CN114592060A - 预测性生物标记的测定法 - Google Patents
预测性生物标记的测定法 Download PDFInfo
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- CN114592060A CN114592060A CN202210168026.1A CN202210168026A CN114592060A CN 114592060 A CN114592060 A CN 114592060A CN 202210168026 A CN202210168026 A CN 202210168026A CN 114592060 A CN114592060 A CN 114592060A
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Abstract
本发明提供用于检测一个生物样品中多个生物标记的存在或量的测定法。
Description
本申请是申请日为2014年3月13日，申请号为201480015681.7，发明名称为“预测性生物标记的测定法”的发明专利的分案申请。
相关专利申请的交叉引用
本申请要求提交于2013年3月15日的美国专利申请61/793，133的优先权，其全部内容以引用方式并入本文用于所有目的。
技术领域
本发明涉及用于确定和检测生物标记的测定法以及治疗癌症患者的方法。
背景技术
尽管在开发成功的癌症治疗进展中有所进步，但是仅仅小群体的患者响应任何特定的治疗。由于众多已有癌症治疗的狭窄治疗指数和毒性的潜在作用，这类不同的响应有可能导致患者经历不必要的、无效的和甚至可能有害的治疗方案。
优化治疗以治疗个体患者的一个方式是确定患者是否具有一种或多种预测物，其与响应于治疗的具体结果相关联。在患者中预测药物敏感度的能力尤其具有挑战性，这是因为药物反应同时反映了靶细胞内在的特性以及宿主代谢的特性。
对于鉴定另外的预测性标记以鉴定特定的癌症患者存在需求，预计患者当实施特定的癌症治疗时具有有利的结果。也需要鉴定用于立即确定样品中超过一种生物标记的存在的测定法。
发明内容
本发明提供一种用于确定生物样品中超过一种生物标记的存在、缺乏或量的方法。
本发明也提供一种治疗具有提高的几率获得响应癌症治疗的有利结果的患者的方法，该方法包括：确定患者中一种或多种预测物的存在、缺乏或量，其中预测物的存在、缺乏或量与至少一种有利结果相关联；并且基于预测物的存在、缺乏或量对患者实施治疗。
具体实施方式
本发明已经发现了用于立即检测和定量生物样品中超过一种生物标记的基因表达测定法。此类生物标记可用于鉴定如下患者：有患病的高风险；有不良预后的高风险；有良性预后的高几率；可能表现出响应于特定治疗的有利结果；或可能表现出响应特定治疗的不利结果。
在不受限的前提下，本发明提供了(a)通过确定一种或多种预测物的存在或量而预测在癌症患者中对治疗的响应的方法，(c)通过基于一种或多种预测物的存在或量来选择患者以治疗癌症的方法，以及(d)基于患者的生物标记特征治疗癌症患者。
在某些实施例中，提供了在癌症患者中用于预测对癌症治疗(例如，使用CYP17抑制剂的治疗，诸如阿比特龙或其可药用的盐)的响应的方法，该方法包括在患者或来自该患者的生物样品中确定预测物的存在或量；并且其中预测物的存在或量与至少一种良性结果相关联。某些实施例包括确定在患者或来自该患者的生物样品中测定第二预测物的存在或量，其中第二预测物的存在或量与至少一种良性结果相关联。
本发明涉及对预测物的鉴定，预测物在本文还称为“变体”、“标记”、“生物标记”和/或“因子”，其与对癌症治疗的有利响应的提高概率相关联。患者对癌症治疗的响应与这些预测物之间的关联可提高更高的特定治疗的安全可信度和/或功效。预测物可以是基因、蛋白质、患者特征或患者病史的方面。
根据本发明并用于本发明测定法的预测物包括：全长雄性激素受体(AR)；AR变体1(ARV1)、AR变体3/变体7(ARV3/V7)、AR变体567(ARV567)、AR变体8(ARV8)、TMPRSS2全长野生型；ERG全长野生型；ETV1全长野生型；TMPRSS2:ETV1融合基因(TMP:ETV)；和TMPRSS2:ERG融合基因(TMP:ERG)；CYP17；CYP11；HSD3B1；AKRIC3；NPY；PSA；KLK2；AGR2；BST1；PTPRC；以及SNPs L701H、H974Y、T877A、V715M；ESR1；Her2；***受体(ER)；PR；CYP19、和Delta3AR。
本发明的测定法检测生物样品中超过一种生物标记，并且可检测样品中生物标记的任何组合。在一个实施例中，该测定法检测TMP:ERG和选自AR、ARV1、ARV3/V7、ARV567、ARV8、TMPRSS2、ERG、ETV和TMP:ETV的一种或多种生物标记。
如本文所用，术语“含有”、“包含”、“具有”以及“包括”以它们开放的、非限制性的意思使用。
“量”可以指数值、强度、浓度、数量、程度或表达水平。例如，基因的量可以是基因或其部分存在于受试者基因组中或该受试者细胞中的次数的数量。量还可以指表达标记的生物样品中的细胞数量、或生物样品中的标记的总体表达水平或强度。量还可以指患者此前可能已暴露的治疗类型或方法的数量。量可以与绝对数量比较，与来自健康患者的参比样品比较、与来自健康患者的平均数量比较或与来自患有类似疾病的患者的平均数量比较。
癌症治疗可包括施用单一药物或治疗，或包含了施用多于一种药物或治疗的组合治疗。癌症治疗可通过化学疗法、放射疗法、或免疫疗法进行；或者癌症治疗可通过骨髓移植进行。
在某些实施例中，癌症治疗包括向患者施用CYP17抑制剂。在一些实施例中，CYP17抑制剂是阿比特龙或其可药用的盐，具体地讲是醋酸阿比特龙。
在某些实施例中，癌症治疗包括使用抗癌剂进行的治疗，抗癌剂包括但不限于乙酰吗喃(acemannan)、阿柔比星(aclarubicin)、阿地白介素(aldesleukin)、阿仑单抗(alemtuzumab)、阿利维A酸(alitretinoin)、六甲蜜胺(altretamine)、氨磷汀(amifostine)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、阿那格雷(anagrelide)、阿那曲唑(anastrozole)、安西司亭(ancestim)、天冬酰胺酶(asparaginase)、贝伐单抗(bevacizumab)、蓓萨罗丁(bexarotene)、溴尿苷(broxuridine)、卡培他滨(capecitabine)、西莫白介素(celmoleukin)、西曲瑞克(cetrorelix)、西妥昔单抗(cetuximab)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、克霉唑(clotrimazole)、达利珠单抗(daclizumab)、右雷佐生(dexrazoxane)、地拉卓(dilazep)、二十二烷醇(docosanol)、去氧氟尿苷(doxifluridine)、溴麦角环肽(bromocriptine)、卡莫司汀(carmustine)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、双氯芬酸(diclofenac)、依地福新(edelfosine)、依决洛单抗(edrecolomab)、依洛尼塞(eflornithine)、乙嘧替氟(emitefur)、依西美坦(exemestane)、依昔舒林(exisulind)、法曲唑(fadrozole)、非格司亭(filgrastim)、非那雄胺(finasteride)、磷酸氟达拉滨(fludarabine phosphate)、福美司坦(formestane)、福莫司汀(fotemustine)、硝酸镓(gallium nitrate)、吉西他滨(gemcitabine)、glycopine、庚铂(heptaplatin)、羟基脲(hydroxyurea)、伊班膦酸(ibandronic acid)、咪喹莫特(imiquimod)、碘苄胍(iobenguane)、伊立替康(irinotecan)、伊索拉定(irsogladine)、兰瑞肽(lanreotide)、来氟米特(leflunomide)、来格司亭(lenograstim)、香菇多糖硫酸酯(lentinan sulfate)、来曲唑(letrozole)、利阿唑(liarozole)、乐巴铂(lobaplatin)、氯尼达明(lonidamine)、马索罗酚(masoprocol)、美拉胂醇(melarsoprol)、美法仑(melphalan)、巯嘌呤、甲氨蝶呤、甲氧氯普胺(metoclopramide)、米非司酮(mifepristone)、米替福新(miltefosine)、米立司亭(mirimostim)、米托胍腙(mitoguazone)、二溴卫矛醇、丝裂霉素(mitomycin)、米托蒽醌、莫拉司亭(molgramostim)、那法瑞林(nafarelin)、那托司亭(nartograstim)、奈达铂(nedaplatin)、尼鲁米特(nilutamide)、诺斯卡品(noscapine)、奥普瑞白介素(oprelvekin)、奥沙特隆(osaterone)、奥沙利铂(oxaliplatin)、帕米膦酸、培门冬酶(pegaspargase)、木聚硫钠(pentosan polysulfate sodium)、喷司他丁(pentostatin)、毕西巴尼(picibanil)、吡柔比星(pirarubicin)、卟菲尔钠(porfimer sodium)、***(prednisone)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、拉布立酶(rasburicase)、利妥昔单抗(rituximab)、罗莫肽(romurtide)、沙格司亭(sargramostim)、香豆酮、索布佐生(sobuzoxane)、索纳明(sonermin)、甾类、苏拉明(suramin)、他索纳明(tasonermin)、他佐罗汀(tazarotene)、替加氟(tegafur)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、十氧化四氯(tetrachlorodecaoxide)、萨力多胺(thalidomide)、胸腺法新(thymalfasin)、促甲状腺素α、托泊替康(topotecan)、托瑞米芬(toremifene)、曲妥单抗(trastuzumab)、苏消安(treosulfan)、维甲酸、曲洛司坦(trilostane)、三甲曲沙(trimetrexate)、乌苯美司(ubenimex)、戊柔比星(valrubicin)、维替泊芬(verteporfin)、长春新碱、长春花碱、长春地辛(vindesine)和长春瑞滨(vinorelbine)。在一个优选的实施例中，癌症治疗包含利妥昔单抗。在其它优选的实施例中，癌症治疗包含美法仑(melphalin)或***，或美法仑与***的组合。
在某些实施例中，癌症治疗为组合治疗。组合治疗可包含使用CYP17抑制剂进行的治疗以及另一种癌症治疗或抗癌剂。在某些实施例中，其它的抗癌剂是皮质类固醇如***。
有利结果可以是总体反应率、总体生存率、总体完全反应率、反应持续期、至下一次治疗的较长时间、无治疗间隔、对治疗的积极响应、更长的至进展时间、较长期的生存和/或更长的无进展生存期。有利结果可以是剂量依赖性的或剂量不依赖性的。有利结果与无治疗相比或与另一癌症治疗或一种或多种癌症治疗相比。
“癌症”或“肿瘤”旨在包括患者中的任何肿瘤生长，包括初始肿瘤和任何转移性肿瘤。癌症可以是血液学癌症或实体瘤类型。血液学癌症包括，诸如，骨髓瘤(例如多发性的骨髓瘤)、白血病(例如，巨球蛋白血综合征、急性骨髓性白血病、慢性淋巴细胞性白血病、粒细胞性白血病、单核细胞性白血病、淋巴球性白血病)以及淋巴瘤(例如，滤泡性淋巴瘤、套细胞淋巴瘤、弥漫大B细胞淋巴瘤、恶性淋巴瘤、浆细胞瘤、网状细胞肉瘤、何杰金氏病、非何杰金氏淋巴瘤或滤泡性B细胞非何杰金氏淋巴瘤)。实体瘤可源自于器官并且包括诸如脑、皮肤、肺、乳腺、***、卵巢、结肠、肾和肝这样的癌症。癌症可以处于原发位点、为癌细胞转移、为难治的(例如，对于一种或多种治疗方法是难治的)和/或复发性的。在某些实施例中，癌症是***癌或乳腺癌。
当预测物存在于患者体内时，可通过从患者获取生物样品并且确定所述生物样品是否包含该预测物或生物样品以何量包含该预测物来评估预测物的存在、缺乏或量。如本文所用，“生物样品”是指从受试者分离的包含组织、细胞、生物液体以及它们的分离物的样品或由以上物质组成的样品，以及受试者体内的组织、细胞和液体。生物样品的例子包括，例如，痰、血液、血细胞(例如，白血细胞)、羊水、血浆、血清、***、唾液、骨髓、组织或细针活检样本、尿液、腹膜液、胸膜液和细胞培养物。生物样品也可以包括组织切片，诸如用于组织学目的的冰冻切片。在某些实施例中，生物样品可以是或可以包括肿瘤细胞。在某些实施例中，生物样品可用***固定。在某些实施例中，生物样品可为循环肿瘤细胞。
对生物样品中的预测物的检测可通过用于检测预测物类型的任何常规方法来进行，例如直接测量、免疫组织化学、免疫印迹法、免疫荧光、免疫吸收、免疫沉淀、蛋白质阵列、原位荧光杂交、FACS分析、杂交、原位杂交、Northern印迹、Southern印迹、Western印迹、ELISA、放射性免疫测定、基因阵列/芯片、PCR、RT-PCR或细胞遗传学分析。
当预测物基于特定的基因型或多态性，可通过基因分型来分析生物样品。术语“基因型”是指存在于来自受试者或患者的存在于DNA中的等位基因，其中等位基因可以由特定位点处的核酸序列中存在的特定核苷酸所定义。基因型通常是单一多态性位点处存在的核苷酸，其已知在人类群体中是可变的。“基因分型”是指通过使用生物测定来确定个体的基因型的方法。实施这个的当前方法包括PCR、DNA测序、反义寡核苷酸探针以及对DNA微阵列或珠粒的杂交。
“单核苷酸多态性”(SNP，发音为snip)是当基因组(或其它共有序列)中的单核苷酸—A、T、C或G—在物种的成员之间(或个体中的成对染色体之间)有所不同时发生的DNA序列变异。例如，来自不同个体的两组DNA片段AAGCCTA对AAGCTTA，包含了在单一核苷酸中的不同。在这种情况下其被称为存在两种等位基因：C和T。几乎全部常见的SNP只有两种等位基因。
对至少一种基因型变异的存在或缺乏的检测涉及使对应于本文鉴定的基因之一的核酸序列或这一基因的产物与探针接触。探针能够通过例如差异性结合或杂交来区分基因或基因产物的特定形式或存在或特定的变异。
当预测物为特定基因或蛋白质的存在或量(包括表达水平)时，存在或量(包括表达水平)可通过生物样品的免疫组织化学来确定。
在某些实施例中，用于治疗患者癌症的方法包括：确定患者或来自患者的生物样品中第一预测物的存在或量；并且确定在患者或来自患者的生物样品中第二预测物的存在或量；并且根据所述患者是否可能响应治疗来选择治疗方法。
本发明还提供了CYP17抑制剂在患者中用于治疗癌症的用途，其中患者特征在于至少一种预测物的存在、缺乏或量，预测物与响应于CYP17抑制剂的至少一种良性结果相关联。
本文引用的所有专利公开均据此以引用方式并入。除非另有定义，否则本文使用的所有技术和科学术语的含义与本发明所属领域的普通技术人员通常所理解的含义相同。
实例1
开发TaqMan qRT-PCR测定法以评估在两个独立的PCa FFPET样品组中是否存在：多种以前鉴定的AR拼接变体(包括ARV1、ARV3/V7、ARV567和ARV8)、AR体细胞突变(包括L701H、V715M、H874Y和T877A)、以及TMPRSS2融合基因、TMPRSS2:ERG和TMPRSS2:ETV1。第一样品组由42个***腺癌样品构成，它们为II期至IV期。结果表明ARV1和ARV3/V7是最常见的变体，所有样品中有92％的样品表达其中一个变体或两个变体。TMPRSS2：ERG存在于所有测试样品中72％的样品内，与AR变体的表达高度一致，常见于较晚期(III/IV)的PCa样品。第二样品组由8个***腺癌样品构成，包括匹配的相邻正常FFPET。在肿瘤和匹配的正常样品中观察到AR变体的相似表达，然而***肿瘤样品显示比匹配的正常样品中的表达(33％)更高和更常见的TMPRSS2:ERG融合基因表达(66.67％)。评估的四个AR突变在任一个样品组中均未检出。
表1：
实例1中使用的引物。
实例2
使用TaqMan qRT-PCR检查213个女性乳腺癌FFPET样品，80个ER-PR-Her2-样品、68个ER-PR-Her2+样品、和64个ER+PR+Her2-样品、以及8个乳腺癌细胞系，检查是否存在ESR1、CYP17、CYP19、全长AR和AR拼接变体ARV1、ARV3/V7、ARV567、以及Delta3AR。ARV3/V7和Delta3AR是ER+PR+Her2-和ER-PR-Her2+样品组中最常见的变体，这些样品中>85％的样品表达这些变体中的一个或二者。另一方面，ARV1、ARV3/V7、和ARV567是ER-PR-Her2-样品组中最常见的变体，这些样品中>90％的样品表达这些变体中的一个或它们的组合。与更低等级的样品相比，在更高等级的ER+PR+Her2-和ER-PR-Her2+样品中观察到大多数AR变体的更低表达值。在所有样品组中CYP19是非常常见的，所有样品中有>75％的样品表达它，而所有测试样品中有<30％的样品中观察到CYP17的表达。
序列表
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<120> 预测性生物标记的测定法
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<400> 3
gattagcagg tcaaaagtga actgat 26
<210> 4
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 4
actctgggag cagct 15
<210> 5
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 5
cggaaatgtt atgaagcagg ga 22
<210> 6
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 6
caaacaccct caagattctt tcaga 25
<210> 7
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 7
ctgggagaaa aattccgggt 20
<210> 8
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 8
ggaaatgtta tgaagcaggg atg 23
<210> 9
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 9
tttgagatgc ttgcaattgc c 21
<210> 10
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 10
cttgcctgat tgcgagag 18
<210> 11
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 11
ctgggagaga gacagcttgt acac 24
<210> 12
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 12
caggtcaaaa gtgaactgat gca 23
<210> 13
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 13
cggcaggaag ccttat 16
<210> 14
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 14
gagctaagca ggaggcgga 19
<210> 15
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 15
taggcacact caaacaacga ctg 23
<210> 16
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 16
ttgaactcac tcaggtacc 19
<210> 17
<211> 26
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 17
tacctatcat tactcgatgc tgttga 26
<210> 18
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 18
ctggtacaaa ctgctcatca ttgtc 25
<210> 19
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 19
ccacaaaacc aagcgag 17
<210> 20
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 20
gccaccgtgc gaggtat 17
<210> 21
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 21
caccatccgc tttttcttgt c 21
<210> 22
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成探针
<400> 22
ccacaagctg aaggc 15
<210> 23
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 23
gcggattctc atggaacaca 20
<210> 24
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成引物
<400> 24
ggtcagccag gagcttcttg 20
Claims (2)
1.用于检测多个生物标记的试剂在制备用于预测癌症患者对用CYP17抑制剂治疗的响应的试剂或药物中的用途，其中所述生物标记是TMPRSS2:ERG融合基因（TMP:ERG）和至少一种选自以下的生物标记：全长雄性激素受体（AR）；AR变体1（ARV1）、AR变体3/变体7（ARV3/V7）、AR变体567（ARV567）、AR变体8（ARV8）、TMPRSS2全长野生型；ERG全长野生型；ETV1全长野生型和TMPRSS2:ETV1融合基因（TMP:ETV）。
2.根据权利要求1所述的用途，其中所述癌症是***癌。
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| US201361793133P | 2013-03-15 | 2013-03-15 | |
| US61/793133 | 2013-03-15 | ||
| PCT/US2014/025383 WO2014151290A2 (en) | 2013-03-15 | 2014-03-13 | Assay for predictive biomarkers |
| CN201480015681.7A CN105308186A (zh) | 2013-03-15 | 2014-03-13 | 预测性生物标记的测定法 |
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| EP (1) | EP2971101A2 (zh) |
| JP (1) | JP6663347B2 (zh) |
| KR (1) | KR102241063B1 (zh) |
| CN (2) | CN114592060A (zh) |
| CA (1) | CA2907124C (zh) |
| IL (1) | IL241063A0 (zh) |
| WO (1) | WO2014151290A2 (zh) |
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| EP3143156B1 (en) | 2014-05-12 | 2020-11-04 | Janssen Pharmaceutica NV | Biological markers for identifying patients for treatment with abiraterone acetate |
| US20160097082A1 (en) * | 2014-09-23 | 2016-04-07 | Ohmx Corporation | Prostate specific antigen proteolytic activity for clinical use |
| SI3268493T1 (sl) * | 2015-03-12 | 2022-04-29 | Janssen Pharmaceutica Nv | MRNA tumorski označevalci na osnovi polne krvi za napovedovanje raka prostate in postopki za odkrivanje le-teh |
| EP3271483B1 (en) | 2015-03-17 | 2021-07-21 | Mayo Foundation for Medical Education and Research | Methods and materials for assessing and treating cancer |
| GR1009872B (el) * | 2019-08-08 | 2020-11-12 | Φαρμασιστ Μονοπροσωπη Εταιρια Περιορισμενης Ευθυνης Με Δτ Φαρμασιστ Μ. Επε | Πολλαπλη μεθοδος για τον ποσοτικο προσδιορισμο του μοτιβου εκφρασης των εναλλακτικων μεταγραφων του υποδοχεα των ανδρογονων σε ενα δειγμα |
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| US20070212702A1 (en) * | 2005-09-12 | 2007-09-13 | Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
| CN101454668A (zh) * | 2005-11-14 | 2009-06-10 | 拜耳医药保健有限责任公司 | 癌症预测与预后以及监测癌症治疗的方法 |
| CN102712953A (zh) * | 2009-09-17 | 2012-10-03 | 密歇根大学董事会 | ***癌中的复发性基因融合物 |
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| US6638727B1 (en) | 1999-01-26 | 2003-10-28 | Cytyc Health Corporation | Methods for identifying treating or monitoring asymptomatic patients for risk reduction or therapeutic treatment of breast cancer |
| WO2003025141A2 (en) | 2001-09-19 | 2003-03-27 | Intergenetics Incorporated | Genetic analysis for stratification of cancer risk |
| EP1576007A2 (en) | 2002-12-23 | 2005-09-21 | Ingenium Pharmaceuticals AG | Methods and agents for diagnosis and prevention, amelioration or treatment of goblet cell-related disorders |
| EP1737980A2 (en) * | 2004-04-09 | 2007-01-03 | Fondazione IRCCS Istituto Nazionale dei Tumori | Gene expression markers for predicting response to chemotherapy |
| JP2006166823A (ja) | 2004-12-17 | 2006-06-29 | Astellas Pharma Inc | 性ホルモン障害治療薬のスクリーニング方法 |
| US7858306B2 (en) | 2005-07-07 | 2010-12-28 | Mayo Foundation For Medical Education And Research | HSD3B1 sequence variants |
| BRPI0616211A2 (pt) | 2005-09-19 | 2011-06-14 | Veridex Llc | mÉtodos para o diagnàstico de cÂncer pancreÁtico |
| JP2010517510A (ja) | 2007-01-09 | 2010-05-27 | ブリストル−マイヤーズ スクイブ カンパニー | 前立腺細胞中のタンパク質チロシンキナーゼおよび／またはタンパク質チロシンキナーゼ経路と相互作用しかつ／またはそれを調節する化合物の活性を予測するためのポリヌクレオチドの同定 |
| EP3018216B1 (en) * | 2007-07-06 | 2018-09-12 | The Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
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| EP3062106B1 (en) | 2008-04-16 | 2020-11-11 | The Johns Hopkins University | Method for determining androgen receptor variants in prostate cancer |
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- 2014-03-13 US US14/207,879 patent/US10041125B2/en active Active
- 2014-03-13 CN CN201480015681.7A patent/CN105308186A/zh active Pending
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| US20070212702A1 (en) * | 2005-09-12 | 2007-09-13 | Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
| CN101454668A (zh) * | 2005-11-14 | 2009-06-10 | 拜耳医药保健有限责任公司 | 癌症预测与预后以及监测癌症治疗的方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP6663347B2 (ja) | 2020-03-11 |
| US20140271631A1 (en) | 2014-09-18 |
| EP2971101A2 (en) | 2016-01-20 |
| US10041125B2 (en) | 2018-08-07 |
| WO2014151290A3 (en) | 2014-11-13 |
| KR20150132206A (ko) | 2015-11-25 |
| KR102241063B1 (ko) | 2021-04-16 |
| WO2014151290A2 (en) | 2014-09-25 |
| CA2907124A1 (en) | 2014-09-25 |
| CA2907124C (en) | 2021-07-06 |
| CN105308186A (zh) | 2016-02-03 |
| IL241063A0 (en) | 2015-11-30 |
| JP2016514827A (ja) | 2016-05-23 |
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