的信息数据使患者获益

在北京协和医学院百年校庆来临之际,北京协和医学院第七届国际医学教育研讨会于9月21日正式举行。会议邀请了国内外知名医学教育专家,共同探讨全球医学教育的发展方向和趋势。 十五年前开始的北京协和医学院国际医学教育研讨会是协和医学院对外交流与合作的主要合作平台之一,也推动了协和医学教育的改革和发展。 在会上,中国医学科学院院长、北京协和医学院校长曹雪涛院士介绍了北京协和医学院的课程改革。创建于1917年的北京协和医学院,是中国现代医学教育的摇篮,开创了我国八年制临床医学教育先河,确立了医预科、八年长学制和住院医师等医学生培养制度,创建了现代中国护理教育和药学专业,在世界上首创定县公共卫生模式,成功开拓现代公共卫生教育,对中国医学医教研一体化发展以及药学、预防医学、公共卫生等健康事业发展起到了决定性作用。 正如曹院长反复提及的“传承卓越,引领创新”,协和医学院自诞生之日起,一直就与世界同步,甚至做到了领先。一百多年前的美国正在进行医学教育改革,其中最成功的就是约翰霍普金斯大学,而协和医学院就是按照约翰霍普金斯大学医学院的模式建立的。 在当天的研讨会上,约翰霍普金斯大学医学院院长、医疗集团CEOPaul B. Rothman院士,对如何运用21世纪的信息数据实现使患者获益的承诺,进行了阐述。 美国医学界在2011年首次提出了“精准医学”的概念,2015年1月20日,奥巴马又在美国国情咨文中提出“精准医学计划”,希望精准医学可以引领一个医学新时代。 Rothman表示,当下疾病的范畴、疾病谱正在改变,我们必须要把这种精准医学的理念引入到教育当中,也许可以叫做精准医学教育。 Rothman强调,精准医学能够使我们更好地了解每一种疾病发生的具体机理,这样我们就可以集中有效的资源投放来解决个性化的医疗问题。以胰腺囊肿分类为例,我们要知道哪些胰腺囊肿的患者是适合接受手术切除而哪些是不适合的。约翰霍普金斯大学医学院的专家在这方面做了一些研究,他们分析了病人瘤囊体中液体的充盈情况和流动情况,就可以估算出病理状况是什么样的,有些情况下因为某种细胞或者是组织的突变,可能会对放射治疗产生耐受性,这也许就需要增加剂量,那么增加多少呢?这些都需要我们有一个精准的预判。 Rothman认为,精准医学的理念和大数据的概念确实给我们的医学改革、医学教育改革带来了很大的深刻影响。比如说通过精准的检测及信息反馈,提示给医生该做哪些临床上的处置,而且我们能够以一种动态的方式来教育患者。在目前医学的发展上,放射技术已经应用在了很多方面,放射的手段有很多种,比如有MRI、CT等。我们也把所有放射检查的数据形成了数据联合或者是数据网,从诊疗和技术上有了很大的提高。另外一些方面,我们收集了大量病人的数据。这些病人的数据是应该高度保密的。所以我们要在收集大量病人信息之后,就要认真地考虑如何来使用并且保护好这些信息。 关于 Paul Rothman Paul B. Rothman是约翰·霍普金斯大学医学院院长、他同时担任着约翰·霍普金斯大学副校长以及约翰·霍普金斯医院的首席执行官。作为院长兼首席执行官,Rothman兼顾着管理医学院和约翰·霍普金斯医疗系统的职责,约翰·霍普金斯医疗系统旗下包括6家医院、数百名社区医生和一个自费的医保计划。 关于约翰·霍普金斯医疗集团 总部位于马里兰州巴尔的摩市的约翰·霍普金斯医疗集团(JHM),是一家总资产达77亿美元的全球一体化医疗产业集团,它将来自约翰·霍普金斯大学医学院的医生、科研人员与约翰·霍普金斯医院和卫生系统的下属机构、医疗从业人员及设施有机整合在一起,成为全美顶级学术保健系统。JHM以提升社区乃至全球人民的健康状况为使命,通过在医学教育、科研和临床护理方面设立卓越的标准,实现其“携手兑现医疗承诺”的宗旨。在多元化和包容的环境下,JHM教育医学生、科研人员、医疗从业人员及公众;开展生物医学研究;提供以患者为中心的医疗服务,来预防、诊断和治疗人类疾病。JHM经营着六家学术和社区医院,四家市郊卫生保健和手术中心,以及超过40家约翰·霍普金斯社区医生框架下的初级和专科医疗门诊点。通过约翰·霍普金斯家庭护理机构,约翰·霍普金斯国际部和约翰·霍普金斯保健责任有限公司,JHM将医疗服务延伸到社区以至全球。约翰·霍普金斯医院创建于1889年,《美国新闻与世界报道》在其28年的历史中,22次将约翰·霍普金斯医院评为全美第一。有关约翰·霍普金斯医疗集团的更多信息,包括研究、教育、临床项目,以及最新健康、科研方面的新闻,请访问www.hopkinsmedicine.org详情>>

2017-09-26 00:00:00
在肿瘤精准医疗中发挥临床试验的作用

新闻在肿瘤精准医疗中发挥临床试验的作用

Fourteen years after the human genome project produced the first comprehensive catalog of human DNA, we have reached the point where the unique genetic signature of an individual’s cancer can be used to guide cancer treatment. This revolution has been a long time coming. Even before the human genome was completed, discovery of the HER2 gene and its role in breast cancer led to multiple targeted therapies for women who have a mutation in the gene. But one gene is just the tip of the iceberg — with comprehensive genomic profiling available today, we can probe hundreds of genes simultaneously to obtain a more complete picture of each person’s disease and potentially identify new, individualized treatment approaches. These technologies are helping to realize the vision of precision medicine. Increasingly, oncologists think of tumors not in terms of which organs they inhabit — lung, breast, liver, and pancreas— but in terms of their genomic alterations. Understanding the role of different markers as primary driver mutations in some cancers, hallmarks of metastases or in conferring response or resistance to certain treatments, is critical for the treatment approach and success for patients. Indeed, the FDA recently made a historic decision by approving an anti-PD-1 immunotherapy for all tumors that have high microsatellite instability (MSI) status, regardless of tissue of origin or where they were located in the body. At the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, data was presented showing responses to a targeted therapy were observed in a wide range of tumors with a specific genetic biomarker, regardless of location within the body. Identifying new genomic biomarkers is the first necessary step in creating new treatment options for patients, but we need more than that. If we want to integrate targeted and personalized treatment approaches into clinical practice, we need to test them in clinical trials. Only then can we realize the promise of precision oncology. Clinical Trial Design and Enrollment -- Challenges to Overcome Clinical trials are the foundation of drug development – they inform us whether a medicine is safe and effective for use and which patients are most likely to benefit from them. Therefore, clinical studies must be designed in such a way  to keep pace with the innovation in cancer genomics and the information gleaned by putting this knowledge into practice. Programs like the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) now assign treatments to patients based on the genetic alterations found in their tumors, regardless of where those tumors are located in the body. The American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (ASCO TAPUR) trial also studies the effects of cancer drugs matched to the genomic profiles of tumors. These clinical studies are helping to ensure that the right medicines get to the right patients. But while these studies and many others have the potential to expand the treatment landscape for cancer, they will succeed only if patients participate. Patient populations are widely distributed geographically, and trial access or even awareness may be limited outside of academic hospitals. On average, only three to five percent of adult cancer patients participate in clinical trials, and 20 percent of all clinical trials never finish because they are unable to reach their enrollment goals. Clearly there is a need for improvement to ensure that clinical trials offer scientists, drug developers and regulators the necessary data  to make informed decisions about safety and efficacy. Equally important is that eligible patients have an opportunity to receive cutting-edge therapy based on their cancer’s genomic profile, an area of rising concern as physicians and patients find it hard to navigate the complex and often elusive landscape of clinical trials. Optimizing trials through genomics Collectively, many in oncology are working hard to apply solutions that help address these challenges. Some programs have a suite of offerings that help accelerate clinical trial enrollment by using genomic information to connect patients to trials. For instance, n a case presented at this year’s ASCO Annual Meeting, Foundation Medicine’s SmartTrials Precision Enrollment approach helped a patient participate in a trial by opening up a new treatment site near the person’s home. The new site was activated and approved, and the patient was enrolled within seven days of identification. Today, SmartTrials is being used across multiple clinical trials, to help enhance patient enrollment, which will ultimately accelerate our understanding of potentially transformative medicines for cancer. Improving clinical trial efficiencies can have a substantial impact on how precision medicine can advance cancer care. Through genomic profiling, we have the opportunity to expand access to clinical trials, connect patients to targeted therapies they are most likely to respond to based  on their cancer’s genomic profile and guide and accelerate the development of new treatments. Together these continuing efforts by all of us in the global cancer research community will ultimately contribute to significant advancements in patient care. Melanie Nallicheri joined Foundation Medicine in October 2016 as chief business officer and head, Biopharma. She brings with her more than 25 years of experience in corporate strategy and business development, deep knowledge across healthcare sectors in the U.S. and internationally, as well as experience building advanced analytics capabilities. She has a track record of helping grow businesses and building high-performing teams. Prior to joining Foundation Medicine, Ms. Nallicheri was senior vice president, corporate strategy and business development, McKesson Distribution Solutions and McKesson Data & Analytics.详情>>

2017-09-18 00:00:00
GWAS研究疾病的价值是否被高估了?

新闻GWAS研究疾病的价值是否被高估了?

原文以New concerns raised over value of genome-wide disease studies为标题 发布在2017年6月15日的《自然》新闻上 原文作者:Ewen Callaway 研究人员表示,大规模分析只是找出“外围”基因关联,并不能对生物研究带来很大贡献。 通过对比大量患病者和未患病者的基因组,应能鉴定出与该疾病相关联的基因变异。这就是全基因组关联研究(GWAS)背后的理论。十多年来,研究人员一直利用它来寻找基因与疾病(如精神分裂症和类风湿性关节炎)的关联。但是现在,一篇分析报告对此发出挑战,使这种研究方法的未来蒙上阴影,并对投资者是否应继续向这些实验投入更多资金提出质疑。 全基因组关联研究在大样本的基础上寻找与某些疾病或性状相关联的DNA变异。Sandor Csudai/Getty Images GWAS的规模正在迅速扩张,其研究范围动辄覆盖上万,甚至数百万的病人(参见“全基因组关联研究热潮”)。但是美国斯坦福大学的遗传学家Jonathan Pritchard表示,生物学家可能会发现,研究规模的扩大只会让人们发现更多对疾病影响微不足道的基因变异——或叫“匹配项”。他提出,GWAS有可能将普通的疾病与成千上万的DNA变异联系在一起:也就是说,每一个碰巧活跃在病变组织中的DNA区域都可能与疾病有关联。 在6月15日发表于《细胞》期刊的一篇论文中,Pritchard和其他两位遗传学家提出,许多GWAS匹配项与疾病并没有特别的生物关联,因此无法被当作有效的药物靶标。实际上,这些“外围”变异很有可能是通过复杂的生化调控网络来影响与疾病有更直接联系的“核心”基因的活动。 “而一直以来,人们对GWAS的隐含假定是当你找到匹配项时,它们与你研究的疾病有直接关联,”他说,“当你开始认为组织中表达的所有基因都能影响疾病时,那么每一个基因背后都存在一个简单的生物联系就变得站不住脚。” 许多遗传学家认为Pritchard的观点可能是正确的——并承认他说出了大家的担忧:由于对生化网络的理解存在空白,解读GWAS结果存在一定困难。美国纽约基因组中心的人类遗传学家Joe Pickrell说:“我认为这个观点相当合理。除非我们弄清这些网络是如何连接的,不然我们可能不会有任何重要发现。” 改编自Manolio, T. Nature 546 360-361 (2017) Pritchard认为,研究人员和资助者应该将精力花在绘制细胞中的调控网络上,而不是进一步增加GWAS的数量,扩大GWAS的规模。他还说,希望找出基因和疾病关联的生物学家应该重点鉴定直接导致病症的变异;有些变异十分罕见,GWAS无法发现它们。 GWAS谜团 GWAS已经鉴定出一些会引发肥胖等疾病发病风险的基因,但同时也生出了一些棘手问题。GWAS发现的大部分遗传突变似乎并不编码合成蛋白质的基因,因此也就很难解释它们与某种疾病或性状的联系。即使是有较强遗传性的性状——意味着具有较大的遗传影响——GWAS发现的所有DNA变异的总体影响并不能彻底解释它们在不同人身上表现出的差异。比如,2014年一项涉及25万人的研究鉴定出了将近700种与身高有关的DNA变异,但是它们只能解释人群中16%的身高差异。 Pritchard团队在发表于《细胞》的论文中,重新分析了2014年研究所得的数据。研究人员估计有多达10万个单碱基DNA变异能够影响人的身高,但是单个影响微乎其微;平均每个只能对身高产生大约0.1毫米的影响。这些变异一般存在于不编码基因的区域,但是这些区域却能影响编码基因区域的活动。 研究人员还重新分析了精神分裂症、类风湿性关节炎和克罗恩病的GWAS数据。他们在与疾病相关联的特定细胞中的DNA区域发现了GWAS匹配项:精神分裂症为神经元,两种自身免疫疾病为免疫细胞。但是团队也发现,在多种身体组织中活跃的DNA区域和只在神经元或免疫细胞中活跃的DNA区域都有同样的可能成为GWAS匹配项。这就进一步佐证了一个想法:大规模的GWAS研究只是简单地选出了对基因调控有影响的大部分DNA变异,而且这些变异碰巧在疾病相关细胞的广泛功能中发挥了作用,而不是在与疾病有关的特定活动中发挥了作用。 但是一些遗传学家表示,这并不意味着研究人员应该停止GWAS。英国牛津大学的人类遗传学家Mark McCarthy表示,虽然GWAS的匹配项对疾病可能只产生外围影响,但是如果能鉴定更多匹配项,科学家就能编织出某种疾病的生物网络并弄清它们是如何互相影响的。目前,他正在针对2型糖尿病开展GWAS,涉及人数达100万左右。“我们开展规模更大的GWAS时,并非漫无目的的,”他说,“而是受到来自GWAS的大量生物信息的启发。” 美国波士顿儿童医院的人类遗传学家Joel Hirschhorn说不是所有大型GWAS发现的匹配项都是外围的。Hirschhorn联合领导了上述2014年的身高研究。他指出,该研究发现了一个重要生长因素的基因关联,而此关联之前并未被规模较小的GWAS识别。 但是美国约翰霍普金斯大学的人类遗传学家Aravinda Chakravarti希望这篇论文能挑战他所称的基因组学研究中的 “牛仔态度”,即强调收集更多的基因关联,而不重视理解它们背后更深刻的生物学含义。“这是一篇出色的论文,因为它就像是一个警示,作为科学家,我们时不时地需要这样的提醒。”详情>>

Nature自然科研
2017-09-06 00:00:00
临床研究之路:NGS上下求索,Biomarker潮流所向

新闻临床研究之路:NGS上下求索,Biomarker潮流所向

“虽然这方面的临床研究一直很少被关注”但哈佛大学医学院医学助理教授Eli Van Allen在今年美国芝加哥召开的美国临床肿瘤学年会(ASCO)上告诉听众说:“让测序的结果成为临床决策的依据现在已经部分实现。” 事实上,首个相关的概念验证试验:试图根据测序的结果选择患者的治疗手段并没有取得成功,这是2015年开展的代号为SHIVA的II期临床研究,结果显示通过测序选择8个靶向药之一治疗的患者和直接接受化疗的患者他们的无进展生存期没有显著差异,今年的会议发布了的参与这项试验患者的总生存期数据,接受基因分析并选择靶向药物治疗的这组患者的总生存期也没有明显的延长。 但是在ASCO会议的其他讨论部分,研究者仍然认为将基因组分析作为社区癌症护理的一部分在技术上是可行的,同时与会者热烈参与讨论,关于这项技术如何能对临床治疗产生积极影响。 ASCO上还有另外几个演讲也对这部分内容进行了阐述,从技术角度看,对肿瘤进行广泛的测序分析是可以实现的。 在其中一个会议主题讨论环节上,法国LéonBérard研究中心医学肿瘤系主任Olivier Tredan展示了ProfiLER研究上获得的数据,这些数据都是通过对69个基因组进行二代测序(NGS)或者全基因组杂交(whole-genome hybridization)的方式获得的,具体采用哪种方法主要取决于采集到的活检组织的大小和纯度,并根据测序结果对晚期难治性肿瘤患者提供靶向药物的治疗选择建议。在会上,Tredan提供了2,676名患者的研究资料。 一个好消息是,从理论上说这个方法的应用已经比较成熟,我们可以有机会对法国的每一个病人进行这样的检测。 “常规的基因检测不受地理位置的限制” Tredan说:“因此我们可以对每一个法国的患者进行这样的检测。” 不幸的是,到目前为止,对法国的每一个患者都进行基因测序并没有让患者得到更多的获益。根据大约2700被纳入研究患者的数据,只有143名大约是7%比例的患者,根据基因测序的结果选择相应的靶向治疗,尽管测序的结果发现他们之中有一半的突变都有对应的治疗方法。 Tredan和他的团队在基因测序的结果上为700名患者提供了治疗方案的推荐,但是其中的大多数患者并没有接受他们所建议的药物治疗。 部分原因是,有些推荐的治疗方法还处于新药临床试验阶段,患者需要入组试验才能获得药物,但这些需要入组临床试验的患者病情都已经十分严重,如果不能尽快获得试验药物的治疗,其中相当一部分就会在执行推荐的治疗方法前疾病进展或者死亡。 这种情况不仅限于那些在美国以外开展的临床研究,虽然“篮子试验(basket trials)”的开展已经让这类情况得到部分改善。(译注:篮子试验是将针对某个特定分子事件如基因突变、融合、扩增等的药物比喻为篮子,将带有这种相同分子事件的不同瘤种放进同一个篮子里进行临床试验就是篮子试验,这种试验突破传统对肿瘤解剖学的限制) 密歇根大学医学肿瘤学家Erin Cobain,描述了一项有500名癌症转移患者参与的研究,其中有20%的患者已经根据测序的结果选择了临床疾病治疗方案,不管这个比例在旁观者眼中是高还是低,但是Cobain特别提到随着篮子试验的增加,能够纳入临床试验的患者数量也开始显著增加。 不过Cobain对于二代测序的观点是,NGS只能被应用于肿瘤晚期转移性患者的治疗方案决策。事实上,随着临床试验的可及性提高,成功治疗的案例数量也不断增加,患者接受测序的时间也在提前。 搜集大量血浆 随着测序手段的进步,它可以筛选的突变范围也越来越多,虽然还没有证据表明数据越多越好。来自哈佛大学的Van Allen就提出警告,认为随着医生临床上能够获得的信息呈指数级增加,而医生的大脑尺寸和记忆能力并没有明显提升,这会造成“临床数据疲劳”的现象。 通过良好的训练同时辅以相应的决策手段支持可以防止数据疲劳,而另一方面就是要明确获得多少的数据量是最合适的,而不是一味提供尽可能多的数据。 有的时候,更多的数据有利于做出更全面的决策,但有的时候,太多的数据也会对决策产生干扰而不是提供更多的帮助。 Dana-Farber癌症研究所医学肿瘤学家Geoffrey Oxnard则告诉听众,在寻找结肠癌细胞可能的突变时,液体活检和组织活检的结果80%是一致的,而对于目前已知的会导致结肠癌发生的7个重要基因的检测,结果则是100%一致。 Oxnard的结论是,如果你只对结肠癌相关的7个基因感兴趣的话,你也只要获得这7个基因的数据就可以了。在会上,Oxnard概述了目前基因测序的情况以及对未来液体活检的预期判断。直至目前,在临床上常规应用的液体活检仅限于对特定基因突变的发现。 但是在临床试验中,用它可以获得肿瘤所有的突变信息,以及这些突变随时间的变化情况,这一点恰是组织活检目前无法实现的。(参看 BioWorld Today,2016年6月7日的文章) Oxnard非常清楚液体活检可以应用的范围,在一个案例讨论中,报告显示在总共440个接受液体活检的肿瘤样本中,有99%都被发现存在“假设可靶向”(hypothetically targetable,可能存在靶向药物治疗)的突变,但这样的突变来源并不明确。他的结论是:“可接受肿瘤靶向治疗”是一个抽象的结论,它不只决定于临床试验的数量,还取决于临床医生对于靶向疗法的乐观程度。 总体而言,他对液体活检应用于临床以及前沿研究都持乐观态度。他对自己的同行其他肿瘤医生的建议是:“收集血浆,我的建议是尽量多地收集血浆。”详情>>

科睿唯安生命科学与制药
2017-09-06 00:00:00