JP2016026496A - Methods and devices for identifying biomarkers of treatment response, and use thereof to predict treatment efficacy - Google Patents
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C12Q2600/00—Oligonucleotides characterized by their use
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Abstract
Description
発明の分野
本発明は、医学的治療に対する患者の感受性、例えば化学療法剤に対する感受性のバイオマーカーを同定するための、ならびにバイオマーカーを使用して治療効果を推定するための方法および装置を特徴とする。
FIELD OF THE INVENTION The present invention features methods and apparatus for identifying biomarkers of patient sensitivity to medical treatment, such as sensitivity to chemotherapeutic agents, and for estimating therapeutic effects using biomarkers. To do.
発明の背景
DNAマイクロアレイは、患者に由来する腫瘍試料における遺伝子発現を測定するために、および診断を迅速化するために使用されている。遺伝子発現は、患者における癌の存在、そのタイプ、病期、および起源、ならびに遺伝子変異の関与の有無を明らかにすることができる。遺伝子発現はさらに、化学療法の効果の推定に役割を果たし得る。この数十年間に米国立癌研究所(NCI)は、60種類のヒト癌細胞株の成長を制限する効果に関して、化学療法剤を含む化合物の検討を行ってきた。NCIはDNAマイクロアレイによって、このような60の癌細胞株における遺伝子発現の測定も行っている。さまざまな研究において、NCIデータセットを使用して、遺伝子発現と化合物の効果の関連が探索されている。
Background of the Invention
DNA microarrays have been used to measure gene expression in tumor samples derived from patients and to expedite diagnosis. Gene expression can reveal the presence of cancer in a patient, its type, stage and origin, and the presence or absence of genetic mutations. Gene expression can also play a role in estimating the effects of chemotherapy. In recent decades, the National Cancer Institute (NCI) has been investigating compounds, including chemotherapeutic agents, for their effects on limiting the growth of 60 human cancer cell lines. NCI is also measuring gene expression in these 60 cancer cell lines using DNA microarrays. In various studies, NCI datasets have been used to explore associations between gene expression and compound effects.
癌の化学療法の過程では、有効な治療法を見つけるためのトライアンドエラー式の方法のために、かなりの時間を要することが少なくない。加えて、癌細胞はしばしば、過去に有効であった治療法に抵抗性を生じることがある。このような状況では、患者の転帰は、抵抗性が早期に検出されれば大きく改善されると考えられる。 In the course of cancer chemotherapy, it often takes a considerable amount of time due to the trial-and-error method of finding an effective treatment. In addition, cancer cells often can become resistant to previously effective treatments. Under such circumstances, patient outcomes are expected to improve significantly if resistance is detected early.
医学的治療に対する癌患者の感受性または抵抗性を推定する、証明済みの方法および装置に関するニーズも依然としてある。 There remains a need for proven methods and devices for estimating the sensitivity or resistance of cancer patients to medical treatment.
発明の概要
本発明は、患者、例えば癌患者の、治療、例えば化学療法剤などの化合物、または放射線を用いる治療に対する感受性もしくは抵抗性を推定するための方法および装置を特徴とする。特に、方法および装置は、例えば、化合物、薬剤、または放射線による治療を含む、任意の医学的治療に対する癌患者の感受性または抵抗性を推定するために使用することができる。本発明の装置および方法は、癌患者(例えば、肺癌、リンパ腫、および脳腫瘍の患者)における治療効果を正確に推定するために使用され、ならびに任意の癌であると診断された患者における治療効果の推定に使用可能である。
SUMMARY OF THE INVENTION The present invention features methods and apparatus for estimating the sensitivity or resistance of a patient, eg, a cancer patient, to treatment, eg, a compound such as a chemotherapeutic agent, or treatment with radiation. In particular, the methods and devices can be used to estimate the sensitivity or resistance of a cancer patient to any medical treatment, including, for example, treatment with compounds, agents, or radiation. The devices and methods of the present invention are used to accurately estimate the therapeutic effect in cancer patients (e.g., patients with lung cancer, lymphoma, and brain tumors), as well as the therapeutic effect in patients diagnosed with any cancer. Can be used for estimation.
一般的な化学療法剤である、ビンクリスチン、シスプラチン、アザグアニン、エトポシド、アドリアマイシン、アクラルビシン、ミトキサントロン、マイトマイシン、パクリタキセル、ゲムシタビン、タキソテール、デキサメタゾン、Ara-C、メチルプレドニゾロン、メトトレキセート、ブレオマイシン、メチル-GAG、カルボプラチン、5-FU(5-フルオロウラシル)、リツキシマブ、放射線、ヒストンデアセチラーゼ(HDAC)阻害剤、および5-アザ-2'-デオキシシチジン(デシタビン)に特異的な化学感受性/化学抵抗性のバイオマーカーを利用する装置も提供される。方法および装置は、疾患条件、例えば癌(例えば、乳房、前立腺、肺、ならびに気管支、結腸および直腸、膀胱、皮膚、腎臓、膵臓、口腔および咽頭、卵巣、甲状腺、副甲状腺、胃、脳、食道、肝臓および肝内胆管、頚部・咽頭、心臓、睾丸、小腸および大腸、肛門、肛門管および肛門直腸、陰門、胆嚢、胸膜、骨および関節、下咽頭、眼および眼窩、鼻、鼻腔および中耳、上咽頭、輸尿管、腹膜、網および腸間膜、または胃腸の癌、ならびに例えば慢性骨髄性白血病、急性リンパ性白血病、非ホジキンリンパ腫、黒色腫、癌、基底細胞癌、悪性中皮腫、神経芽腫、多発性骨髄腫、白血病、網膜芽腫、急性骨髄性白血病、慢性リンパ性白血病、ホジキンリンパ腫、カルチノイド腫瘍、急性腫瘍、もしくは軟部組織肉芽種を含む任意の癌)であると診断された対象(例えば癌患者)の、治療、例えば化合物または薬剤、例えば化学療法剤もしくは放射線による治療に対する感受性もしくは抵抗性を推定するために使用することができる。 Common chemotherapeutic agents, vincristine, cisplatin, azaguanine, etoposide, adriamycin, aclarubicin, mitoxantrone, mitomycin, paclitaxel, gemcitabine, taxotere, dexamethasone, Ara-C, methylprednisolone, methotrexate, bleomycin, methyl-GAG, Chemosensitive / chemical resistant biospecific for carboplatin, 5-FU (5-fluorouracil), rituximab, radiation, histone deacetylase (HDAC) inhibitor, and 5-aza-2'-deoxycytidine (decitabine) Devices that utilize the markers are also provided. The methods and devices are used for disease conditions such as cancer (e.g., breast, prostate, lung, and bronchial, colon and rectum, bladder, skin, kidney, pancreas, oral cavity and pharynx, ovary, thyroid, parathyroid, stomach, brain, esophagus. , Liver and intrahepatic bile duct, cervix / pharynx, heart, testis, small intestine and large intestine, anus, anal canal and anorectum, vulva, gallbladder, pleura, bone and joint, hypopharynx, eyes and orbits, nose, nasal cavity and middle ear , Nasopharynx, ureter, peritoneum, omentum, mesentery, or gastrointestinal cancer, and for example, chronic myelogenous leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, melanoma, cancer, basal cell carcinoma, malignant mesothelioma, nerve Blastoma, multiple myeloma, leukemia, retinoblastoma, acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, carcinoid tumor, acute tumor, or any cancer including soft tissue granulation) Diagnosed subject (e.g., cancer patients), the treatment can be used, for example, compounds or agents, for example, to estimate the sensitivity or resistance to treatment with chemotherapeutic agents or radiation.
第1の局面では、本発明は、遺伝子が、
からなる群より選択され、遺伝子の発現レベルの変化は、患者が治療に感受性または抵抗性を有することを意味する、少なくとも1つの遺伝子の発現レベルを決定することによって、患者の細胞(例えば癌細胞)における、癌の治療に対する癌患者の感受性を推定する方法を特徴とする。ある態様では、方法は、列挙された遺伝子の2つ、より好ましくは、列挙された遺伝子の3つ、4つ、5つ、6つ、7つ、8つ、9つ、または10、ならびに最も好ましくは、列挙された遺伝子の20、30、40、50、60、70、80、90、または100、もしくはこれ以上の発現を判定する段階を含む。別の態様では、治療に感受性を有することが既知である細胞または組織における遺伝子の発現レベルに対する遺伝子の発現レベルの変化(例えば上昇もしくは低下)が判定され、患者の細胞または組織によって示される遺伝子の発現レベルが同等であることが、患者が治療に感受性を有することを意味する。別の態様では、治療に抵抗性を有することが既知である細胞または組織における遺伝子の発現レベルに対する、遺伝子の発現レベルの変化(例えば上昇もしくは低下)が判定され、患者の細胞または組織に見られる遺伝子の発現レベルが同等であることが、患者が治療に抵抗性を有することを意味する。
In the first aspect, the present invention provides a gene comprising:
A change in the expression level of a gene is selected from the group consisting of a patient cell (e.g., a cancer cell) by determining the expression level of at least one gene, which means that the patient is sensitive or resistant to treatment. In the method of estimating the sensitivity of a cancer patient to the treatment of cancer. In some embodiments, the method comprises two of the listed genes, more preferably three, four, five, six, seven, eight, nine, or ten of the listed genes, and most Preferably, the method includes determining the expression of 20, 30, 40, 50, 60, 70, 80, 90, or 100, or more of the listed genes. In another aspect, a change (eg, increase or decrease) in the expression level of a gene relative to the expression level of the gene in a cell or tissue that is known to be susceptible to treatment is determined, and the gene Equivalent expression levels mean that the patient is sensitive to treatment. In another aspect, a change (eg, increase or decrease) in the expression level of a gene relative to the expression level of the gene in a cell or tissue that is known to be resistant to treatment is determined and found in the patient's cell or tissue Equivalent gene expression levels mean that the patient is resistant to treatment.
別の態様では、少なくとも1つの遺伝子は、RPS4X、S100A4、NDUFS6、C14orf139、SLC25A5、RPL10、RPL12、EIF5A、RPL36A、BLMH、CTBP1、TBCA、MDH2、およびDXS9879Eからなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がビンクリスチンによる治療に感受性を有することを意味する。または方法はさらに、UBB、B2M、MAN1A1、およびSUI1からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がビンクリスチンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of RPS4X, S100A4, NDUFS6, C14orf139, SLC25A5, RPL10, RPL12, EIF5A, RPL36A, BLMH, CTBP1, TBCA, MDH2, and DXS9879E, one of these Alternatively, an increase in the expression level of multiple genes means that the patient is sensitive to treatment with vincristine. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of UBB, B2M, MAN1A1, and SUI1, wherein the increased expression level of one or more of these genes is Is sensitive to treatment with vincristine.
別の態様では、少なくとも1つの遺伝子は、C1QR1、SLA、PTPN7、ZNFN1A1、CENTB1、IFI16、ARHGEF6、SEC31L2、CD3Z、GZMB、CD3D、MAP4K1、GPR65、PRF1、ARHGAP15、TM6SF1、およびTCF4からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がシスプラチンによる治療に感受性を有することを意味する。または方法はさらに、HCLS1、CD53、PTPRCAP、およびPTPRCからなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がシスプラチンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of C1QR1, SLA, PTPN7, ZNFN1A1, CENTB1, IFI16, ARHGEF6, SEC31L2, CD3Z, GZMB, CD3D, MAP4K1, GPR65, PRF1, ARHGAP15, TM6SF1, and TCF4 An increase in the expression level of one or more of these genes means that the patient is sensitive to treatment with cisplatin. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of HCLS1, CD53, PTPRCAP, and PTPRC, wherein the increased expression level of one or more of these genes is Is sensitive to treatment with cisplatin.
別の態様では、少なくとも1つの遺伝子は、SRM、SCARB1、SIAT1、CUGBP2、ICAM1、WASPIP、ITM2A、PALM2-AKAP2、PTPNS1、MPP1、LNK、FCGR2A、RUNX3、EVI2A、BTN3A3、LCP2、BCHE、LY96、LCP1、IFI16、MCAM、MEF2C、SLC1A4、FYN、C1orf38、CHS1、FCGR2C、TNIK、AMPD2、SEPT6、RAFTLIN、SLC43A3、RAC2、LPXN、CKIP-1、FLJ10539、FLJ35036、DOCK10、TRPV2、IFRG28、LEF1、およびADAMTS1からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がアザグアニンによる治療に感受性を有することを意味する。または方法はさらに、MSN、SPARC、VIM、GAS7、ANPEP、EMP3、BTN3A2、FN1、およびCAPN3からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、遺伝子の発現の上昇は、患者が治療に感受性を有することを意味し、ならびに治療はアザグアニンによる治療である。 In another embodiment, the at least one gene is SRM, SCARB1, SIAT1, CUGBP2, ICAM1, WASPIP, ITM2A, PALM2-AKAP2, PTPNS1, MPP1, LNK, FCGR2A, RUNX3, EVI2A, BTN3A3, LCP2, BCHE, LY96, LCP1 , IFI16, MCAM, MEF2C, SLC1A4, FYN, C1orf38, CHS1, FCGR2C, TNIK, AMPD2, SEPT6, RAFTLIN, SLC43A3, RAC2, LPXN, CKIP-1, FLJ10539, FLJ35036, DOCK10, TRPV1, IFRG28, TS1 An increase in the expression level of one or more of these genes selected from the group means that the patient is sensitive to treatment with azaguanine. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of MSN, SPARC, VIM, GAS7, ANPEP, EMP3, BTN3A2, FN1, and CAPN3, wherein the increased expression of the gene Means that the patient is sensitive to treatment, as well as treatment with azaguanine.
別の態様では、少なくとも1つの遺伝子は、CD99、INSIG1、PRG1、MUF1、SLA、SSBP2、GNB5、MFNG、PSMB9、EVI2A、PTPN7、PTGER4、CXorf9、ZNFN1A1、CENTB1、NAP1L1、HLA-DRA、IFI16、ARHGEF6、PSCDBP、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、GZMB、SCN3A、RAFTLIN、DOCK2、CD3D、RAC2、ZAP70、GPR65、PRF1、ARHGAP15、NOTCH1、およびUBASH3Aからなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がエトポシドによる治療に感受性を有することを意味する。または方法はさらに、LAPTM5、HCLS1、CD53、GMFG、PTPRCAP、PTPRC、CORO1A、およびITKからなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がエトポシドによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is CD99, INSIG1, PRG1, MUF1, SLA, SSBP2, GNB5, MFNG, PSMB9, EVI2A, PTPN7, PTGER4, CXorf9, ZNFN1A1, CENTB1, NAP1L1, HLA-DRA, IFI16, ARHGEF6 , PSCDBP, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, GZMB, SCN3A, RAFTLIN, DOCK2, CD3D, RAC2, ZAP70, GPR65, PRF1, ARHGAP15, NOTCH1, and UBASH3A, one or more of these An increase in the expression level of the gene means that the patient is sensitive to treatment with etoposide. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of LAPTM5, HCLS1, CD53, GMFG, PTPRCAP, PTPRC, CORO1A, and ITK, and one or more of these genes An increase in the expression level means that the patient is sensitive to treatment with etoposide.
別の態様では、少なくとも1つの遺伝子は、CD99、ALDOC、SLA、SSBP2、IL2RG、CXorf9、RHOH、ZNFN1A1、CENTB1、CD1C、MAP4K1、CD3G、CCR9、CXCR4、ARHGEF6、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、CD1A、LAIR1、TRB@、CD3D、WBSCR20C、ZAP70、IFI44、GPR65、AIF1、ARHGAP15、NARF、およびPACAPからなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がアドリアマイシンによる治療に感受性を有することを意味する。または方法はさらに、LAPTM5、HCLS1、CD53、GMFG、PTPRCAP、TCF7、CD1B、PTPRC、CORO1A、HEM1、およびITKからなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がアドリアマイシンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is CD99, ALDOC, SLA, SSBP2, IL2RG, CXorf9, RHOH, ZNFN1A1, CENTB1, CD1C, MAP4K1, CD3G, CCR9, CXCR4, ARHGEF6, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A , CD1A, LAIR1, TRB @, CD3D, WBSCR20C, ZAP70, IFI44, GPR65, AIF1, ARHGAP15, NARF, and PACAP, the increased expression level of one or more of these genes Means sensitive to treatment with adriamycin. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of LAPTM5, HCLS1, CD53, GMFG, PTPRCAP, TCF7, CD1B, PTPRC, CORO1A, HEM1, and ITK, and An increase in the expression level of one or more genes means that the patient is sensitive to treatment with adriamycin.
別の態様では、少なくとも1つの遺伝子は、RPL12、RPLP2、MYB、ZNFN1A1、SCAP1、STAT4、SP140、AMPD3、TNFAIP8、DDX18、TAF5、RPS2、DOCK2、GPR65、HOXA9、FLJ12270、およびHNRPDからなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がアクラルビシンによる治療に感受性を有することを意味する。または方法はさらに、RPL32、FBL、およびPTPRCからなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がアクラルビシンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of RPL12, RPLP2, MYB, ZNFN1A1, SCAP1, STAT4, SP140, AMPD3, TNFAIP8, DDX18, TAF5, RPS2, DOCK2, GPR65, HOXA9, FLJ12270, and HNRPD An increase in the expression level of one or more of these genes means that the patient is sensitive to treatment with aclarubicin. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of RPL32, FBL, and PTPRC, wherein the increased expression level of one or more of these genes is determined by the patient Means sensitive to treatment with
別の態様では、少なくとも1つの遺伝子は、PGAM1、DPYSL3、INSIG1、GJA1、BNIP3、PRG1、G6PD、PLOD2、LOXL2、SSBP2、C1orf29、TOX、STC1、TNFRSF1A、NCOR2、NAP1L1、LOC94105、ARHGEF6、GATA3、TFPI、LAT、CD3Z、AF1Q、MAP1B、TRIM22、CD3D、BCAT1、IFI44、CUTC、NAP1L2、NME7、FLJ21159、およびCOL5A2からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がミトキサントロンによる治療に感受性を有することを意味する。または方法はさらに、BASP1、COL6A2、PTPRC、PRKCA、CCL2、およびRAB31からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がミトキサントロンによる治療に感受性を有することを意味する。 In another embodiment, at least one gene is PGAM1, DPYSL3, INSIG1, GJA1, BNIP3, PRG1, G6PD, PLOD2, LOXL2, SSBP2, C1orf29, TOX, STC1, TNFRSF1A, NCOR2, NAP1L1, LOC94105, ARHGEF6, GATA3, TFPI Selected from the group consisting of LAT, CD3Z, AF1Q, MAP1B, TRIM22, CD3D, BCAT1, IFI44, CUTC, NAP1L2, NME7, FLJ21159, and COL5A2, and increased expression level of one or more of these genes Is sensitive to treatment with mitoxantrone. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of BASP1, COL6A2, PTPRC, PRKCA, CCL2, and RAB31, and the expression level of one or more of these genes An increase means that the patient is sensitive to treatment with mitoxantrone.
別の態様では、少なくとも1つの遺伝子は、STC1、GPR65、DOCK10、COL5A2、FAM46A、およびLOC54103からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がマイトマイシンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of STC1, GPR65, DOCK10, COL5A2, FAM46A, and LOC54103, and the increased expression level of one or more of these genes is indicated when the patient is treated with mitomycin It means that it has sensitivity.
別の態様では、少なくとも1つの遺伝子は、RPL10、RPS4X、NUDC、DKC1、DKFZP564C186、PRP19、RAB9P40、HSA9761、GMDS、CEP1、IL13RA2、MAGEB2、HMGN2、ALMS1、GPR65、FLJ10774、NOL8、DAZAP1、SLC25A15、PAF53、DXS9879E、PITPNC1、SPANXC、およびKIAA1393からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がパクリタキセルによる治療に感受性を有することを意味する。または方法はさらに、RALYの発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がパクリタキセルによる治療に感受性を有することを意味する。 In another aspect, the at least one gene is RPL10, RPS4X, NUDC, DKC1, DKFZP564C186, PRP19, RAB9P40, HSA9761, GMDS, CEP1, IL13RA2, MAGEB2, HMGN2, ALMS1, GPR65, FLJ10774, NOL8, DAZAP1, PA3, SLC25A15 , DXS9879E, PITPNC1, SPANXC, and KIAA1393, an increase in the expression level of one or more of these genes means that the patient is sensitive to treatment with paclitaxel. Alternatively, the method further comprises measuring the expression level of RALY, increasing the expression level of one or more of these genes means that the patient is sensitive to treatment with paclitaxel.
別の態様では、少なくとも1つの遺伝子は、PFN1、PGAM1、K-ALPHA-1、CSDA、UCHL1、PWP1、PALM2-AKAP2、TNFRSF1A、ATP5G2、AF1Q、NME4、およびFHOD1からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がゲムシタビンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of PFN1, PGAM1, K-ALPHA-1, CSDA, UCHL1, PWP1, PALM2-AKAP2, TNFRSF1A, ATP5G2, AF1Q, NME4, and FHOD1. An increase in the expression level of one or more genes means that the patient is sensitive to treatment with gemcitabine.
別の態様では、少なくとも1つの遺伝子は、ANP32B、GTF3A、RRM2、TRIM14、SKP2、TRIP13、RFC3、CASP7、TXN、MCM5、PTGES2、OBFC1、EPB41L4B、およびCALML4からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がタキソテールによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of ANP32B, GTF3A, RRM2, TRIM14, SKP2, TRIP13, RFC3, CASP7, TXN, MCM5, PTGES2, OBFC1, EPB41L4B, and CALML4. Alternatively, increased expression levels of multiple genes means that the patient is sensitive to treatment with taxotere.
別の態様では、少なくとも1つの遺伝子は、IFITM2、UBE2L6、USP4、ITM2A、IL2RG、GPRASP1、PTPN7、CXorf9、RHOH、GIT2、ZNFN1A1、CEP1、TNFRSF7、MAP4K1、CCR7、CD3G、ATP2A3、UCP2、GATA3、CDKN2A、TARP、LAIR1、SH2D1A、SEPT6、HA-1、ERCC2、CD3D、LST1、AIF1、ADA、DATF1、ARHGAP15、PLAC8、CECR1、LOC81558、およびEHD2からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がデキサメタゾンによる治療に感受性を有することを意味する。または方法はさらに、LAPTM5、ITGB2、ANPEP、CD53、CD37、ADORA2A、GNA15、PTPRC、CORO1A、HEM1、FLII、およびCREB3L1からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がデキサメタゾンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is IFITM2, UBE2L6, USP4, ITM2A, IL2RG, GPRASP1, PTPN7, CXorf9, RHOH, GIT2, ZNFN1A1, CEP1, TNFRSF7, MAP4K1, CCR7, CD3G, ATP2A3, UCP2, NATA, UCP2, N Selected from the group consisting of TARP, LAIR1, SH2D1A, SEPT6, HA-1, ERCC2, CD3D, LST1, AIF1, ADA, DATF1, ARHGAP15, PLAC8, CECR1, LOC81558, and EHD2, and one or more genes thereof An increase in the expression level means that the patient is sensitive to treatment with dexamethasone. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of LAPTM5, ITGB2, ANPEP, CD53, CD37, ADORA2A, GNA15, PTPRC, CORO1A, HEM1, FLII, and CREB3L1, An increase in the expression level of one or more of these genes means that the patient is sensitive to treatment with dexamethasone.
別の態様では、少なくとも1つの遺伝子は、ITM2A、RHOH、PRIM1、CENTB1、NAP1L1、ATP5G2、GATA3、PRKCQ、SH2D1A、SEPT6、NME4、CD3D、CD1E、ADA、およびFHOD1からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がAra-Cによる治療に感受性を有することを意味する。または方法はさらに、GNA15、PTPRC、およびRPL13からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がAra-Cによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of ITM2A, RHOH, PRIM1, CENTB1, NAP1L1, ATP5G2, GATA3, PRKCQ, SH2D1A, SEPT6, NME4, CD3D, CD1E, ADA, and FHOD1. An increase in the expression level of one or more genes means that the patient is sensitive to treatment with Ara-C. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of GNA15, PTPRC, and RPL13, wherein the increased expression level of one or more of these genes is determined by the patient Means sensitive to treatment with -C.
別の態様では、少なくとも1つの遺伝子は、
からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメチルプレドニゾロンによる治療に感受性を有することを意味する。または方法はさらに、SRRM1、LAPTM5、ITGB2、CD53、CD37、GMFG、PTPRCAP、GNA15、BLM、PTPRC、CORO1A、PRKCB1、HEM1、およびUGT2B17からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメチルプレドニゾロンによる治療に感受性を有することを意味する。
In another embodiment, the at least one gene is
An increase in the expression level of one or more of these genes selected from the group consisting of means that the patient is sensitive to treatment with methylprednisolone. Or the method further measures the expression level of at least one gene selected from the group consisting of SRRM1, LAPTM5, ITGB2, CD53, CD37, GMFG, PTPRCAP, GNA15, BLM, PTPRC, CORO1A, PRKCB1, HEM1, and UGT2B17 Increasing the expression level of one or more of these genes, including stages, means that the patient is sensitive to treatment with methylprednisolone.
別の態様では、少なくとも1つの遺伝子は、PRPF8、RPL18、GOT2、RPL13A、RPS15、RPLP2、CSDA、KHDRBS1、SNRPA、IMPDH2、RPS19、NUP88、ATP5D、PCBP2、ZNF593、HSU79274、PRIM1、PFDN5、OXA1L、H3F3A、ATIC、CIAPIN1、RPS2、PCCB、SHMT2、RPLP0、HNRPA1、STOML2、SKB1、GLTSCR2、CCNB1IP1、MRPS2、FLJ20859、およびFLJ12270からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメトトレキセートによる治療に感受性を有することを意味する。または方法はさらに、RNPS1、RPL32、EEF1G、PTMA、RPL13、FBL、RBMX、およびRPS9からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメトトレキセートによる治療に感受性を有することを意味する。 In another aspect, the at least one gene is PRPF8, RPL18, GOT2, RPL13A, RPS15, RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2, RPS19, NUP88, ATP5D, PCBP2, ZNF593, HSU79274, PRIM1, PFDN5, OXA1L, H3F3A Selected from the group consisting of ATIC, CIAPIN1, RPS2, PCCB, SHMT2, RPLP0, HNRPA1, STOML2, SKB1, GLTSCR2, CCNB1IP1, MRPS2, FLJ20859, and FLJ12270. Means that the patient is sensitive to treatment with methotrexate. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of RNPS1, RPL32, EEF1G, PTMA, RPL13, FBL, RBMX, and RPS9, and one or more of these genes An increase in the expression level means that the patient is sensitive to treatment with methotrexate.
別の態様では、少なくとも1つの遺伝子は、
からなる群より、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がブレオマイシンによる治療に感受性を有することを意味する。または方法はさらに、MSN、ACTR2、AKR1B1、VIM、ITGA3、OPTN、M6PRBP1、COL1A1、BASP1、ANPEP、TGFB1、NFIL3、NK4、CSPG2、PLAU、COL6A2、UBC、FGFR1、BAX、COL4A2、およびRAB31からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がブレオマイシンによる治療に感受性を有することを意味する。
In another embodiment, the at least one gene is
An increase in the expression level of one or more of these genes from the group consisting of means that the patient is sensitive to treatment with bleomycin. Or the method further comprises the group consisting of MSN, ACTR2, AKR1B1, VIM, ITGA3, OPTN, M6PRBP1, COL1A1, BASP1, ANPEP, TGFB1, NFIL3, NK4, CSPG2, PLAU, COL6A2, UBC, FGFR1, BAX, COL4A2, and RAB31 Measuring the expression level of at least one gene more selected, and increasing the expression level of one or more of these genes means that the patient is sensitive to treatment with bleomycin.
別の態様では、少なくとも1つの遺伝子は、SSRP1、NUDC、CTSC、AP1G2、PSME2、LBR、EFNB2、SERPINA1、SSSCA1、EZH2、MYB、PRIM1、H2AFX、HMGA1、HMMR、TK2、WHSC1、DIAPH1、LAMB3、DPAGT1、UCK2、SERPINB1、MDN1、BRRN1、G0S2、RAC2、MGC21654、GTSE1、TACC3、PLEK2、PLAC8、HNRPD、およびPNAS-4からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメチル-GAGによる治療に感受性を有することを意味する。または方法はさらに、PTMAの発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がメチル-GAGによる治療に感受性を有することを意味する。 In another embodiment, at least one gene is SSRP1, NUDC, CTSC, AP1G2, PSME2, LBR, EFNB2, SERPINA1, SSSCA1, EZH2, MYB, PRIM1, H2AFX, HMGA1, HMMR, TK2, WHSC1, DIAPH1, LAMB3, DPAGT1 Selected from the group consisting of UCK2, SERPNB1, MDN1, BRRN1, G0S2, RAC2, MGC21654, GTSE1, TACC3, PLEK2, PLAC8, HNRPD, and PNAS-4. , Meaning that the patient is sensitive to treatment with methyl-GAG. Alternatively, the method further comprises measuring the expression level of PTMA, and increasing the expression level of one or more of these genes means that the patient is sensitive to treatment with methyl-GAG.
別の態様では、少なくとも1つの遺伝子は、ITGA5、TNFAIP3、WNT5A、FOXF2、LOC94105、IFI16、LRRN3、DOCK10、LEPRE1、COL5A2、およびADAMTS1からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がカルボプラチンによる治療に感受性を有することを意味する。または方法はさらに、MSN、VIM、CSPG2、およびFGFR1からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がカルボプラチンによる治療に感受性を有することを意味する。 In another embodiment, the at least one gene is selected from the group consisting of ITGA5, TNFAIP3, WNT5A, FOXF2, LOC94105, IFI16, LRRN3, DOCK10, LEPRE1, COL5A2, and ADAMTS1, and the expression of one or more of these genes An elevated level means that the patient is sensitive to treatment with carboplatin. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of MSN, VIM, CSPG2, and FGFR1, wherein the increased expression level of one or more of these genes is Is sensitive to treatment with carboplatin.
別の態様では、少なくとも1つの遺伝子は、RPL18、RPL10A、ANAPC5、EEF1B2、RPL13A、RPS15、AKAP1、NDUFAB1、APRT、ZNF593、MRP63、IL6R、SART3、UCK2、RPL17、RPS2、PCCB、TOMM20、SHMT2、RPLP0、GTF3A、STOML2、DKFZp564J157、MRPS2、ALG5、およびCALML4からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者が5-フルオロウラシル(5-FU)による治療に感受性を有することを意味する。または方法はさらに、RNPS1、RPL13、RPS6、およびRPL3からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者が5-フルオロウラシル(5-FU)による治療に感受性を有することを意味する。 In another aspect, the at least one gene is RPL18, RPL10A, ANAPC5, EEF1B2, RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, MRP63, IL6R, SART3, UCK2, RPL17, RPS2, PCCB, TOMM20, SHMT2, RPLP0 Selected from the group consisting of GTF3A, STOML2, DKFZp564J157, MRPS2, ALG5, and CALML4. It means having. Or the method further comprises measuring the expression level of at least one gene selected from the group consisting of RNPS1, RPL13, RPS6, and RPL3, wherein the increased expression level of one or more of these genes is Is sensitive to treatment with 5-fluorouracil (5-FU).
別の態様では、少なくとも1つの遺伝子は、
からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がリツキシマブによる治療に感受性を有することを意味する。または方法はさらに、ITK、RALY、PSMC5、MYL6、CD1B、STMN1、GNA15、MDK、CAPG、ACTN1、CTNNA1、FARSLA、E2F4、CPSF1、SEPW1、TFRC、ABL1、TCF7、FGFR1、NUCB2、SMA3、FAT、VIM、およびATP2A3からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がリツキシマブによる治療に感受性を有することを意味する。
In another embodiment, the at least one gene is
An increase in the expression level of one or more of these genes selected from the group consisting of means that the patient is sensitive to treatment with rituximab. Or the method is further ITK, RALY, PSMC5, MYL6, CD1B, STMN1, GNA15, MDK, CAPG, ACTN1, CTNNA1, FARSLA, E2F4, CPSF1, SEPW1, TFRC, ABL1, TCF7, FGFR1, NUCB2, SMA3, FAT, VIM Measuring the expression level of at least one gene selected from the group consisting of ATP2A3, wherein increasing the expression level of one or more of these genes indicates that the patient is sensitive to treatment with rituximab means.
別の態様では、少なくとも1つの遺伝子は、
からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者が放射線療法による治療に感受性を有することを意味する。または方法はさらに、WARS、CD81、CTSB、PKM2、PPP2CB、CNN3、ANXA2、JAK1、EIF4G3、COL1A1、DYRK2、NFIL3、ACTN1、CAPN2、BTN3A2、IGFBP3、FN1、COL4A2、およびKPNB1からなる群より選択される少なくとも1つの遺伝子の発現レベルを測定する段階を含み、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者が放射線療法による治療に感受性を有することを意味する。
In another embodiment, the at least one gene is
An increase in the expression level of one or more of these genes selected from the group consisting of means that the patient is sensitive to treatment with radiation therapy. Alternatively, the method is further selected from the group consisting of WARS, CD81, CTSB, PKM2, PPP2CB, CNN3, ANXA2, JAK1, EIF4G3, COL1A1, DYRK2, NFIL3, ACTN1, CAPN2, BTN3A2, IGFBP3, FN1, COL4A2, and KPNB1 Measuring the expression level of at least one gene, and increasing the expression level of one or more of these genes means that the patient is sensitive to treatment with radiation therapy.
別の態様では、少なくとも1つの遺伝子は、
からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者がヒストンデアセチラーゼ(HDAC)阻害剤による治療に感受性を有することを意味する。
In another embodiment, the at least one gene is
An increase in the expression level of one or more of these genes selected from the group consisting of means that the patient is sensitive to treatment with a histone deacetylase (HDAC) inhibitor.
別の態様では、少なくとも1つの遺伝子は、CD99、SNRPA、CUGBP2、STAT5A、SLA、IL2RG、GTSE1、MYB、PTPN7、CXorf9、RHOH、ZNFN1A1、CENTB1、LCP2、HIST1H4C、CCR7、APOBEC3B、MCM7、LCP1、SELPLG、CD3Z、PRKCQ、GZMB、SCN3A、LAIR1、SH2D1A、SEPT6、CG018、CD3D、C18orf10、PRF1、AIF1、MCM5、LPXN、C22orf18、ARHGAP15、およびLEF1からなる群より選択され、これらの1つもしくは複数の遺伝子の発現レベルの上昇は、患者が5-アザ-2'-デオキシシチジン(デシタビン)による治療に感受性を有することを意味する。 In another aspect, the at least one gene is CD99, SNRPA, CUGBP2, STAT5A, SLA, IL2RG, GTSE1, MYB, PTPN7, CXorf9, RHOH, ZNFN1A1, CENTB1, LCP2, HIST1H4C, CCR7, APOBEC3B, MCM7, LCP1, SELP One or more genes selected from the group consisting of CD3Z, PRKCQ, GZMB, SCN3A, LAIR1, SH2D1A, SEPT6, CG018, CD3D, C18orf10, PRF1, AIF1, MCM5, LPXN, C22orf18, ARHGAP15, and LEF1 An increase in the expression level means that the patient is sensitive to treatment with 5-aza-2'-deoxycytidine (decitabine).
本発明の第2の局面は、患者(すなわち患者の癌細胞などの細胞)が、過去に患者が感受性を有していた治療に対して抵抗性を発生するようになったか否かを判定する方法を特徴とする。この方法は、本発明の第1の局面に記載された1つもしくは複数の遺伝子の発現のレベルを決定する段階を含み、治療に感受性を有することが既知である細胞もしくは組織では低下する遺伝子の発現レベルの上昇が、患者が治療に抵抗性を有するか、または抵抗性を示す傾向を有することを意味する。または、治療に感受性を有することが既知である細胞または組織では上昇する遺伝子の発現レベルの低下は、患者が治療に抵抗性を有するか、もしくは抵抗性を示す傾向を有することを意味する。 The second aspect of the invention determines whether a patient (i.e. a cell such as a patient's cancer cells) has developed resistance to a treatment that the patient has previously been sensitive to. Features method. This method comprises the step of determining the level of expression of one or more genes described in the first aspect of the invention, wherein the level of genes that are reduced in cells or tissues known to be sensitive to treatment. An increase in expression level means that the patient is resistant to or tends to be resistant to treatment. Alternatively, a decrease in the expression level of a gene that is elevated in cells or tissues that are known to be sensitive to treatment means that the patient has or tends to be resistant to treatment.
本発明の第3の局面は、本発明の第1の局面に記載された少なくとも1つの遺伝子の少なくとも5残基の連続したヌクレオチド(より好ましくは、少なくとも10残基、15残基、20残基、25残基、30残基、35残基、40残基、45残基、50残基、55残基、60残基、65残基、70残基、75残基、80残基、85残基、90残基、95残基、100残基、150残基、200残基、250残基、300残基、もしくはこれ以上の連続ヌクレオチドに相補的であるか、または同一であり;核酸が5〜20残基、25残基、5〜50残基、50〜100残基、または100残基を上回る連続ヌクレオチド長の場合もある)の1本鎖核酸(例えばデオキシリボ核酸もしくはリボ核酸)を含み、1本鎖核酸と、遺伝子またはその相補物にコードされた核酸との間における特異的なハイブリダイゼーションを可能とすることで、遺伝子の発現の検出に十分なキットを特徴とする。キットはさらに、同キットの使用によって遺伝子の発現レベルが変化していること(すなわち、本発明の第1の局面と関連して上述されたように、治療に感受性または抵抗性を有することが既知である対照試料(すなわち組織もしくは細胞)に対して上昇または低下であること)を示す、癌患者由来(例えば患者の細胞由来)の試料から回収された核酸に適用し、1本鎖核酸とハイブリダイズする遺伝子の発現のレベルを決定し、ならびに癌の治療に対する患者の感受性を推定するための指示書を含む。ある態様では、指示書にはさらに、対照試料(例えば、治療に対する感受性または抵抗性が既知である細胞もしくは組織)における遺伝子の発現に対する遺伝子の発現レベルの変化が、治療に対する患者の感受性の変化を意味する(すなわち、治療に感受性を有する細胞で発現されることが既知である遺伝子の発現のレベルの低下は、患者が治療に抵抗性を有しつつあるか、または治療に抵抗性を有する可能性が高いこと、およびこの逆を意味する)ことが記載されている。 A third aspect of the present invention provides at least 5 contiguous nucleotides (more preferably at least 10 residues, 15 residues, 20 residues) of at least one gene described in the first aspect of the present invention. , 25 residues, 30 residues, 35 residues, 40 residues, 45 residues, 50 residues, 55 residues, 60 residues, 65 residues, 70 residues, 75 residues, 80 residues, 85 Complementary or identical to contiguous nucleotides of residues, 90 residues, 95 residues, 100 residues, 150 residues, 200 residues, 250 residues, 300 residues, or more; Single-stranded nucleic acid (e.g., deoxyribonucleic acid or ribonucleic acid) of 5-20 residues, 25 residues, 5-50 residues, 50-100 residues, or even longer than 100 residues) Detection of gene expression by allowing specific hybridization between a single-stranded nucleic acid and a nucleic acid encoded by a gene or its complement And wherein the sufficient kit. The kit is further known to have altered gene expression levels through the use of the kit (i.e., sensitive or resistant to treatment as described above in connection with the first aspect of the invention). Applied to nucleic acid recovered from a sample from a cancer patient (e.g., from a patient's cells) that shows an increase or decrease relative to a control sample (i.e. tissue or cell) that is hybridized with a single-stranded nucleic acid. Includes instructions for determining the level of gene expression to soy as well as estimating the patient's susceptibility to cancer treatment. In some embodiments, the instructions further include a change in the expression level of the gene relative to the expression of the gene in a control sample (e.g., a cell or tissue that is known to be sensitive or resistant to treatment), indicating a change in the patient's sensitivity to treatment. Means (i.e. reduced level of expression of a gene known to be expressed in cells sensitive to treatment) patient may be resistant to treatment or may be resistant to treatment It means high performance and vice versa).
ある態様では、キットは、ビンクリスチン、シスプラチン、アドリアマイシン、エトポシド、アザグアニン、アクラルビシン、ミトキサントロン、パクリタキセル、マイトマイシン、ゲムシタビン、タキソテール、デキサメタゾン、メチルプレドニゾロン、Ara-C、メトトレキセート、ブレオマイシン、メチル-GAG、リツキシマブ、ヒストンデアセチラーゼ(HDAC)阻害剤、および5-アザ-2'-デオキシシチジン(デシタビン)に対する患者の抵抗性もしくは感受性を、本発明の第1の局面に記載され、ならびにこれらの薬剤による治療に感受性を有する患者では高まることが既知である1つもしくは複数の遺伝子の発現レベルを決定することで判定するために使用可能である(すなわち患者は、仮に1つもしくは複数の遺伝子の発現のレベルが対照試料(すなわち細胞もしくは組織)における遺伝子の発現のレベルに対して高ければ、指定の治療に感受性を有するか、または感受性を有する可能性が高いか判定され、遺伝子の発現レベルの上昇は、治療に感受性を有するか、またはこの逆を意味する。 In some embodiments, the kit comprises vincristine, cisplatin, adriamycin, etoposide, azaguanine, aclarubicin, mitoxantrone, paclitaxel, mitomycin, gemcitabine, taxotere, dexamethasone, methylprednisolone, Ara-C, methotrexate, bleomycin, methyl-GAB, riomycin A patient's resistance or sensitivity to histone deacetylase (HDAC) inhibitors and 5-aza-2'-deoxycytidine (decitabine) is described in the first aspect of the invention, and for treatment with these agents. It can be used to determine by determining the expression level of one or more genes that are known to be elevated in susceptible patients (i.e., the patient has a level of expression of one or more genes Control sample (i.e. If it is high relative to the level of gene expression in the cell or tissue), it is determined whether it is sensitive or likely to be sensitive to the specified treatment, and an increase in gene expression level is sensitive to the treatment Or vice versa.
ある態様では、核酸は、癌患者から回収された試料中の遺伝子に相補的な核酸を特異的に同定する能力によって特徴づけられる。 In some embodiments, the nucleic acid is characterized by the ability to specifically identify a nucleic acid that is complementary to a gene in a sample collected from a cancer patient.
本発明の第4の局面は、(例えば、1種類の遺伝子プローブを使用するか、または1つの遺伝子に対する複数の遺伝子プローブを使用する、遺伝子の発現の検出によって)さまざまな細胞タイプにおける遺伝子の発現レベルの複数の測定結果、および癌に対する治療の非存在下における細胞の成長のタイプに対する癌の治療の存在下における、このような細胞タイプの成長に関する測定結果を得て;細胞における遺伝子の発現レベルの個々の複数の測定結果を細胞の成長と相関させて相関係数を得て;遺伝子に関して計算される相関係数の中央値を選択し;ならびに遺伝子を、相関係数の中央値が0.3を上回る場合には、癌の治療に対する癌患者の感受性の判定に使用されるバイオマーカーとして同定することで(好ましくは遺伝子は、相関係数が0.4、0.5、0.6、0.7、0.8、0.9、0.95、もしくは0.99、またはこれ以上を上回る場合に、治療に対する患者の感受性のバイオマーカーとして同定される)、癌の治療に対する癌患者の感受性の指標となるバイオマーカーを同定する方法を特徴とする。ある態様では、方法は、第2の治療の存在下で実施される。 A fourth aspect of the invention is the expression of genes in various cell types (e.g., by detecting the expression of genes, using one gene probe or using multiple gene probes for one gene) Obtain multiple measurements of levels and measurements of the growth of such cell types in the presence of cancer treatment versus the type of growth of cells in the absence of treatment for cancer; the level of gene expression in the cell Correlate multiple individual measurements with cell growth to obtain a correlation coefficient; select the median correlation coefficient calculated for the gene; and select a gene with a median correlation coefficient of 0.3 If so, by identifying it as a biomarker used to determine the susceptibility of a cancer patient to cancer treatment (preferably a gene has a correlation coefficient of 0.4, 0 .5, 0.6, 0.7, 0.8, 0.9, 0.95, or 0.99, or higher, identified as a biomarker of patient susceptibility to treatment), an indicator of cancer patient susceptibility to cancer treatment Features a method of identifying a biomarker. In certain embodiments, the method is performed in the presence of a second treatment.
本発明の第5の局面は、患者に由来する試料(例えば細胞もしくは組織)からバイオマーカー遺伝子の発現に関する測定結果を得て;癌の治療に対する感受性を推定し、線形和、最近傍、最近似重心(nearest centroids)、線形判別分析、サポートベクタマシン、およびニューラルネットワークからなる群より選択されるアルゴリズムを使用して開発されるモデルを測定結果に適用し;ならびに患者が癌の治療に反応するか否かを推定することで、癌の治療に対する患者(例えば癌患者)の感受性を推定する方法を特徴とする。ある態様では、測定結果は、治療に感受性または抵抗性を有することが既知である細胞におけるバイオマーカーの遺伝子発現を調べることで得られる。別の態様ではモデルは、線形和、線形判別分析、サポートベクタマシン、ニューラルネットワーク、k-最近傍、および最近似重心で得られた結果を組み合わせるか、またはモデルは、複数の測定結果の無作為標本を用いて相互検証される。別の態様では、治療、例えば、化合物は過去に、患者における効果を示すのに失敗している。複数の態様では、線形和が、感受性を有することが既知である参照母集団の和と比較され;参照母集団の和は、集団構成員のバイオマーカー遺伝子の発現に由来する和の中央値である。別の態様では、モデルは、独立成分分析で得られたデータセットの成分に由来するか、または主成分分析で得られたデータセットの成分に由来する。 The fifth aspect of the present invention obtains a measurement result relating to the expression of a biomarker gene from a sample (eg, cell or tissue) derived from a patient; estimates sensitivity to cancer treatment, linear sum, nearest neighbor, nearest approximation Apply a model developed using an algorithm selected from the group consisting of nearest centroids, linear discriminant analysis, support vector machines, and neural networks to the measurement results; and whether the patient responds to cancer treatment It features a method for estimating the sensitivity of a patient (eg, a cancer patient) to cancer treatment by estimating whether or not. In certain embodiments, the measurement results are obtained by examining gene expression of biomarkers in cells that are known to be sensitive or resistant to treatment. In another aspect, the model combines results obtained with linear sums, linear discriminant analysis, support vector machines, neural networks, k-nearest neighbors, and closest centroids, or the model is a randomization of multiple measurements Cross-validated using specimens. In another aspect, the treatment, eg, the compound, has previously failed to show an effect in the patient. In embodiments, the linear sum is compared to a reference population sum known to be sensitive; the reference population sum is the median of the sums derived from the expression of the biomarker genes of the population members. is there. In another aspect, the model is derived from a component of the data set obtained by independent component analysis or from a component of the data set obtained by principal component analysis.
本発明の第6の局面は、本発明の第5の局面に記載の方法の実施に使用されるキット、装置、およびソフトウェアを特徴とする。 A sixth aspect of the invention features a kit, apparatus, and software used to perform the method described in the fifth aspect of the invention.
本発明の全ての局面の複数の態様では、遺伝子の発現レベルは、遺伝子から転写されるmRNAのレベルを検出することで、遺伝子のタンパク質産物のレベルを検出することで、または遺伝子のタンパク質産物の生物学的活性のレベルを検出することで決定される。本発明の全ての局面の別の態様では、治療に感受性を有する細胞もしくは組織における遺伝子の発現レベルに対する遺伝子の発現レベルの上昇または低下は、治療に対する癌患者の感受性の上昇を意味する。または、治療に抵抗性を有する細胞もしくは組織における遺伝子の発現レベルに対する、遺伝子の発現レベルの上昇もしくは低下は、治療に対する癌患者の抵抗性の上昇を意味する。本発明の全ての局面の別の態様では、細胞は癌細胞である。本発明の全ての局面の別の態様では、遺伝子の発現レベルは、定量逆転写ポリメラーゼ連鎖反応(qRT-PCR)で測定される。本発明の全ての局面の態様では、列挙された遺伝子の2つの発現のレベルが検討され、より好ましくは、列挙された遺伝子の3つ、4つ、5つ、6つ、7つ、8つ、9つ、または10の発現のレベルが検討され、ならびに最も好ましくは、列挙された遺伝子の20、30、40、50、60、70、80、90、または100、もしくはこれ以上が検討される。本発明の全ての局面の別の態様では、遺伝子の発現レベルは、本発明の第3の局面のキットを使用して決定される。 In embodiments of all aspects of the invention, the level of gene expression is detected by detecting the level of mRNA transcribed from the gene, by detecting the level of the protein product of the gene, or of the protein product of the gene. It is determined by detecting the level of biological activity. In another embodiment of all aspects of the invention, increasing or decreasing the expression level of a gene relative to the expression level of the gene in a cell or tissue that is sensitive to treatment means an increase in the sensitivity of the cancer patient to the treatment. Alternatively, an increase or decrease in the expression level of a gene relative to the expression level of the gene in a cell or tissue that is resistant to treatment means an increase in the resistance of the cancer patient to the treatment. In another embodiment of all aspects of the invention, the cell is a cancer cell. In another embodiment of all aspects of the invention, the level of gene expression is measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In embodiments of all aspects of the invention, the level of expression of the two listed genes is examined, more preferably three, four, five, six, seven, eight of the listed genes. , 9 or 10 expression levels are considered, and most preferably 20, 30, 40, 50, 60, 70, 80, 90, or 100 or more of the listed genes are considered . In another embodiment of all aspects of the invention, the expression level of the gene is determined using the kit of the third aspect of the invention.
本発明の全ての局面の別の態様では、治療は、ビンクリスチン、シスプラチン、アドリアマイシン、エトポシド、アザグアニン、アクラルビシン、ミトキサントロン、パクリタキセル、マイトマイシン、ゲムシタビン、タキソテール、デキサメタゾン、メチルプレドニゾロン、Ara-C、メトトレキセート、ブレオマイシン、メチル-GAG、リツキシマブ、ヒストンデアセチラーゼ(HDAC)阻害剤、および5-アザ-2'-デオキシシチジン(デシタビン)からなる群より選択される化学療法剤などの化合物である。本発明の全ての局面の別の態様では、化合物は過去に、対象(例えば、治療に感受性を有することが推定される亜集団から選択される対象、治療なしには死亡すると推定される亜集団から選択される対象、治療なしには疾患症状を有すると推定される亜集団から選択される対象、治療なしに治癒すると推定される亜集団から選択される対象)における効果を示すことに失敗している。 In another embodiment of all aspects of the invention, the treatment comprises vincristine, cisplatin, adriamycin, etoposide, azaguanine, aclarubicin, mitoxantrone, paclitaxel, mitomycin, gemcitabine, taxotere, dexamethasone, methylprednisolone, Ara-C, methotrexate, Compounds such as chemotherapeutic agents selected from the group consisting of bleomycin, methyl-GAG, rituximab, histone deacetylase (HDAC) inhibitors, and 5-aza-2′-deoxycytidine (decitabine). In another embodiment of all aspects of the invention, the compound has previously been selected in a subject (e.g., a subject selected from a subpopulation presumed to be sensitive to treatment, a subpopulation presumed to die without treatment). , Subjects selected from subpopulations presumed to have disease symptoms without treatment, or subjects selected from subpopulations presumed to cure without treatment). ing.
本発明の全ての局面の別の態様では、治療は例えば、化合物、タンパク質、抗体、オリゴヌクレオチド、化学療法剤、または放射線の患者への投与である。本発明の全ての局面の態様では、治療は例えば、例えばビンクリスチン、シスプラチン、アザグアニン、エトポシド、アドリアマイシン、アクラルビシン、ミトキサントロン、マイトマイシン、パクリタキセル、ゲムシタビン、タキソテール、デキサメタゾン、Ara-C、メチルプレドニゾロン、メトトレキセート、ブレオマイシン、メチル-GAG、カルボプラチン、5-FU(5-フルオロウラシル)、MABTHERA(商標)(リツキシマブ)、ヒストンデアセチラーゼ(HDAC)阻害剤、5-アザ-2'-デオキシシチジン(デシタビン)などの化学療法剤、アスタチン-211、ビスマス-212、ビスマス-213、鉛-212、ラジウム-223、アクチニウム-225、およびトリウム-227などのアルファ放射体、トリチウム、ストロンチウム-90、セシウム-137、炭素-11、窒素-13、酸素-15、フッ素-18、鉄-52、コバルト-55、コバルト-60、銅-61、銅-62、銅-64、亜鉛-62、亜鉛-63、ヒ素-70、ヒ素-71、ヒ素-74、臭素-76、臭素-79、ルビジウム-82、イットリウム-86、ジルコニウム-89、インジウム-110、ヨウ素-120、ヨウ素-124、ヨウ素-129、ヨウ素-131、ヨウ素-125、キセノン-122、テクネチウム-94m、テクネチウム-94、テクネチウム-99m、およびテクネチウム-99などのベータ放射体、コバルト-60、セシウム-137、およびテクネチウム-99mなどのガンマ放射体、アレムツズマブ、ダクリズマブ、リツキシマブ(MABTHERA(商標))、トラスツズマブ(HERCEPTIN(商標))、ゲムツズマブ、イブリツマブ、エドレコロマブ、トシツモマブ、CeaVac、エプラツズマブ、ミツモマブ、ベバシズマブ、セツキシマブ、エドレコロマブ、リンツズマブ、MDX-210、IGN-101、MDX-010、MAb、AME、ABX-EGF、EMD 72 000、アポリズマブ(Apolizumab)、ラベツズマブ(Labetuzumab)、ior-t1、MDX-220、MRA、H-11 scFv、オレゴポマブ、huJ591 MAb、BZL、ビシリズマブ(Visilizumab)、TriGem、TriAb、R3、MT-201、G-250、非抱合型、ACA-125、Onyvax-105、CDP-860、BrevaRex MAb、AR54、IMC-1C11、GlioMAb-H、ING-1、抗LCG MAb、MT-103、KSB-303、Therex、KW-2871、抗HMI.24、抗PTHrP、2C4抗体、SGN-30、TRAIL-RI MAb、CAT、前立腺癌抗体、H22xKi-4、ABX-MA1、イミュテラン(Imuteran)、モノファーム-C、アシビシン、アクラルビシン、塩酸アコダゾール、アクロニン、アドゼレシン、アドリアマイシン、アルデスロイキン、アルトレタミン、アンボマイシン、酢酸アメタントロン、アミノグルテチミド、アムサクリン、アナストロゾール、アントラマイシン、アスパラギナーゼ、アスペルリン、アザシチジン、アゼテパ、アゾトマイシン、バチマスタット、ベンゾデパ、ビカルタミド、塩酸ビサントレン、ビスナフィドジメシラート、ビゼレシン、硫酸ブレオマイシン、ブレキナールナトリウム、ブロピリミン、ブスルファン、カクチノマイシン、カルステロン、カンプトセシン、カラセミド、カルベチマー、カルボプラチン、カルムスチン、塩酸カルビシン、カルゼレシン、セデフィンゴール、クロランブシル、シロレマイシン、シスプラチン、クラドリビン、コンブレタスタチン(Combretestatin)A-4、メシル酸クリスナトール、シクロホスファミド、シタラビン、ダカルバジン、DACA(N-[2-(ジメチル-アミノ)エチル]アクリジン-4-カルボキサミド)、ダクチノマイシン、塩酸ダウノルビシン、ダウノマイシン、デシタビン、デキソルマプラチン、デザグアニン、メシル酸デザグアニン、ジアジコン、ドセタキセル、ドルサチン(Dolasatin)、ドキソルビシン、塩酸ドキソルビシン、ドロロキシフェン、クエン酸ドロロキシフェン、プロピオン酸ドロスタノロン、デュアゾマイシン、エダトレキサート、塩酸エフロルニチン、エリプチシン、エルサミトルシン、エンロプラチン、エンプロメート、エピプロピジン、塩酸エピルビシン、エルブロゾール、塩酸エソルビシン、エストラムスチン、エストラムスチンリン酸ナトリウム、エタニダゾール、エチオダイズド油I 131、エトポシド、リン酸エトポシド、エトプリン、塩酸ファドロゾール、ファザラビン、フェンレチニド、フロキシウリジン、リン酸フルダラビン、フルオロウラシル、5-FdUMP、フルロシタビン、ホスキドン、ホスホトリエシンナトリウム、ゲムシタビン、塩酸ゲムシタビン、金Au 198、ホモカンプトセシン、ヒドロキシ尿素、塩酸イダルビシン、イホスファミド、イルモホシン、インターフェロンアルファ-2a、インターフェロンアルファ-2b、インターフェロンアルファ-nl、インターフェロンアルファ-n3、インターフェロンベータ-Ia、インターフェロンガンマ-Ib、イプロプラチン、塩酸イリノテカン、酢酸ランレオチド、レトロゾール、酢酸ロイプロイド、塩酸リアロゾール、ロメトレキソールナトリウム、ロムスチン、塩酸ロソキサントロン、マソプロコール、メイタンシン、塩酸メクロレタミン、酢酸メゲストロール、酢酸メレンゲストロール、メルファラン、メノガリル、メルカプトプリン、メトトレキセート、メトトレキセートナトリウム、メトプリン(Metoprine)、メツレデパ、ミチンドミド、ミトカルシン、ミトクロミン、マイトジリン、ミトマルシン、マイトマイシン、ミトスパー、ミトタン、塩酸ミトキサントロン、ミコフェノール酸、ノコダゾール、ノガラマイシン、オルマプラチン、オキシスラン、パクリタキセル、ペグアスパルガーゼ、ペリオマイシン、ペンタムスチン、硫酸ペプロイシン(PeploycinSulfate)、ペルホスファミド、ピポブロマン、ピポスルファン、塩酸ピロキサントロン、プリカマイシン、プロメスタン、ポルフィマーナトリウム、ポルフィロマイシン、プレドニムスチン、塩酸プロカルバジン、ピューロマイシン、塩酸ピューロマイシン、ピラゾフリン、リゾキシン、リゾキシンD、リボプリン、ログレチミド、サフィンゴール、塩酸サフィンゴール、セムスチン、シムトラゼン、スパルフォセートナトリウム、スパルソマイシン、塩酸スピロゲルマニウム、スピロムスチン、スピロプラチン、ストレプトニグリン、ストレプトゾシン、塩化ストロンチウムSr 89、スロフェヌル、タリソマイシン、タキサン、タキソイド、テコガランナトリウム、テガフール、塩酸テロキサントロン、テモポルフィン、テニポシド、テロキシロン、テストラクトン、チアミプリン、チオグアニン、チオテパ、チミタック、チアゾフリン、チラパザミン、トムデックス、TOP53、塩酸トポテカン、クエン酸トレミフェン、酢酸トレストロン、リン酸トリシリビン、トリメトレキサート、グルクロン酸トリメトレキサート、トリプトレリン、塩酸ツブロゾール、ウラシル・マスタード、ウレデパ、バプレオチド、ベルテポルフィン、ビンブラスチン、硫酸ビンブラスチン、ビンクリスチン、硫酸ビンクリスチン、ビンデシン、硫酸ビンデシン、硫酸ビネジピン、硫酸ビングリシネート、硫酸ビンレウロシン、酒石酸ビノレルビン、硫酸ビンロシジン、硫酸ビンゾリジン、ボロゾール、ゼニプラチン、ジノスタチン、塩酸ゾルビシン、2-クロロデオキシアデノシン、2'デオキシホルマイシン、9-アミノカンプトセシン、ラルチトレキセド、N-プロパルギル-5,8-ジデアザ葉酸、2-クロロ-2'-アラビノ-フルオロ-2'-デオキシアデノシン、2-クロロ-2'-デオキシアデノシン、アニソマイシン、トリコスタチンA、hPRL-G129R、CEP-751、リノミド、硫黄マスタード、ナイトロジェンマスタード(メクロレタミン)、シクロホスファミド、メルファラン、クロランブシル、イホスファミド、ブスルファン、N-メチル-Nニトロソ尿素(MNU)、N,N'-ビス(2-クロロエチル)-N-ニトロソ尿素(BCNU)、N-(2-クロロエチル)-N'シクロヘキシル-N-ニトロソ尿素(CCNU)、N-(2-クロロエチル)-N'-(トランス-4-メチルシクロヘキシル-N-ニトロソ尿素(MeCCNU)、N-(2-クロロエチル)-N'-(ジエチル)エチルホスホネート-N-ニトロソ尿素(フォテムスチン)、ストレプトゾトシン、ジカルバジン(DTIC)、ミトゾロミド、テモゾロマイド、チオテパ、マイトマイシンC、AZQ、アドゼレシン、シスプラチン、カルボプラチン、オルマプラチン、オキサリプラチン、C1-973、DWA 2114R、JM216、JM335、ビス(白金)、トムデックス、アザシチジン、シタラビン、ゲムシタビン、6-メルカプトプリン、6-チオグアニン、ヒポキサンチン、テニポシド9-アミノカンプトセシン、トポテカン、CPT-11、ドキソルビシン、ダウノマイシン、エピルビシン、ダルビシン、ミトキサントロン、ロソキサントロン、ダクチノマイシン(アクチノマイシンD)、アムサクリン、ピラゾロアクリジン、全トランス型レチノール、14-ヒドロキシ-レトロ-レチノール、全トランス型レチノイン酸、N-(4-ヒドロキシフェニル)レチナミド、13-シスレチノイン酸、3-メチルTTNEB、9-シスレチノイン酸、フルダラビン(2-F-ara-AMP)、2-クロロデオキシアデノシン(2-Cda)、20-pi-1,25ジヒドロキシビタミンD3、5-エチニルウラシル、アビラテロン、アクラルビシン、アシルフルベン、アデシペノール、アドゼレシン、アルデスロイキン、ALL-TKアンタゴニスト、アルトレタミン、アンバムスチン、アミドックス、アミフォスチン、アミノレブリン酸、アムルビシン、アムサクリン、アナグレリド、アナストロゾール、アンドログラホリド、血管形成阻害剤、アンタゴニストD、アンタゴニストG、アンタレリックス、抗背方化形態形成タンパク質-1、抗アンドロゲン、前立腺癌、抗エストロゲン、アンチネオプラストン、アンチセンスオリゴヌクレオチド、グリシン酸アフィディコリン、アポトーシス遺伝子調節因子、アポトーシス調節因子、アプリン酸、ara-CDP-DL-PTBA、アルギニンデアミナーゼ、アスラクリン、アタメスタン、アトリムスチン、アキシナスタチン1、アキシナスタチン2、アキシナスタチン3、アザセトロン、アザトキシン、アザチロシン、バッカチンIII誘導体、バラノール、バチマスタット、BCR/ABLアンタゴニスト、ベンゾクロリンス、ベンゾイルスタウロスポリン、ベータラクタム誘導体、ベータ-アレチン、ベタクラマイシンB、ベツリン酸、bFGF阻害剤、ビカルタミド、ビサントレン、ビサジリジニルスペルミン、ビスナフィド、ビストラテンA、ビゼレシン、ブレフレート、ブレオマイシンA2、ブレオマイシンB2、ブロピリミン、ブドチタン、ブチオニンスルフォキシミン、カルシポトリオール、カルフォスチンC、カンプトセシン誘導体(例えば10-ヒドロキシ-カンプトセシン)、カナリア痘IL-2、カペシタビン、カルボキサミド-アミノ-トリアゾール、カルボキシアミドトリアゾール、CaRest M3、CARN 700、軟骨由来阻害剤、カルゼレシン、カゼインキナーゼ阻害剤(ICOS)、カスタノスペルミン、セクロピンB、セトロレリクス、クロリンス、クロロキノキサリンスルホンアミド、シカプロスト、シス-ポルフィリン、クラドリビン、クロミフェン類似体、クロトリマゾール、コリスマイシンA、コリスマイシンB、コンブレタスタチンA4、コンブレタスタチン類似体、コナゲニン、クラムベシジン816、クリスナトール、クリプトフィシン8、クリプトフィシンA誘導体、キュラシンA、シクロペンタントラキノン、シクロプラタム、シペマイシン、シタラビンオクフォスファート、細胞溶解因子、サイトスタチン、ダクリキシマブ、デシタビン、デヒドロダイデムニンB、2'デオキシコホルマイシン(DCF)、デスロレリン、デキシフォスファミド、デクスラゾキサン、デクスベラパミル、ジアジクォン、ジデムニンB、ジドックス、ジエチルノルスペルミン、ジヒドロ-5-アザシチジン、ジヒドロタキソール、9-、ジオキサマイシン、ジフェニルスピロムスチン、ディスコデルモライド、ドコサノール、ドラセトロン、ドキシフルリジン、ドロロキシフェン、
ドロナビノール、デュオカルマイシンSA、エブセレン、エコムスチン、エデルホシン、エドレコロマブ、エフロルニチン、エレメン、エミテフール、エピルビシン、エポシロン(A、R=H、B、R=Me)、エピシロン、エプリステリド、エストラムスチン類似体、エストロゲンアゴニスト、エストロゲンアンタゴニスト、エタニダゾール、エトポシド、エトポシド4'-リン酸(etopofos)、エキセメスタン、ファドロゾール、ファザラビン、フェンレチニド、フィルグラスチム、フィナステリド、フラボピリドール、フレゼラスチン、フルアステロン、フルダラビン、塩酸フルオロダウノルビシン、ホルフェニメクス、ホルメスタン、ホストリエシン、フォテムスチン、ガドリニウムテキサフィリン、硝酸ガリウム、ガロシタビン、ガニレリクス、ゼラチナーゼ阻害剤、ゲムシタビン、グルタチオン阻害剤、ヘプスルファム、ヘレグリン、ヘキサメチレンビサセタミド(hexamethylene bisacetamide)、ホモハリントニン(HHT)、ヒペリシン、イバンドロン酸、イダルビシン、イドキシフェン、イドラマントン、イルモホシン、イロマスタット、イミダゾアクリドン、イミキモド、免疫賦活性ペプチド、インスリン様成長因子-1受容体阻害剤、インターフェロンアゴニスト、インターフェロン、インターロイキン、イオベングアン、ヨードドキソルビシン、イポメアノール、4-、イリノテカン、イロプラクト、イルソグラジン、イソベンガゾール、イソホモハリコンドリンB、イタセトロン、ジャスプラキノリド、カハラリドF、ラメラリン-Nトリアセテート、ランレオチド、レイナマイシン、レノグラスチム、硫酸レンチナン、レプトールスタチン、レトロゾール、白血病抑制因子、白血球アルファインターフェロン、ロイプロリド+エストロゲン+プロゲステロン、リュープロレリン、レバミゾール、リアロゾール、直鎖ポリアミン類似体、脂溶性二糖ペプチド、脂溶性白金化合物、リソクリンアミド7、ロバプラチン、ロンブリシン、ロメトレキソール、ロニダミン、ロソキサントロン、ロバスタチン、ロキソリビン、ルロトテカン(lurtotecan)、ルテチウムテキサフィリン、リソフィリン、溶解ペプチド、メイタンシン、マンノスタチンA、マリマスタット、マソプロコール、マスピン、マトリリシン阻害剤、マトリックスメタロプロテイナーゼ阻害剤、メノガリル、メルバロン、メテレリン、メチオニナーゼ、メトクロプラミド、MIF阻害剤、イフェプリストン(ifepristone)、ミルテホシン、ミリモスチム、ミスマッチを含む2本鎖RNA、ミトラシン、ミトグアゾン、ミトラクトール、マイトマイシン類似体、ミトナフィド、ミトトキシン線維芽細胞成長因子-サポリン、ミトキサントロン、モファロテン、モルグラモスチム、モノクローナル抗体、ヒト絨毛性ゴナドトロピン、モノホスホリル脂質A+ミオバクテリウム細胞壁sk、モピダモール、多剤耐性遺伝子阻害剤、多発性腫瘍抑制因子1ベースの治療薬、マスタード抗癌剤、マイカペルオキシドB、マイコバクテリウム細胞壁抽出物、ミリアポロン、N-アセチルジナリン、N-置換ベンズアミド、ナファレリン、ナグレスチップ、ナロキソン+ペンタゾシン、ナパビン、ナフテルピン、ナルトグラスチム、ネダプラチン、ネモルビシン、ネリドロン酸、中性エンドペプチダーゼ、ニルタミド、ニサマイシン、一酸化窒素調節物質、ニトロキシド抗酸化剤、ニトルリン、06-ベンジルグアニン、オクトレオチド、オキセノン、オリゴヌクレオチド、オナプリストン、オンダンセトロン、オンダンセトロン、オラシン、経口サイトカイン誘導物質、オルマプラチン、オサテロン、オキサリプラチン、オキザウノマイシン、パクリタキセル類似体、パクリタキセル誘導体、パラウアミン、パルミトイルリゾキシン、パミドロン酸、パナキシトリオール、パノミフェン、パラバクチン、パゼリプチン、ペガスパルガーゼ、ペルデシン、ペントサンポリサルフェートナトリウム、ペントスタチン、ペントロゾール、ペルフルブロン、ペルホスファミド、ペリリルアルコール、フェナジノマイシン、フェニル酢酸、ホスファターゼ阻害剤、ピシバニール、塩酸ピロカルピン、ピラルビシン、ピリトレキシム、プラセチンA、プラセチンB、プラスミノーゲンアクチベーター阻害剤、白金錯体、白金化合物、白金-トリアミン錯体、ポドフィロトキシン、ポルフィマーナトリウム、ポルフィロマイシン、プロピルビス-アクリドン、プロスタグランジンJ2、プロテアソーム阻害剤、タンパク質Aベースの免疫調節因子、タンパク質キナーゼC阻害剤、タンパク質キナーゼC阻害剤(微細藻類)、タンパク質チロシンホスファターゼ阻害剤、プリンヌクレオシドホスホリラーゼ阻害剤、プルプリン、ピラゾロアクリジン、ピリドキシル化ヘモグロビンポリオキシエチレンコンジュゲート、rafアンタゴニスト、ラルチトレキセド、ラモセトロン、rasファルネシルタンパク質トランスフェラーゼ阻害剤、ras阻害剤、ras-GAP阻害剤、脱メチル化レテリプチン、エチドロン酸レニウムRe 186、リゾキシン、リボザイム、RIIレチナミド、ログレチミド、ロヒツキン、ロムルチド、ロキニメクス、ルビギノンB1、ルボキシル、サフィンゴール、サイントピン、SarCNU、サルコフィトールA、サルグラモスチム、Sdi 1模倣物、セムスチン、老化由来阻害剤1、センスオリゴヌクレオチド、シグナル伝達阻害剤、シグナル伝達調節因子、1本鎖抗原結合タンパク質、シゾフィラン、ソブゾキサン、ボロカプタートナトリウム、フェニル酢酸ナトリウム、ソルベロール、ソマトメジン結合タンパク質、ソネルミン、スパルホス酸、スピカマイシンD、スピロムスチン、スプレノペンチン、スポンジスタチン1、スクアラミン、幹細胞阻害剤、幹細胞分裂阻害剤、スチピアミド、ストロメライシン阻害剤、スルフィノシン、超活性血管作用性腸管ペプチドアンタゴニスト、スラディスタ(suradista)、スラミン、スワインソニン、合成グリコサミノグリカン、タリムスチン、タモキシフェンメチオダイド、タウロムスチン、タザロテン、テコガランナトリウム、テガフール、テルラピリリウム、テロメラーゼ阻害剤、テモポルフィン、テモゾロマイド、テニポシド、テトラクロロデカオキシド、テトラゾミン、サリブラスチン、サリドマイド、チオコラリン、トロンボポエチン、トロンボポエチン模倣物、サイマルファシン、サイモポエチン受容体アゴニスト、チモトリナン、甲状腺刺激ホルモン、スズエチルエチオプルプリン、チラパザミン、チタノセンジクロリド、トポテカン、トプセンチン、トレミフェン、全能性幹細胞因子、翻訳阻害剤、トレチノイン、トリアセチルウリジン、トリシリビン、トリメトレキサート、トリプトレリン、トロピセトロン、ツロステリド、チロシンキナーゼ阻害剤、トリホスチン(tyrphostin)、UBC阻害剤、ウベニメクス、尿生殖洞由来増殖阻害因子、ウロキナーゼ受容体アンタゴニスト、バプレオチド、バリオリン(variolin)B、ベクター系、赤血球遺伝子治療薬、ベラレソール、ベラミン、ベルディンス(verdins)、ベルテポルフィン、ビノレルビン、ビンキサルチン、バイタクシン、ボロゾール、ザノテロン、ゼニプラチン、ジラスコルブ、またはジノスタチンスチマラマーの投与である。本発明の全ての局面の別の態様では、第2の治療が、患者に由来する試料における遺伝子発現を判定するために使用される。
In another embodiment of all aspects of the invention, the treatment is, for example, administration of a compound, protein, antibody, oligonucleotide, chemotherapeutic agent, or radiation to a patient. In embodiments of all aspects of the invention, the treatment is, for example, vincristine, cisplatin, azaguanine, etoposide, adriamycin, aclarubicin, mitoxantrone, mitomycin, paclitaxel, gemcitabine, taxotere, dexamethasone, Ara-C, methylprednisolone, methotrexate, Chemistry such as bleomycin, methyl-GAG, carboplatin, 5-FU (5-fluorouracil), MABTHERA (trademark) (rituximab), histone deacetylase (HDAC) inhibitor, 5-aza-2'-deoxycytidine (decitabine) Therapies, alpha emitters such as astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, actinium-225, and thorium-227, tritium, strontium-90, cesium-137, carbon-11 , Nitrogen-13, oxygen-15, fluorine-18, iron-52, cobalt-55 Cobalt-60, copper-61, copper-62, copper-64, zinc-62, zinc-63, arsenic-70, arsenic-71, arsenic-74, bromine-76, bromine-79, rubidium-82, yttrium- 86, zirconium-89, indium-110, iodine-120, iodine-124, iodine-129, iodine-131, iodine-125, xenon-122, technetium-94m, technetium-94, technetium-99m, and technetium-99 Beta emitters such as, cobalt-60, cesium-137, and gamma emitters such as technetium-99m, alemtuzumab, daclizumab, rituximab (MABTHERA (TM)), trastuzumab (HERCEPTIN (TM)), gemtuzumab, ibritumumab, edrecolomab, Tositumomab, CeaVac, Epratuzumab, Mitsumomab, Bevacizumab, Cetuximab, Edrecolomab, Lintuzumab, MDX-210, IGN-101, MDX-010, MAb, AME, ABX-EGF, EMD 72 000, Apolizumab , Labetuzumab, ior-t1, MDX-220, MRA, H-11 scFv, oregopomab, huJ591 MAb, BZL, Visilizumab, TriGem, TriAb, R3, MT-201, G-250, unconjugated , ACA-125, Onyvax-105, CDP-860, BrevaRex MAb, AR54, IMC-1C11, GlioMAb-H, ING-1, Anti-LCG MAb, MT-103, KSB-303, Therex, KW-2871, Anti-HMI .24, anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, CAT, prostate cancer antibody, H22xKi-4, ABX-MA1, Immuteran, Monofarm-C, acivicin, aclarubicin, acodazole hydrochloride, acronin , Adzelesin, Adriamycin, Aldesleukin, Altrethamine, Ambomycin, Amethadrone acetate, Aminoglutethimide, Amsacrine, Anastrozole, Anthramycin, Asparaginase, Asperlin, Azacitidine, Azetepa, Azotomycin, Batimastat, Benzodepa, Bi Rutamide, bisantrene hydrochloride, bisnafidodimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropyrimine, busulfan, kactinomycin, carsterone, camptothecin, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, calzelesin, cedefhingolol roslamcin Cisplatin, cladribine, combretastatin A-4, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, DACA (N- [2- (dimethyl-amino) ethyl] acridine-4-carboxamide), Dactinomycin, Daunorubicin hydrochloride, Daunomycin, Decitabine, Dexolmaplatin, Dezaguanine, Dezaguanine mesylate, Diadicon, Docetaxel, Dollar Dolasatin, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, ellipticine, elsamitrucin, enroplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozol, hydrochloric acid Esorubicin, estramustine, estramustine sodium phosphate, etanidazole, etio soybean oil I 131, etoposide, etoposide phosphate, etoprin, fadrozol hydrochloride, fazalabine, fenretinide, furoxyuridine, fludarabine phosphate, fluorouracil, 5-FdUMP, flurositadine Phosphotriescin sodium, gemcitabine, gemcitabine hydrochloride, gold Au 198, homocamptothesi , Hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosin, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, Letrozole, leuproid acetate, riarosol hydrochloride, lometrexol sodium, lomustine, rosoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogalyl, mercaptopurine, methotrexate, methotrexate sodium, methoprin ( Metoprine), metredepa, mitindomide, mitocalcin, mitochromin, mitodiline Mitomarcin, mitomycin, mitosper, mitoxane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogaramycin, ormaplatin, oxythran, paclitaxel, pegaspargase, peromycin, pentamustine, peploycin sulfate (PeploycinSulfate), perphosphamide, pipofrompione Santron, pricamycin, promestan, porfimer sodium, porphyromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, lysoxine, lysoxin D, ribopurine, logretimide, saphingol, saphingol hydrochloride, semustine, simtrazen, Sparfosate sodium, sparsomycin, spirogermani hydrochloride , Spiromustine, Spiroplatin, Streptonigrin, Streptozocin, Strontium chloride Sr 89, Sulofenur, Tarisomycin, Taxane, Taxoid, Tecogalane sodium, Tegafur, Teloxantrone hydrochloride, Temoporphine, Teniposide, Teroxilone, Test lactone, Thiamipurine, Thioguanine , Thiotepa, Timitac, Thiazofurin, Tilapazamine, Tomdex, TOP53, Topotecan hydrochloride, Toremifene citrate, Trestron acetate, Triciribine phosphate, Trimetrexate, Trimethrexate glucuronate, Triptorelin, Tubrozol hydrochloride, Uracil mustard, Uredepa, Vapreotide , Verteporfin, vinblastine, vinblastine sulfate, vincristine, vincristine sulfate, vindesi Vindecine sulfate, vinezpine sulfate, vinlicine sulfate sulfate, vinreurocin sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, borosol, xeniplatin, dinostatin, zorubicin hydrochloride, 2-chlorodeoxyadenosine, 2'deoxyformomycin, 9-aminocamptocete Syn, raltitrexed, N-propargyl-5,8-dideazafolate, 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine, anisomycin, trichostatin A, hPRL -G129R, CEP-751, linimide, sulfur mustard, nitrogen mustard (mechloretamine), cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-methyl-N nitrosourea (MNU), N, N'-bis (2-Chloroethyl) -N-nitrosourea (BCNU), N- (2-Chloroethyl) ) -N'cyclohexyl-N-nitrosourea (CCNU), N- (2-chloroethyl) -N '-(trans-4-methylcyclohexyl-N-nitrosourea (MeCCNU), N- (2-chloroethyl)- N '-(diethyl) ethylphosphonate-N-nitrosourea (fotemustin), streptozotocin, dicarbazine (DTIC), mitozolomide, temozolomide, thiotepa, mitomycin C, AZQ, adzelesin, cisplatin, carboplatin, ormaplatin, oxaliplatin, C1-973, DWA 2114R, JM216, JM335, bis (platinum), Tomdex, azacitidine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, hypoxanthine, teniposide 9-aminocamptothecin, topotecan, CPT-11, doxorubicin, daunomycin , Epirubicin, Darubicin, Mitoxantrone, Losoxanthrone, Dactinomycin ( Actinomycin D), amsacrine, pyrazoloacridine, all-trans retinol, 14-hydroxy-retro-retinol, all-trans retinoic acid, N- (4-hydroxyphenyl) retinamide, 13-cis retinoic acid, 3-methylTTNEB , 9-cis retinoic acid, fludarabine (2-F-ara-AMP), 2-chlorodeoxyadenosine (2-Cda), 20-pi-1,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acyl fulvene , Adesipenol, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambmustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antale Ricks, Dorsalization morphogenic protein-1, antiandrogen, prostate cancer, antiestrogen, antineoplaston, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene regulator, apoptosis regulator, aprinic acid, ara-CDP-DL -PTBA, arginine deaminase, aslacrine, atamestan, atormistin, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, valanol, batimastat, BCR / ABL antagonist, benzochlorin, Benzoylstaurosporine, beta-lactam derivatives, beta-alletin, betaclamycin B, betulinic acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinyl spermine, bisnafide, bistratate A, Vizelesin, Breflate, Bleomycin A2, Bleomycin B2, Bropyrimine, Bud Titanium, Buthionine Sulfoximine, Calcipotriol, Calfostin C, Camptothecin Derivatives (eg 10-hydroxy-camptothecin), Canary 痘 IL-2, Capecitabine, Carboxamide -Amino-triazole, carboxamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitor, calzeresin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorinse, chloroquinoxaline sulfonamide, cicaprost, cis- Porphyrin, cladribine, clomiphene analog, clotrimazole, chorismycin A, chorismycin B, combretastatin A4, combretastatin analog, conagenin, clambecidin 816 Crisnatol, cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentanetraquinone, cycloplatam, cypemycin, cytarabine okphosphato, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodidemnin B, 2'deoxyco Formycin (DCF), Deslorelin, Dexifosfamide, Dexrazoxane, Dexverapamil, Diadiquone, Didemnin B, Zidox, Diethylnorspermine, Dihydro-5-azacytidine, Dihydrotaxol, 9-, Dioxamycin, Diphenylspiromustine, Disco Delmolide, docosanol, dolasetron, doxyfluridine, droloxifene,
Dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosin, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epothilone (A, R = H, B, R = Me), episilon, epristeride, estramustine analogue, estrogen agonist , Estrogen antagonists, etanidazole, etoposide, etoposide 4'-phosphate (etopofos), exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, freslastin, fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenix Formestane, host riecin, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase Harmful agent, gemcitabine, glutathione inhibitor, hepsulfam, heregulin, hexamethylene bisacetamide, homohalintonin (HHT), hypericin, ibandronic acid, idarubicin, idoxifene, idramanton, ilmofosin, ilomastoid, imidazoacridone, Immunostimulatory peptide, insulin-like growth factor-1 receptor inhibitor, interferon agonist, interferon, interleukin, iobenguan, iododoxorubicin, ipomeanol, 4-, irinotecan, iropract, irsogladine, isobengazole, isohomicohalindrin B, itasetron , Jaspraquinolide, kahalalide F, lamellarin-N triacetate, lanreotide, reinamycin, lenograstim, wrench sulfate , Leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogs, fat-soluble disaccharide peptides, fat-soluble platinum compounds, lysocrine amide 7, Lovaplatin, lombricin, lometrexol, lonidamine, rosoxantrone, lovastatin, loxoribine, lulototecan, lutetium texaphyrin, lysophylline, lytic peptide, maytansine, mannostatin A, marimastat, masoprocol, maspin, matrilysin inhibitor, matrix metalloprotease inhibitor Agent, menogalil, melvalon, metereline, methioninase, metoclopramide, MIF inhibitor, ifepristone stone), miltefosine, mirimostim, mismatched double-stranded RNA, mitracin, mitoguazone, mitactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, morphothelone, morglamostim, monoclonal antibody, human chorionic Gonadotropin, monophosphoryl lipid A + myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitor, multiple tumor suppressor 1-based therapeutic agent, mustard anticancer drug, micaperoxide B, mycobacterial cell wall extract, myriapolone, N -Acetyldinarine, N-substituted benzamide, nafarelin, nagres chip, naloxone + pentazocine, napabin, naphtherpine, nartograstim, nedaplatin, nemorubicin, neridronate, neutral endopeptide Oxidase, nilutamide, nisamycin, nitric oxide modulator, nitroxide antioxidant, nitrulline, 06-benzylguanine, octreotide, oxenone, oligonucleotide, onapristone, ondansetron, ondansetron, olacin, oral cytokine inducer, ormaplatin , Osaterone, Oxaliplatin, Oxaunomycin, Paclitaxel analog, Paclitaxel derivative, Parauamine, Palmitoyl lysoxine, Pamidronic acid, Panaxitriol, Panomiphene, Parabactin, Pazelliptin, Pegaspargase, Perdesin, Pentosan polysulfate sodium, Pentostatin , Pentrozole, perfulbron, perphosphamide, perillyl alcohol, phenazinomycin, phenylacetic acid, phosphata Inhibitor, picibanil, pilocarpine hydrochloride, pirarubicin, pyritrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compound, platinum-triamine complex, podophyllotoxin, porfimer sodium, porphyromycin , Propylbis-acridone, prostaglandin J2, proteasome inhibitor, protein A-based immunomodulator, protein kinase C inhibitor, protein kinase C inhibitor (microalgae), protein tyrosine phosphatase inhibitor, purine nucleoside phosphorylase inhibitor , Purpurin, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonist, raltitrexed, ramosetron, ras farnesyl protein transfer Inhibitor, ras inhibitor, ras-GAP inhibitor, demethylated retelliptin, etidronate rhenium Re 186, lysoxin, ribozyme, RII retinamide, logretimide, lohitskin, lomultide, rokinimex, rubiginone B1, ruboxil, saphingol, signpin , SarCNU, sarcophytol A, sargramostim, Sdi 1 mimic, semustine, aging-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction regulator, single-stranded antigen binding protein, schizophyllan, sobuzoxane, borocaptoate Sodium, sodium phenylacetate, sorbelol, somatomedin binding protein, sonermine, spalphos acid, spicamycin D, spiromustine, splenopentin, spongestatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, Stipiamide, stromelysin inhibitor, sulfinosine, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycan, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan Sodium, tegafur, tellurapyrylium, telomerase inhibitor, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, salivlastine, thalidomide, thiocoraline, thrombopoietin, thrombopoietin mimetic, thymaporcin, thymopoietin receptor agonist, thymotrinan tin, thyroid gland Ethyl etiopurpurin, tirapazamine, titanocene dichloride, topotecan, topcentin, toremif , Totipotent stem cell factor, translation inhibitor, tretinoin, triacetyluridine, triciribine, trimethrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitor, tyrphostin, UBC inhibitor, ubenimex, urogenital sinus Growth inhibitor, urokinase receptor antagonist, bapreotide, variolin B, vector system, erythrocyte gene therapy drug, veralesole, veramine, verdins, verteporfin, vinorelbine, vinxartine, vitaxin, borozole, zanoplatin, xeniplatin, dilascorb Or administration of dinostatin stimamarer. In another embodiment of all aspects of the invention, a second treatment is used to determine gene expression in a sample derived from a patient.
本発明の全ての局面の別の態様では、遺伝子は、
からなる群より選択される。
In another embodiment of all aspects of the invention, the gene is
Selected from the group consisting of
列挙された各遺伝子の核酸配列は、Genbankデータベースに公開されている。遺伝子配列は、Affymetrix社のHG-U133A GeneChipの一部としても含まれている。 The nucleic acid sequence for each listed gene is published in the Genbank database. The gene sequence is also included as part of Affymetrix's HG-U133A GeneChip.
本明細書で用いる、「抵抗性を有する」または「抵抗性」という表現は、細胞、腫瘍、ヒト、または生物体が、治療、例えば化学療法剤などの化合物もしくは放射線療法を使用する治療に、治療が細胞、例えば癌細胞の成長をインビトロで、または腫瘍、ヒト、もしくは生物体において、治療に曝露されていない細胞の成長に対して10%未満、20%未満、30%未満、40%未満、50%未満、60%未満、もしくは70%未満、阻害するという点で抵抗可能なことを意味する。治療に対する抵抗性は、治療対象の細胞の成長を、本明細書に記載されたNCI60アッセイ法を実施するために使用される入射光ビームの細胞の吸光度の関数として測定する細胞ベースのアッセイ法で判定することができる。この例では、より高い吸光度は、より活発な細胞の成長、ひいては治療に対する抵抗性を意味する。成長のより小さな低下は、治療に対するより大きな抵抗性を意味する。「化学抵抗性を有する」または「化学抵抗性」という表現は、化合物に対する抵抗性を意味する。 As used herein, the expression “resistant” or “resistant” refers to treatment of a cell, tumor, human, or organism using a compound such as a chemotherapeutic agent or radiation therapy, for example, Less than 10%, less than 20%, less than 30%, less than 40% of the growth of cells that are not exposed to treatment in vitro, or in tumors, humans, or organisms , Less than 50%, less than 60%, or less than 70%. Resistance to treatment is a cell-based assay that measures the growth of cells to be treated as a function of the absorbance of the cells in the incident light beam used to perform the NCI60 assay described herein. Can be determined. In this example, higher absorbance means more active cell growth and thus resistance to treatment. A smaller drop in growth means greater resistance to treatment. The expression “having chemical resistance” or “chemical resistance” means resistance to a compound.
本明細書で用いる、「感受性を有する」または「感受性」という表現は、細胞、腫瘍、ヒト、または生物体が、治療、例えば化学療法剤などの化合物もしくは放射線療法を使用する治療に、治療が細胞、例えば癌細胞の成長をインビトロで、または腫瘍、ヒト、または生物体において、70%、80%、90%、95%、99%、もしくは100%阻害するという点で反応することを意味する。治療に対する感受性は、治療対象の細胞の成長を、本明細書に記載されたNCI60アッセイ法を実施するために使用される入射光ビームの細胞の吸光度の関数として測定する細胞ベースのアッセイ法で判定することができる。この例では、より低い吸光度は、より低い細胞の成長、ひいては治療に対する感受性を意味する。成長のより大きい減少は、治療に対する、より大きな感受性を意味する。「化学感受性を有する」または「化学感受性」という表現は、化合物に対する感受性を意味する。 As used herein, the expression “sensitive” or “sensitive” means that a cell, tumor, human, or organism is treated, eg, treatment using a compound such as a chemotherapeutic agent or radiation therapy. Means to react in terms of inhibiting the growth of cells, e.g. cancer cells, in vitro or in tumors, humans or organisms by 70%, 80%, 90%, 95%, 99%, or 100% . Sensitivity to treatment is determined by a cell-based assay that measures the growth of the cells to be treated as a function of the absorbance of the cells in the incident light beam used to perform the NCI60 assay described herein. can do. In this example, lower absorbance means lower cell growth and thus sensitivity to treatment. A greater decrease in growth means greater sensitivity to treatment. The expression “having chemical sensitivity” or “chemical sensitivity” means sensitivity to a compound.
本明細書で用いる、核酸配列の「相補物」または「相補的である」核酸配列は、一方の配列の5'端が、もう一方の配列の3'端と対をなすように核酸配列と並置されたときに、「逆平行結合」の関係にあるオリゴヌクレオチドを意味する。ヌクレオチドおよび他の塩基は相補物を有する場合があり、ならびに相補的な核酸中に存在する場合がある。本発明の核酸に含まれる可能性があるものの、天然の核酸中に通常見出されない塩基には例えば、イノシンや7-デアザグアニンが含まれる。「相補性」は完全ではない場合があり;相補的な核酸の安定な2本鎖は、ミスマッチを含む塩基対、すなわち不適合塩基を含む場合がある。核酸技術の当業者であれば、2本鎖の安定性を、例えばオリゴヌクレオチドの長さ、オリゴヌクレオチド中のシトシン塩基およびグアニン塩基のパーセント濃度、イオン強度、ならびにミスマッチを含む塩基対の存在率を含む、いくつかの変数を考慮して実験的に決定することができる。 As used herein, a “complement” or “complementary” nucleic acid sequence is a nucleic acid sequence such that the 5 ′ end of one sequence is paired with the 3 ′ end of the other sequence. It means an oligonucleotide in an “antiparallel bond” relationship when juxtaposed. Nucleotides and other bases can have complements and can be present in complementary nucleic acids. Bases that may be included in the nucleic acids of the present invention but are not normally found in natural nucleic acids include, for example, inosine and 7-deazaguanine. “Complementarity” may not be perfect; a stable duplex of complementary nucleic acids may contain mismatched base pairs, ie mismatched bases. Those skilled in the art of nucleic acid technology will determine the stability of the duplex by, for example, the length of the oligonucleotide, the percent concentration of cytosine and guanine bases in the oligonucleotide, the ionic strength, and the presence of base pairs, including mismatches. It can be determined experimentally taking into account several variables, including:
相補的な核酸配列が安定な2本鎖を形成する場合、それらは相互に「ハイブリダイズした」、もしくは「ハイブリダイズする」と表現されるか、または「ハイブリダイゼーション」が生じたと表現される。核酸は、ワトソン-クリックの塩基対合規則(例えばGとC、AとT、もしくはAとU)に従って水素結合を形成可能なヌクレオチドもしくはヌクレオチドのホモログ、または例えばジアミノプリンとT、5-メチルCとG、2-チオチミジンとA、イノシンとC、プソイドイソシトシンとGなどの他の水素結合モチーフを含む場合に、「相補的である」と言われる。アンチセンスRNAは、他のオリゴヌクレオチド、例えばmRNAに対して相補的な場合がある。 When complementary nucleic acid sequences form stable duplexes, they are said to be “hybridized” or “hybridized” to each other or “hybridized” to occur. Nucleic acids can be nucleotides or nucleotide homologues capable of forming hydrogen bonds according to Watson-Crick base pairing rules (e.g., G and C, A and T, or A and U), or diaminopurine and T, 5-methyl C And G, 2-thiothymidine and A, inosine and C, pseudoisocytosine and G, etc. are said to be “complementary”. Antisense RNA may be complementary to other oligonucleotides, such as mRNA.
本明細書で用いる「バイオマーカー」は、その発現が、治療に対する感受性または抵抗性を意味する遺伝子を意味する。 As used herein, a “biomarker” refers to a gene whose expression means sensitivity or resistance to treatment.
本明細書で用いる「化合物」は、疾患の治療に使用可能か、またはインビボもしくはインビトロにおける生物学的活性を有する、化学的物質もしくは生物学的物質、例えば、薬剤、タンパク質、抗体、またはオリゴヌクレオチドを意味する。好ましい化合物は、米国食品医薬品庁(FDA)から承認されている場合もあれば、承認されていない場合もある。好ましい化合物は例えば、癌の成長を阻害可能な化学療法剤を含む。好ましい化学療法剤は例えば、ビンクリスチン、シスプラチン、アザグアニン、エトポシド、アドリアマイシン、アクラルビシン、ミトキサントロン、マイトマイシン、パクリタキセル、ゲムシタビン、タキソテール、デキサメタゾン、Ara-C、メチルプレドニゾロン、メトトレキセート、ブレオマイシン、メチル-GAG、カルボプラチン、5-FU(5-フルオロウラシル)、MABTHERA(商標)(リツキシマブ)、放射線、ヒストンデアセチラーゼ(HDAC)阻害剤、および5-アザ-2'-デオキシシチジン(デシタビン)を含む。例示的な放射性化学療法剤は、アスタチン-211、ビスマス-212、ビスマス-213、鉛-212、ラジウム-223、アクチニウム-225、およびトリウム-227などのアルファ放射体、トリチウム、ストロンチウム-90、セシウム-137、炭素-11、窒素-13、酸素-15、フッ素-18、鉄-52、コバルト-55、コバルト-60、銅-61、銅-62、銅-64、亜鉛-62、亜鉛-63、ヒ素-70、ヒ素-71、ヒ素-74、臭素-76、臭素-79、ルビジウム-82、イットリウム-86、ジルコニウム-89、インジウム-110、ヨウ素-120、ヨウ素-124、ヨウ素-129、ヨウ素-131、ヨウ素-125、キセノン-122、テクネチウム-94m、テクネチウム-94、テクネチウム-99m、およびテクネチウム-99などのベータ放射体、またはコバルト-60、セシウム-137、およびテクネチウム-99mなどのガンマ放射体を含む化合物を含む。例示的な化学療法剤は、アレムツズマブ、ダクリズマブ、リツキシマブ(MABTHERA(商標))、トラスツズマブ(HERCEPTIN(商標))、ゲムツズマブ、イブリツマブ、エドレコロマブ、トシツモマブ、CeaVac、エプラツズマブ、ミツモマブ、ベバシズマブ、セツキシマブ、エドレコロマブ、リンツズマブ、MDX-210、IGN-101、MDX-010、MAb、AME、ABX-EGF、EMD 72 000、アポリズマブ、ラベツズマブ、ior-t1、MDX-220、MRA、H-11 scFv、オレゴポマブ、huJ591 MAb、BZL、ビシリズマブ、TriGem、TriAb、R3、MT-201、G-250、非抱合型、ACA-125、Onyvax-105、CDP-860、BrevaRex MAb、AR54、IMC-1C11、GlioMAb-H、ING-1、抗LCG MAb、MT-103、KSB-303、Therex、KW-2871、抗HMI.24、抗PTHrP、2C4抗体、SGN-30、TRAIL-RI MAb、CAT、前立腺癌抗体、H22xKi-4、ABX-MA1、イミュテラン、およびモノファーム-Cなどの抗体も含む。例示的な化学療法剤は、アシビシン;アクラルビシン;塩酸アコダゾール;アクロニン;アドゼレシン;アドリアマイシン;アルデスロイキン;アルトレタミン;アンボマイシン;酢酸アメタントロン;アミノグルテチミド;アムサクリン;アナストロゾール;アントラマイシン;アスパラギナーゼ;アスペルリン;アザシチジン;アゼテパ;アゾトマイシン;バチマスタット;ベンゾデパ;ビカルタミド;塩酸ビサントレン;ビスナフィドジメシラート;ビゼレシン;硫酸ブレオマイシン;ブレキナールナトリウム;ブロピリミン;ブスルファン;カクチノマイシン;カルステロン;カンプトセシン;カラセミド;カルベチマー;カルボプラチン;カルムスチン;塩酸カルビシン;カルゼレシン;セデフィンゴール;クロランブシル;シロレマイシン;シスプラチン;クラドリビン;コンブレタスタチンA-4;メシル酸クリスナトール;シクロホスファミド;シタラビン;ダカルバジン;DACA(N-[2-(ジメチル-アミノ)エチル]アクリジン-4-カルボキサミド);ダクチノマイシン;塩酸ダウノルビシン;ダウノマイシン;デシタビン;デキソルマプラチン;デザグアニン;メシル酸デザグアニン;ジアジコン;ドセタキセル;ドルサチン;ドキソルビシン;塩酸ドキソルビシン;ドロロキシフェン;クエン酸ドロロキシフェン;プロピオン酸ドロスタノロン;デュアゾマイシン;エダトレキサート;塩酸エフロルニチン;エリプチシン;エルサミトルシン;エンロプラチン;エンプロメート;エピプロピジン;塩酸エピルビシン;エルブロゾール;塩酸エソルビシン;エストラムスチン;エストラムスチンリン酸ナトリウム;エタニダゾール;エチオダイズド油I 131;エトポシド;リン酸エトポシド;エトプリン;塩酸ファドロゾール;ファザラビン;フェンレチニド;フロキシウリジン;リン酸フルダラビン;フルオロウラシル;5-FdUMP;フルロシタビン;ホスキドン;ホスホトリエシンナトリウム;ゲムシタビン;塩酸ゲムシタビン;金Au 198;ホモカンプトセシン;ヒドロキシ尿素;塩酸イダルビシン;イホスファミド;イルモホシン;インターフェロンアルファ-2a;インターフェロンアルファ-2b;インターフェロンアルファ-nl;インターフェロンアルファ-n3;インターフェロンベータ-Ia;インターフェロンガンマ-Ib;イプロプラチン;塩酸イリノテカン;酢酸ランレオチド;レトロゾール;酢酸ロイプロイド;塩酸リアロゾール;ロメトレキソールナトリウム;ロムスチン;塩酸ロソキサントロン;マソプロコール;メイタンシン;塩酸メクロレタミン;酢酸メゲストロール;塩酸メレンゲストロール;メルファラン;メノガリル;メルカプトプリン;メトトレキセート;メトトレキセートナトリウム;メトプリン;メツレデパ;ミチンドミド;ミトカルシン;ミトクロミン;マイトジリン;ミトマルシン;マイトマイシン;ミトスパー;ミトタン;塩酸ミトキサントロン;ミコフェノール酸;ノコダゾール;ノガラマイシン;オルマプラチン;オキシスラン;パクリタキセル;ペグアスパルガーゼ;ペリオマイシン;ペンタムスチン;硫酸ペプロイシン;ペルホスファミド;ピポブロマン;ピポスルファン;塩酸ピロキサントロン;プリカマイシン;プロメスタン;ポルフィマーナトリウム;ポルフィロマイシン;プレドニムスチン;塩酸プロカルバジン;ピューロマイシン;塩酸ピューロマイシン;ピラゾフリン;リゾキシン;リゾキシンD;リボプリン;ログレチミド;サフィンゴール;塩酸サフィンゴール;セムスチン;シムトラゼン;スパルフォセートナトリウム;スパルソマイシン;塩酸スピロゲルマニウム;スピロムスチン;スピロプラチン;ストレプトニグリン;ストレプトゾシン;塩化ストロンチウムSr 89;スロフェヌル;タリソマイシン;タキサン;タキソイド;テコガランナトリウム;テガフール;塩酸テロキサントロン;テモポルフィン;テニポシド;テロキシロン;テストラクトン;チアミプリン;チオグアニン;チオテパ;チミタック;チアゾフリン;チラパザミン;トムデックス;TOP53;塩酸トポテカン;クエン酸トレミフェン;酢酸トレストロン;リン酸トリシリビン;トリメトレキサート;グルクロン酸トリメトレキサート;トリプトレリン;塩酸ツブロゾール;ウラシル・マスタード;ウレデパ;バプレオチド;ベルテポルフィン;ビンブラスチン;硫酸ビンブラスチン;ビンクリスチン;硫酸ビンクリスチン;ビンデシン;硫酸ビンデシン;硫酸ビネジピン;硫酸ビングリシネート;硫酸ビンレウロシン;酒石酸ビノレルビン;硫酸ビンロシジン;硫酸ビンゾリジン;ボロゾール;ゼニプラチン;ジノスタチン;塩酸ゾルビシン;2-クロロデオキシアデノシン;2'デオキシホルマイシン;9-アミノカンプトセシン;ラルチトレキセド;N-プロパルギル-5,8-ジデアザ葉酸;2-クロロ-2'-アラビノ-フルオロ-2'-デオキシアデノシン;2-クロロ-2'-デオキシアデノシン;アニソマイシン;トリコスタチンA;hPRL-G129R;CEP-751;リノミド;硫黄マスタード;ナイトロジェンマスタード(メクロレタミン);シクロホスファミド;メルファラン;クロランブシル;イホスファミド;ブスルファン;N-メチル-Nニトロソ尿素(MNU);N,N'-ビス(2-クロロエチル)-N-ニトロソ尿素(BCNU);N-(2-クロロエチル)-N'シクロヘキシル-N-ニトロソ尿素(CCNU);N-(2-クロロエチル)-N'-(トランス-4-メチルシクロヘキシル-N-ニトロソ尿素(MeCCNU);N-(2-クロロエチル)-N'-(ジエチル)エチルホスホネート-N-ニトロソ尿素(フォテムスチン);ストレプトゾトシン;ジカルバジン(DTIC);ミトゾロミド;テモゾロマイド;チオテパ;マイトマイシンC;AZQ;アドゼレシン;シスプラチン;カルボプラチン;オルマプラチン;オキサリプラチン;C1-973;DWA 2114R;JM216;JM335;ビス(白金);トムデックス;アザシチジン;シタラビン;ゲムシタビン;6-メルカプトプリン;6-チオグアニン;ヒポキサンチン;テニポシド9-アミノカンプトセシン;トポテカン;CPT-11;ドキソルビシン;ダウノマイシン;エピルビシン;ダルビシン;ミトキサントロン;ロソキサントロン;ダクチノマイシン(アクチノマイシンD);アムサクリン;ピラゾロアクリジン;全トランス型レチノール;14-ヒドロキシ-レトロ-レチノール;全トランス型レチノイン酸;N-(4-ヒドロキシフェニル)レチナミド;13-シスレチノイン酸;3-メチルTTNEB;9-シスレチノイン酸;フルダラビン(2-F-ara-AMP);または2-クロロデオキシアデノシン(2-Cda)も含む。 As used herein, a “compound” is a chemical or biological substance, such as a drug, protein, antibody, or oligonucleotide, that can be used to treat a disease or has biological activity in vivo or in vitro. Means. Preferred compounds may or may not be approved by the US Food and Drug Administration (FDA). Preferred compounds include, for example, chemotherapeutic agents capable of inhibiting cancer growth. Preferred chemotherapeutic agents are e.g. vincristine, cisplatin, azaguanine, etoposide, adriamycin, aclarubicin, mitoxantrone, mitomycin, paclitaxel, gemcitabine, taxotere, dexamethasone, Ara-C, methylprednisolone, methotrexate, bleomycin, methyl-GAG, carbomycin Contains 5-FU (5-fluorouracil), MABTHERA ™ (rituximab), radiation, histone deacetylase (HDAC) inhibitors, and 5-aza-2′-deoxycytidine (decitabine). Exemplary radiochemotherapeutic agents include alpha emitters such as astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, actinium-225, and thorium-227, tritium, strontium-90, cesium -137, Carbon-11, Nitrogen-13, Oxygen-15, Fluorine-18, Iron-52, Cobalt-55, Cobalt-60, Copper-61, Copper-62, Copper-64, Zinc-62, Zinc-63 Arsenic-70, Arsenic-71, Arsenic-74, Bromine-76, Bromine-79, Rubidium-82, Yttrium-86, Zirconium-89, Indium-110, Iodine-120, Iodine-124, Iodine-129, Iodine Beta emitters such as -131, iodine-125, xenon-122, technetium-94m, technetium-94, technetium-99m, and technetium-99, or gamma emissions such as cobalt-60, cesium-137, and technetium-99m Includes compounds containing the body. Exemplary chemotherapeutic agents include: alemtuzumab, daclizumab, rituximab (MABTHERATM), trastuzumab (HERCEPTINTM), gemtuzumab, ibritumumab, edrecolomab, tositumomab, CeaVac, epratuzumab, mituzumab, bevacizumab, bevacizumab MDX-210, IGN-101, MDX-010, MAb, AME, ABX-EGF, EMD 72 000, apolizumab, ravetuzumab, ior-t1, MDX-220, MRA, H-11 scFv, oregopomab, huJ591 MAb, BZL, Bicilizumab, TriGem, TriAb, R3, MT-201, G-250, unconjugated, ACA-125, Onyvax-105, CDP-860, BrevaRex MAb, AR54, IMC-1C11, GlioMAb-H, ING-1, anti LCG MAb, MT-103, KSB-303, Therex, KW-2871, Anti-HMI.24, Anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI MAb, CAT, Prostate cancer antibody, H22xKi-4, ABX-MA1 , Antibodies, such as Immuteran, and Monofarm-C. Exemplary chemotherapeutic agents are: acivicin; aclarubicin; acodazole hydrochloride; acronin; adzelesin; adriamycin; aldesleukin; altretamine; ambomycin; Azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidodimesylate; bizzelecin; Carbicin hydrochloride; Calzelesin; Sedefhingal; Chlorambucil; Cisplatin; cladribine; combretastatin A-4; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; DACA (N- [2- (dimethyl-amino) ethyl] acridine-4-carboxamide); dactino Daunorubicin hydrochloride; Daunomycin; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diazicon; Docetaxel; Dorsatin; Doxorubicin; Doxorubicin hydrochloride; Ephrornitine hydrochloride; Ellipticin; Elsamitrucin; Enloplatin; Enpromate; Epipropidin; Epirubicin hydrochloride; Erbrozol; Esorubicin hydrochloride; Estramustine; Estradinazole; Ethiodide Oil I 131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozol Hydrochloride; Fazarabine; Fenretinide; Floxyuridine; Gemcitabine hydrochloride; gold Au 198; homocamptothecin; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; interferon alfa-2b; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-Ia; -Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuproid acetate; riarozo hydrochloride Romethrexol sodium; lomustine; rosoxanthrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol hydrochloride; melengestrol hydrochloride; melphalan; Mitodiline; mitmarcin; mitomycin; mitospar; mitopane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogaramycin; ormaplatin; Santron; Pricamycin; Promestan Porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; lysoxine; lysoxine D; ribopurine; logretimide; saphingol; saphingol: semustine; simtrazene; Spirogermanium hydrochloride; Spiroplatin; Spiroplatin; Streptonigrin; Streptozocin; Strontium chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalane sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Lactone; thiapurine; thioguanine; thiotepa; timitac; thiazofurin; tirapazamine; TOP53; Topotecan hydrochloride; Toremitofen citrate; Trestron acetate; Tricitrebin phosphate; Trimetrexate; Trimetrexate glucuronide; Triptorelin; Tubulolazole hydrochloride; Vincristine sulfate; vindesine; vindesine sulfate; vinezpine sulfate; bingricinate sulfate; vinrelosin sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; 9-aminocamptothecin; raltitrexed; N-propargyl-5,8-dideazafolate; 2-chloro-2'-arabino-fluoro-2'-deoxy 2-chloro-2'-deoxyadenosine; anisomycin; trichostatin A; hPRL-G129R; CEP-751; linamide; sulfur mustard; nitrogen mustard (mechloretamine); cyclophosphamide; melphalan; chlorambucil; ifosfamide N-methyl-N nitrosourea (MNU); N, N'-bis (2-chloroethyl) -N-nitrosourea (BCNU); N- (2-chloroethyl) -N'cyclohexyl-N-nitrosourea (CCNU); N- (2-chloroethyl) -N ′-(trans-4-methylcyclohexyl-N-nitrosourea (MeCCNU); N- (2-chloroethyl) -N ′-(diethyl) ethylphosphonate-N— Nitrosourea (fotemustine); streptozotocin; dicarbazine (DTIC); mitozolomide; temozolomide; thiotepa; mitomycin C; AZQ; adzelesin; cisplatin; carboplatin; C1-973; DWA 2114R; JM216; JM335; bis (platinum); Tomdex; azacitidine; cytarabine; gemcitabine; 6-mercaptopurine; 6-thioguanine; hypoxanthine; teniposide 9-aminocamptothecin; -11; doxorubicin; daunomycin; epirubicin; darubicin; mitoxantrone; rosoxantrone; dactinomycin (actinomycin D); amsacrine; pyrazoloacridine; all-trans-retinol; 14-hydroxy-retro-retinol; all-trans-retinoic acid N- (4-hydroxyphenyl) retinamide; 13-cis retinoic acid; 3-methyl TTNEB; 9-cis retinoic acid; fludarabine (2-F-ara-AMP); or 2-chlorodeoxyadenosine (2-Cda) Including.
他の化学療法剤は、20-pi-1,25ジヒドロキシビタミンD3;5-エチニルウラシル;アビラテロン;アクラルビシン;アシルフルベン;アデシペノール;アドゼレシン;アルデスロイキン;ALL-TKアンタゴニスト;アルトレタミン;アンバムスチン;アミドックス;アミホスチン;アミノレブリン酸;アムルビシン;アムサクリン;アナグレリド;アナストロゾール;アンドログラホリド;血管形成阻害剤;アンタゴニストD;アンタゴニストG;アンタレリックス;抗背方化形態形成タンパク質-1;抗アンドロゲン、前立腺癌;抗エストロゲン;アンチネオプラストン;アンチセンスオリゴヌクレオチド;グリシン酸アフィディコリン;アポトーシス遺伝子調節因子;アポトーシス調節因子;アプリン酸;ara-CDP-DL-PTBA;アルギニンデアミナーゼ;アスラクリン;アタメスタン;アトリムスチン;アキシナスタチン1;アキシナスタチン2;アキシナスタチン3;アザセトロン;アザトキシン;アザチロシン;バッカチンIII誘導体;バラノール;バチマスタット;BCR/ABLアンタゴニスト;ベンゾクロリンス;ベンゾイルスタウロスポリン;ベータラクタム誘導体;ベータ-アレチン;ベタクラマイシンB;ベツリン酸;bFGF阻害剤;ビカルタミド;ビサントレン;ビサジリジニルスペルミン;ビスナフィド;ビストラテンA;ビゼレシン;ブレフレート;ブレオマイシンA2;ブレオマイシンB2;ブロピリミン;ブドチタン;ブチオニンスルフォキシミン;カルシポトリオール;カルフォスチンC;カンプトセシン誘導体(例えば10-ヒドロキシ-カンプトセシン);カナリア痘IL-2;カペシタビン;カルボキサミド-アミノ-トリアゾール;カルボキシアミドトリアゾール;CaRest M3;CARN 700;軟骨由来阻害剤;カルゼレシン;カゼインキナーゼ阻害剤(ICOS);カスタノスペルミン;セクロピンB;セトロレリクス;クロリンス;クロロキノキサリンスルホンアミド;シカプロスト;シス-ポルフィリン;クラドリビン;クロミフェン類似体;クロトリマゾール;コリスマイシンA;コリスマイシンB;コンブレタスタチンA4;コンブレタスタチン類似体;コナゲニン;クラムベシジン816;クリスナトール;クリプトフィシン8;クリプトフィシンA誘導体;キュラシンA;シクロペンタントラキノン;シクロプラタム;シペマイシン;シタラビンオクフォスファート;細胞溶解因子;サイトスタチン;ダクリキシマブ;デシタビン;デヒドロダイデムニンB;2'デオキシコホルマイシン(DCF);デスロレリン;デキシフォスファミド;デクスラゾキサン;デクスベラパミル;ジアジクォン;ジデムニンB;ジドックス;ジエチルノルスペルミン;ジヒドロ-5-アザシチジン;ジヒドロタキソール、9-;ジオキサマイシン;ジフェニルスピロムスチン;ディスコデルモライド;ドコサノール;ドラセトロン;ドキシフルリジン;ドロロキシフェン;ドロナビノール;デュオカルマイシンSA;エブセレン;エコムスチン;エデルホシン;エドレコロマブ;エフロルニチン;エレメン;エミテフール;エピルビシン;エポシロン(A、R=H;B、R=Me);エピシロン;エプリステリド;エストラムスチン類似体;エストロゲンアゴニスト;エストロゲンアンタゴニスト;エタニダゾール;エトポシド;エトポシド4'-リン酸(etopofos);エキセメスタン;ファドロゾール;ファザラビン;フェンレチニド;フィルグラスチム;フィナステリド;フラボピリドール;フレゼラスチン;フルアステロン;フルダラビン;塩酸フルオロダウノルビシン;ホルフェニメクス;ホルメスタン;ホストリエシン;フォテムスチン;ガドリニウムテキサフィリン;硝酸ガリウム;ガロシタビン;ガニレリクス;ゼラチナーゼ阻害剤;ゲムシタビン;グルタチオン阻害剤;ヘプスルファム;ヘレグリン;ヘキサメチレンビサセタミド;ホモハリントニン(HHT);ヒペリシン;イバンドロン酸;イダルビシン;イドキシフェン;イドラマントン;イルモホシン;イロマスタット;イミダゾアクリドン;イミキモド;免疫賦活性ペプチド;インスリン様成長因子-1受容体阻害剤;インターフェロンアゴニスト;インターフェロン;インターロイキン;イオベングアン;ヨードドキソルビシン;イポメアノール、4-;イリノテカン;イロプラクト;イルソグラジン;イソベンガゾール;イソホモハリコンドリンB;イタセトロン;ジャスプラキノリド;カハラリドF;ラメラリン-Nトリアセテート;ランレオチド;レイナマイシン;レノグラスチム;硫酸レンチナン;レプトールスタチン;レトロゾール;白血病抑制因子;白血球アルファインターフェロン;ロイプロリド+エストロゲン+プロゲステロン;リュープロレリン;レバミゾール;リアロゾール;直鎖ポリアミン類似体;脂溶性二糖ペプチド;脂溶性白金化合物;リソクリンアミド7;ロバプラチン;ロンブリシン;ロメトレキソール;ロニダミン;ロソキサントロン;ロバスタチン;ロキソリビン;ルロトテカン;ルテチウムテキサフィリン;リソフィリン;溶解ペプチド;メイタンシン;マンノスタチンA;マリマスタット;マソプロコール;マスピン;マトリリシン阻害剤;マトリックスメタロプロテイナーゼ阻害剤;メノガリル;メルバロン;メテレリン;メチオニナーゼ;メトクロプラミド;MIF阻害剤;イフェプリストン;ミルテホシン;ミリモスチム;ミスマッチを含む2本鎖RNA;ミトラシン;ミトグアゾン;ミトラクトール;マイトマイシン類似体;ミトナフィド;ミトトキシン線維芽細胞成長因子-サポリン;ミトキサントロン;モファロテン;モルグラモスチム;モノクローナル抗体、ヒト絨毛性ゴナドトロピン;モノホスホリル脂質A+ミオバクテリウム細胞壁sk;モピダモール;多剤耐性遺伝子阻害剤;多発性腫瘍抑制因子1ベースの治療薬;マスタード抗癌剤;マイカペルオキシドB;マイコバクテリウム細胞壁抽出物;ミリアポロン;N-アセチルジナリン;N-置換ベンズアミド;ナファレリン;ナグレスチップ;ナロキソン+ペンタゾシン;ナパビン;ナフテルピン;ナルトグラスチム;ネダプラチン;ネモルビシン;ネリドロン酸;中性エンドペプチダーゼ;ニルタミド;ニサマイシン;一酸化窒素調節物質;ニトロキシド抗酸化剤;ニトルリン;06-ベンジルグアニン;オクトレオチド;オキセノン;オリゴヌクレオチド;オナプリストン;オンダンセトロン;オンダンセトロン;オラシン;経口サイトカイン誘導物質;オルマプラチン;オサテロン;オキサリプラチン;オキザウノマイシン;パクリタキセル類似体;パクリタキセル誘導体;パラウアミン;パルミトイルリゾキシン;パミドロン酸;パナキシトリオール;パノミフェン;パラバクチン;パゼリプチン;ペガスパルガーゼ;ペルデシン;ペントサンポリサルフェートナトリウム;ペントスタチン;ペントロゾール;ペルフルブロン;ペルホスファミド;ペリリルアルコール;フェナジノマイシン;フェニル酢酸;ホスファターゼ阻害剤;ピシバニール;塩酸ピロカルピン;ピラルビシン;ピリトレキシム;プラセチンA;プラセチンB;プラスミノーゲンアクチベーター阻害剤;白金錯体;白金化合物;白金-トリアミン錯体;ポドフィロトキシン;ポルフィマーナトリウム;ポルフィロマイシン;プロピルビス-アクリドン;プロスタグランジンJ2;プロテアソーム阻害剤;タンパク質Aベースの免疫調節因子;タンパク質キナーゼC阻害剤;タンパク質キナーゼC阻害剤(微細藻類);タンパク質チロシンホスファターゼ阻害剤;プリンヌクレオシドホスホリラーゼ阻害剤;プルプリン;ピラゾロアクリジン;ピリドキシル化ヘモグロビンポリオキシエチレンコンジュゲート;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasファルネシルタンパク質トランスフェラーゼ阻害剤;ras阻害剤;ras-GAP阻害剤;脱メチル化レテリプチン;エチドロン酸レニウムRe 186;リゾキシン;リボザイム;RIIレチナミド;ログレチミド;ロヒツキン;ロムルチド;ロキニメクス;ルビギノンB1;ルボキシル;サフィンゴール;サイントピン;SarCNU;サルコフィトールA;サルグラモスチム;Sdi 1模倣物;セムスチン;老化由来阻害剤1;センスオリゴヌクレオチド;シグナル伝達阻害剤;シグナル伝達調節因子;1本鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ボロカプタートナトリウム;フェニル酢酸ナトリウム;ソルベロール;ソマトメジン結合タンパク質;ソネルミン;スパルホス酸;スピカマイシンD;スピロムスチン;スプレノペンチン;スポンジスタチン1;スクアラミン;幹細胞阻害剤;幹細胞分裂阻害剤;スチピアミド;ストロメライシン阻害剤;スルフィノシン;超活性血管作用性腸管ペプチドアンタゴニスト;スラディスタ;スラミン;スワインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオダイド;タウロムスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリリウム;テロメラーゼ阻害剤;テモポルフィン;テモゾロマイド;テニポシド;テトラクロロデカオキシド;テトラゾミン;サリブラスチン;サリドマイド;チモトリナン;トロンボポエチン;トロンボポエチン模倣物;サイマルファシン;サイモポエチン受容体アゴニスト;チモトリナン;甲状腺刺激ホルモン;スズエチルエチオプルプリン;チラパザミン;チタノセンジクロリド;トポテカン;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害剤;トレチノイン;トリアセチルウリジン;トリシリビン;トリメトレキサート;トリプトレリン;トロピセトロン;ツロステリド;チロシンキナーゼ阻害剤;チルホスチン;UBC阻害剤;ウベニメクス;尿生殖洞由来増殖阻害因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリンB;ベクター系、赤血球遺伝子治療薬;ベラレソール;ベラミン;ベルディンス;ベルテポルフィン;ビノレルビン;ビンキサルチン;バイタクシン;ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;およびジノスタチンスチマラマーを含むが、これらに限定されない。 Other chemotherapeutic agents are: 20-pi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelic; Anti-dorrogens morphogenic protein-1; Antiandrogen, prostate cancer; Neoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; apric acid; ara-CDP-DL-PTBA; arginine deaminase; Ataxastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; valanol; batimastat; BCR / ABL antagonist; benzochlorin; Beta-alletin; betaclamin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantren; bisaziridinyl spermine; bisnafide; bistratene A; vizeresin; breflate; bleomycin A2; Calfopotinol; calphostin C; camptothecin derivatives (eg 10-hydroxy-camptothecin); canary 痘 IL-2; capecitabine; carboxamide-ami Carazole amide; Carnestinase inhibitor; Calzelesin; Casein kinase inhibitor (ICOS); Castanospermine; Cecropine B; Setrorelix; Clorins; Chloroquinoxaline sulfonamide; Cicaprost; Cis-porphyrin; Cladribine; clomiphene analog; clotrimazole; chorismycin A; chorismycin B; combretastatin A4; combretastatin analog; conagenin; clambecidin 816; crisnatol; cryptophycin 8; cryptophysin A derivative; Cycloplatam; Cypemycin; Cytarabine okphosphatate; Cytolytic factor; Cytostatin; Dacliximab; Decitabine; Dehydrodaidemnin B; 2'deoxycoformy Deslorelin; Dexifazoxan; Dexverazoxan; Dexverapamil; Diadiquone; Didemnin B; Zidox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Ride; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelforosine; edrecolomab; eflornithine; elemene; Epsilon; estramustine analogues; estrogen agonists; estrogen antagonists; etanidazole; etoposide; etoposide 4'-phosphate (etopofos); exemestane Fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; frazelastine; fluasterone; fludarabine; fluorodaunorubicin hydrochloride; phorphenimex; formestane; Gemcitabine; Glutathione inhibitor; Hepsulfam; Heregulin; Hexamethylenebisacetamide; Homohalintonin (HHT); Hypericin; Ibandronic acid; Idarubicin; Idoxifen; Insulin-like growth factor-1 receptor inhibitor; interferon agonist; inter Ferron; Interleukin; Iobunguan; Iododoxorubicin; Ipomeanol, 4-; Irinotecan; Iropract; Irsograzine; Isobengalzole; Isohomacarichondrin B; Itasetron; Jaspraquinolide; Lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analog; fat-soluble disaccharide peptide; Risoclinamide 7; Lovaplatin; Lombricin; Lometrexol; Lonidamine; Losoxanthrone; Lovastatin; Loxoribine; Cante; lutetium texaphyrin; lysophylline; lytic peptide; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitor; matrix metalloproteinase inhibitor; menogalyl; melvalon; Miltefosin; Millimostim; Mismatched double-stranded RNA; Mitracin; Mitguazone; Mitractol; Mitomycin analog; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofaroten; Molegramostim; Monoclonal antibody; Phosphoryl lipid A + myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based Therapeutic Agents; Mustard Anticancer Agents; Mica Peroxide B; Mycobacterial Cell Wall Extract; Myriapolone; N-Acetyldinarine; N-Substituted Benzamide; Nafarelin; Nagres Chips; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulator; Nitroxide antioxidant; Nitrulin; 06-Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel analog; paclitaxel derivative; parauamine; Zoxine; Pamidronic acid; Panaxitriol; Panomiphene; Parabactin; Pazelliptin; Pegaspargase; Perdesin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perphosphamide; Perillyl alcohol; Phenazinomycin; Pisibanil; pilocarpine hydrochloride; pirarubicin; pyritrexim; pracetin A; prasetin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; podophyllotoxin; porfimer sodium; Acridone; prostaglandin J2; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; protein Kinase C inhibitor (microalgae); protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; demethylated retelliptin; etidronate rhenium Re 186; lysoxin; ribozyme; RII retinamide; logretimide; rohitkin; lomultide; rokinimex; rubiginone B1; ruboxil; A; Sargramostim; Sdi 1 mimetic; Semustine; Aging-derived inhibitor 1; Sense oligonucleotide; Signaling inhibitor; Signaling modulator; Single-chain antigen binding protein; schizophyllan; sobuzoxane; sodium borocaptate; sodium phenylacetate; sorbelol; somatomedin binding protein; sonermine; spalphos acid; spicamycin D; spiromustine; Stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; sladista; suramin; swainsonine; synthetic glycosaminoglycan; talimustine; tamoxifen methiodide; Tecogalan sodium; tegafur; tellrapylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; Thyrimastine; Thymopoietin receptor agonists; Thymotrinan; Thyroid ethiopurine; Tilapazamine; Titanocene dichloride; Topotecan; Translation inhibitor; tretinoin; triacetyluridine; triciribine; trimethrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; Variolin B; vector system, erythrocyte gene therapy drug; veralesol; veramine; verdins; verteporfin; Norerubin; Binkisaruchin; Vitaxin; vorozole; Zanoteron; Zenipurachin; Jirasukorubu; and including zinostatin Lamar, without limitation.
本明細書で用いる、「成長を阻害する」という表現は、インビボもしくはインビトロにおける細胞の成長を、治療の非存在下における細胞のサイズまたは数に対して、治療(例えば化合物)に曝露された細胞のサイズの縮小または数の減少から明らかになるように、例えば10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、もしくは99%、またはこれ以上、低下させることを意味する。成長阻害は、細胞のアポトーシスを誘導する、細胞の壊死を誘導する、細胞周期の進行を減速する、細胞代謝を乱す、細胞溶解を誘導する、または細胞のサイズもしくは数を減じる他のいくつかの機構を誘導する治療の結果である場合がある。 As used herein, the expression “inhibit growth” refers to the growth of cells in vivo or in vitro relative to the size or number of cells in the absence of treatment, which is exposed to a treatment (eg, a compound). For example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, as will be apparent from the reduction in size or number Or it means lowering any more. Growth inhibition induces cell apoptosis, induces cell necrosis, slows cell cycle progression, disrupts cell metabolism, induces cell lysis, or some other that reduces cell size or number It may be the result of a treatment inducing mechanism.
本明細書で用いる、「マーカー遺伝子」または「バイオマーカー遺伝子」は、その発現が、治療(例えば化合物に対する曝露)に対する細胞(ひいては細胞入手元となる患者)の感受性または抵抗性と相関する細胞内の遺伝子を意味する。 As used herein, a “marker gene” or “biomarker gene” is an intracellular expression whose expression correlates with the sensitivity or resistance of a cell (and thus the patient from whom the cell was obtained) to treatment (eg, exposure to a compound). Means the gene.
本明細書で用いる「マイクロアレイ」は、1つもしくは複数の対象となるオリゴヌクレオチド、例えばDNAもしくはRNA、またはこれらの類似体を同時に定量する任意の方法に使用される装置を意味する。マイクロアレイの1つの例示的なクラスは、ガラスまたは石英の表面に結合したDNAプローブからなる。例えば、Affymetrix社製の製品を含む、いくつかのマイクロアレイは、1つの遺伝子の発現を見極めるための複数のプローブを使用する。DNAマイクロアレイは例えば、RNAまたはRNAの一部分とハイブリダイズするcDNAの断片に相補的な完全長のcDNAの場合のある、オリゴヌクレオチドプローブを含む場合がある。例示的なRNAは、mRNA、miRNA、およびmiRNA前駆体を含む。例示的なマイクロアレイは、個々の結合状態の複数の核酸に対するハイブリダイゼーションが個別に検出可能な、基質に結合した状態の複数の核酸を有する「核酸マイクロアレイ」も含む。基質は、固体または多孔性、平面状または非平面状、一体型または分散型の場合がある。例示的な核酸マイクロアレイは、Schena (ed.), DNA Microarrays: A Practical Approach (Practical Approach Series), Oxford University Press (1999);Nature Genet. 21(1)(suppl.):1-60 (1999);Schena (ed.), Microarray Biochip: Tools and Technology, Eaton Publishing Company/BioTechniques Books Division (2000)に記載されている装置の全てを含む。加えて、例示的な核酸マイクロアレイは、複数の核酸が、特にBrenner et al., Proc. Natl. Acad. Sci. USA 97(4):1665-1670 (2000)に記載されているように、一体型の平面状の基質上ではなく複数のビーズの表面に配置された、基質に結合した状態の複数の核酸を含む。核酸マイクロアレイの例は、内容の全体が参照により本明細書に組み入れられる、米国特許第6,391,623号、第6,383,754号、第6,383,749号、第6,380,377号、第6,379,897号、第6,376,191号、第6,372,431号、第6,351,712号、第6,344,316号、第6,316,193号、第6,312,906号、第6,309,828号、第6,309,824号、第6,306,643号、第6,300,063号、第6,287,850号、第6,284,497号、第6,284,465号、第6,280,954号、第6,262,216号、第6,251,601号、第6,245,518号、第6,263,287号、第6,251,601号、第6,238,866号、第6,228,575号、第6,214,587号、第6,203,989号、第6,171,797号、第6,103,474号、第6,083,726号、第6,054,274号、第6,040,138号、第6,083,726号、第6,004,755号、第6,001,309号、第5,958,342号、第5,952,180号、第5,936,731号、第5,843,655号、第5,814,454号、第5,837,196号、第5,436,327号、第5,412,087号、第5,405,783号に記載されている。 As used herein, “microarray” means a device used in any method that simultaneously quantifies one or more oligonucleotides of interest, such as DNA or RNA, or analogs thereof. One exemplary class of microarrays consists of DNA probes bound to a glass or quartz surface. For example, some microarrays, including products from Affymetrix, use multiple probes to determine the expression of a single gene. A DNA microarray may include oligonucleotide probes, which may be, for example, full-length cDNA complementary to a fragment of cDNA that hybridizes to RNA or a portion of RNA. Exemplary RNAs include mRNA, miRNA, and miRNA precursor. Exemplary microarrays also include “nucleic acid microarrays” having a plurality of nucleic acids bound to a substrate, wherein hybridization to a plurality of individually bound nucleic acids can be individually detected. The substrate can be solid or porous, planar or non-planar, monolithic or distributed. Exemplary nucleic acid microarrays are Schena (ed.), DNA Microarrays: A Practical Approach (Practical Approach Series), Oxford University Press (1999); Nature Genet. 21 (1) (suppl.): 1-60 (1999) Including all of the devices described in Schena (ed.), Microarray Biochip: Tools and Technology, Eaton Publishing Company / BioTechniques Books Division (2000). In addition, an exemplary nucleic acid microarray includes a plurality of nucleic acids, particularly as described in Brenner et al., Proc. Natl. Acad. Sci. USA 97 (4): 1665-1670 (2000). It includes a plurality of nucleic acids bound to a substrate that are disposed on the surface of a plurality of beads rather than on a planar substrate of body shape. Examples of nucleic acid microarrays are described in U.S. Pat. 6,351,712, 6,344,316, 6,316,193, 6,312,906, 6,309,828, 6,309,824, 6,306,643, 6,300,063, 6,287,850, 6,284,497, 6,284,465, 6,280,95262, 216,6,216 6,251,601, 6,245,518, 6,263,287, 6,251,601, 6,238,866, 6,228,575, 6,214,587, 6,203,989, 6,171,797, 6,103,474, 6,083, 274, 6,055 6,040,138, 6,083,726, 6,004,755, 6,001,309, 5,958,342, 5,952,180, 5,936,731, 5,843,655, 5,814,454, 5,837,196, 5,436,327, 5,312,087 It is described in.
例示的なマイクロアレイは、結合状態の個々の複数のポリペプチドに対するオリゴヌクレオチド、ペプチド、もしくはタンパク質の結合が個別に検出可能な、基質に結合した状態の複数のポリペプチドを有する「ペプチドマイクロアレイ」または「タンパク質マイクロアレイ」を含む場合もある。またはペプチドマイクロアレイは、特異的なオリゴヌクレオチド、ペプチド、もしくはタンパク質の結合を特異的に検出可能な、モノクローナル抗体、ポリクローナル抗体、ファージディスプレイ結合剤、酵母ツーハイブリッド結合剤、アプタマーを含むが、これらに限定されない複数の結合剤を有する場合がある。ペプチドアレイの例は、内容の全体が参照により本明細書に組み入れられる、WO 02/31463、WO 02/25288、WO 01/94946、WO 01/88162、WO 01/68671、WO 01/57259、WO 00/61806、WO 00/54046、WO 00/47774、WO 99/40434、WO 99/39210、WO 97/42507、および米国特許第6,268,210号、第5,766,960号、第5,143,854号に記載されている。 Exemplary microarrays are "peptide microarrays" or "peptide microarrays" having a plurality of polypeptides bound to a substrate, wherein the binding of oligonucleotides, peptides, or proteins to the respective plurality of bound polypeptides can be individually detected. It may also include a “protein microarray”. Or peptide microarrays include, but are not limited to, monoclonal antibodies, polyclonal antibodies, phage display binders, yeast two-hybrid binders, aptamers that can specifically detect binding of specific oligonucleotides, peptides, or proteins. May have multiple binders that are not. Examples of peptide arrays are WO 02/31463, WO 02/25288, WO 01/94946, WO 01/88162, WO 01/68671, WO 01/57259, WO, the entire contents of which are incorporated herein by reference. 00/61806, WO 00/54046, WO 00/47774, WO 99/40434, WO 99/39210, WO 97/42507, and US Pat. Nos. 6,268,210, 5,766,960, and 5,143,854.
本明細書で用いる「遺伝子発現」は、細胞内、組織内、生物体内、または対象内における遺伝子産物の量、例えば、DNA、RNA、もしくはタンパク質の量、DNA、RNA、もしくはタンパク質の修飾(スプライシング、リン酸化、アセチル化、もしくはメチル化など)の量、または所定の遺伝子と関連するDNA、RNA、もしくはタンパク質の活性の量を意味する。 As used herein, “gene expression” refers to the amount of a gene product in a cell, tissue, organism, or subject, such as the amount of DNA, RNA, or protein, DNA, RNA, or protein modification (splicing). , Phosphorylation, acetylation, or methylation), or the amount of DNA, RNA, or protein activity associated with a given gene.
本明細書で用いる「NCI60」は、以下の癌細胞株を含む、肺癌、結腸癌、乳癌、卵巣癌、白血病、腎癌、黒色腫、前立腺癌、および脳腫瘍に由来する60種類の癌細胞株のパネルを意味する:
。
As used herein, “NCI60” refers to 60 cancer cell lines derived from lung cancer, colon cancer, breast cancer, ovarian cancer, leukemia, kidney cancer, melanoma, prostate cancer, and brain tumor, including the following cancer cell lines: Means the panel:
.
「治療」または「医学的治療」は、化合物(例えば、薬剤、タンパク質、抗体、オリゴヌクレオチド、化学療法剤、および放射性薬剤)を、対象もしくは生物体に投与すること、または細胞もしくは腫瘍に曝露すること、または、癌もしくは癌の症状の治療または予防に使用される他の医学的介入(例えば冷凍手術や放射線療法)を意味する。放射線療法は、粒子加速器や、X線、ガンマ線、または電子(ベータ放射)ビームを放出する、関連する医学的装置などの供給源から発生させた放射線の患者への照射を含む。治療はさらに、例えば、腫瘍を対象または生物体から除去するために、手術を含む場合がある。 “Treatment” or “medical treatment” refers to administering a compound (eg, drug, protein, antibody, oligonucleotide, chemotherapeutic agent, and radiopharmaceutical) to a subject or organism, or exposing to a cell or tumor. Or other medical intervention (eg cryosurgery or radiation therapy) used to treat or prevent cancer or symptoms of cancer. Radiation therapy involves the irradiation of a patient with radiation generated from a source, such as a particle accelerator or an associated medical device that emits an X-ray, gamma ray, or electron (beta radiation) beam. Treatment may further include surgery, for example, to remove the tumor from the subject or organism.
本発明の他の特徴および利点は、以下の詳細な説明、図面、およびクレームから明らかとなる。 Other features and advantages of the invention will be apparent from the following detailed description, drawings, and claims.
詳細な説明
本発明は、治療に対する感受性、例えば化合物に対する化学感受性、または抵抗性のバイオマーカーを同定する方法、バイオマーカーを含む装置、装置を含むキット、および患者(例えば癌と診断された患者)における治療効果を推定する方法を特徴とする。本発明のキットは、対象に由来するか、または対象から得られる核酸とハイブリダイズする、治療(例えば化学療法剤による治療)に対する感受性または抵抗性のバイオマーカーであるオリゴヌクレオチドプローブを有するマイクロアレイ、および治療に対する対象の感受性または抵抗性を推定するための装置の使用に関する指示書を含む。本発明は、対象、例えば癌患者が、治療、例えば化学療法剤に感受性または抵抗性のどちらを有するかを判定するためにマイクロアレイを使用する方法も特徴とする。治療効果、例えば癌細胞の成長阻害に対する遺伝子バイオマーカーの発現の相関を元に、医学的治療に対する感受性または抵抗性の遺伝子バイオマーカーを同定する方法も特徴とする。対象が治療に感受性または抵抗性のどちらを有するかを判定するための遺伝子バイオマーカーは、治療に対する感受性または抵抗性が判明済みの患者集団内で同定される場合もある。したがって、本発明の方法、装置、およびキットを、一般集団における疾患(例えば癌)の治療には有効でないと考えられる治療に反応する患者の亜集団を同定するために使用することができる。より一般的には、化合物または他の医学的治療に対する癌患者の感受性は、治療に対する患者の応答性に関する事前の知見の有無にかかわらず、バイオマーカー遺伝子の発現を使用することで推定可能である。本発明の方法は、マイクロアレイに接続された、遺伝子発現を測定する装置で実行されるソフトウェアを使用して実施可能である。対象に由来する腫瘍試料の処理用のキットに含まれるマイクロアレイ(例えばDNAマイクロアレイ)、およびマイクロアレイを読みとるための装置、ならびに結果を対象の化学感受性プロファイルに変換するための装置を、本発明の方法の実施に使用することができる。
DETAILED DESCRIPTION The present invention is a method for identifying biomarkers that are sensitive to treatment, eg, chemosensitivity or resistance to compounds, devices comprising the biomarkers, kits comprising the devices, and patients (eg, patients diagnosed with cancer). It is characterized by a method of estimating the therapeutic effect in The kit of the invention comprises a microarray having oligonucleotide probes that are biomarkers that are sensitive or resistant to treatment (e.g., treatment with a chemotherapeutic agent) that hybridize with a nucleic acid derived from or obtained from a subject, and Includes instructions for using the device to estimate a subject's susceptibility or resistance to treatment. The invention also features a method of using a microarray to determine whether a subject, eg, a cancer patient, is sensitive or resistant to a treatment, eg, a chemotherapeutic agent. Also featured is a method for identifying genetic biomarkers that are sensitive or resistant to medical treatment based on the correlation of the expression of the gene biomarkers to therapeutic effects, such as growth inhibition of cancer cells. Genetic biomarkers for determining whether a subject is susceptible or resistant to treatment may be identified within a patient population that has been known to be sensitive or resistant to treatment. Thus, the methods, devices, and kits of the present invention can be used to identify subpopulations of patients that respond to treatments that are deemed ineffective for the treatment of diseases (eg, cancer) in the general population. More generally, the sensitivity of a cancer patient to a compound or other medical treatment can be estimated using biomarker gene expression, with or without prior knowledge of the patient's responsiveness to the treatment . The method of the present invention can be performed using software running on a device for measuring gene expression connected to a microarray. A microarray (e.g., a DNA microarray) included in a kit for processing a tumor sample from a subject, and a device for reading the microarray, and a device for converting the results into a chemosensitivity profile of the subject, are included in the method of the present invention. Can be used for implementation.
オリゴヌクレオチドプローブを含むマイクロアレイ
本発明のマイクロアレイは、例えば以下に列挙するバイオマーカー遺伝子の少なくとも5残基、8残基、12残基、20残基、30残基、40残基、60残基、80残基、100残基、150残基、もしくは200残基の連続ヌクレオチド(またはヌクレオチド類似体)と同一であるか、または相補的であるヌクレオチド配列を有する、1つもしくは複数のオリゴヌクレオチドプローブを含む。オリゴヌクレオチドプローブは例えば、5〜20残基、25残基、5〜50残基、50〜100残基、または100残基を上回るヌクレオチド長の場合がある。オリゴヌクレオチドプローブは、デオキシリボ核酸(DNA)またはリボ核酸(RNA)の場合がある。化学感受性の遺伝子バイオマーカーとして使用される、オリゴヌクレオチドプローブ内の連続ヌクレオチド(例えば、5〜20残基、25残基、5〜50残基、50〜100残基、または100残基を上回る連続ヌクレオチド)は、表1〜21または以下に列挙された遺伝子のヌクレオチドの、例えば1残基目、10残基目、20残基目、30残基目、40残基目、50残基目、60残基目、70残基目、80残基目、90残基目、100残基目、150残基目、200残基目、500残基目、もしくは1000残基目、またはこれらの近傍から開始される、本明細書に記載された1つもしくは複数の遺伝子中における連続ヌクレオチドとして存在する場合もある。表1〜21のカラムリスト_2006は、化合物リストに対する好ましい遺伝子バイオマーカーを意味する。表1〜21のカラムリスト_Preferredは、最も好ましい遺伝子バイオマーカーを意味する。表1〜21のカラムリスト_2005は、実施例1〜8で使用される他のバイオマーカーを意味する。表1〜21のカラム相関は、癌細胞の成長阻害に対するバイオマーカー遺伝子の発現の相関係数を意味する。遺伝子バイオマーカーの以下の組み合わせが、記載された治療に対する対象の感受性を検出するために使用されている:
a)発現が、ビンクリスチンに対する化学感受性を意味する、SFRS3、CCT5、RPL39、SLC25A5、UBE2S、EEF1A1、RPLP2、RPL24、RPS23、RPL39、RPL18、NCL、RPL9、RPL10A、RPS10、EIF3S2、SHFM1、RPS28、REA、RPL36A、GAPD、HNRPA1、RPS11、HNRPA1、LDHB、RPL3、RPL11、MRPL12、RPL18A、COX7B、およびRPS7の1つまたは複数の遺伝子配列、好ましくは、UBB、RPS4X、S100A4、NDUFS6、B2M、C14orf139、MAN1A1、SLC25A5、RPL10、RPL12、EIF5A、RPL36A、SUI1、BLMH、CTBP1、TBCA、MDH2、およびDXS9879Eの遺伝子配列、ならびに最も好ましくは、RPS4X、S100A4、NDUFS6、C14orf139、SLC25A5、RPL10、RPL12、EIF5A、RPL36A、BLMH、CTBP1、TBCA、MDH2、およびDXS9879Eの遺伝子配列。
b)発現が、シスプラチンに対する化学感受性を意味する、B2M、ARHGDIB、FTL、NCL、MSN、SNRPF、XPO1、LDHB、SNRPF、GAPD、PTPN7、ARHGDIB、RPS27、IFI16、C5orf13、およびHCLS1の1つまたは複数の遺伝子配列、好ましくは、C1QR1、HCLS1、CD53、SLA、PTPN7、PTPRCAP、ZNFN1A1、CENTB1、PTPRC、IFI16、ARHGEF6、SEC31L2、CD3Z、GZMB、CD3D、MAP4K1、GPR65、PRF1、ARHGAP15、TM6SF1、およびTCF4の遺伝子配列、ならびに最も好ましくは、C1QR1、SLA、PTPN7、ZNFN1A1、CENTB1、IFI16、ARHGEF6、SEC31L2、CD3Z、GZMB、CD3D、MAP4K1、GPR65、PRF1、ARHGAP15、TM6SF1、およびTCF4の遺伝子配列。
c)発現が、アザグアニンに対する化学感受性を意味する、PRPS1、DDOST、B2M、SPARC、LGALS1、CBFB、SNRPB2、MCAM、MCAM、EIF2S2、HPRT1、SRM、FKBP1A、GYPC、UROD、MSN、HNRPA1、SND1、COPA、MAPRE1、EIF3S2、ATP1B3、EMP3、ECM1、ATOX1、NARS、PGK1、OK/SW-cl.56、FN1、EEF1A1、GNAI2、PRPS1、RPL7、PSMB9、GPNMB、PPP1R11、MIA、RAB7、VIM、およびSMSの1つまたは複数の遺伝子配列、好ましくは、MSN、SPARC、VIM、SRM、SCARB1、SIAT1、CUGBP2、GAS7、ICAM1、WASPIP、ITM2A、PALM2-AKAP2、ANPEP、PTPNS1、MPP1、LNK、FCGR2A、EMP3、RUNX3、EVI2A、BTN3A3、LCP2、BCHE、LY96、LCP1、IFI16、MCAM、MEF2C、SLC1A4、BTN3A2、FYN、FN1、C1orf38、CHS1、CAPN3、FCGR2C、TNIK、AMPD2、SEPT6、RAFTLIN、SLC43A3、RAC2、LPXN、CKIP-1、FLJ10539、FLJ35036、DOCK10、TRPV2、IFRG28、LEF1、およびADAMTS1の遺伝子配列、ならびに最も好ましくは、SRM、SCARB1、SIAT1、CUGBP2、ICAM1、WASPIP、ITM2A、PALM2-AKAP2、PTPNS1、MPP1、LNK、FCGR2A、RUNX3、EVI2A、BTN3A3、LCP2、BCHE、LY96、LCP1、IFI16、MCAM、MEF2C、SLC1A4、FYN、C1orf38、CHS1、FCGR2C、TNIK、AMPD2、SEPT6、RAFTLIN、SLC43A3、RAC2、LPXN、CKIP-1、FLJ10539、FLJ35036、DOCK10、TRPV2、IFRG28、LEF1、およびADAMTS1の遺伝子配列。
d)発現が、エトポシドに対する化学感受性を意味する、B2M、MYC、CD99、RPS24、PPIF、PBEF1、およびANP32Bの1つまたは複数の遺伝子配列、好ましくは、CD99、INSIG1、LAPTM5、PRG1、MUF1、HCLS1、CD53、SLA、SSBP2、GNB5、MFNG、GMFG、PSMB9、EVI2A、PTPN7、PTGER4、CXorf9、PTPRCAP、ZNFN1A1、CENTB1、PTPRC、NAP1L1、HLA-DRA、IFI16、CORO1A、ARHGEF6、PSCDBP、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、GZMB、SCN3A、ITK、RAFTLIN、DOCK2、CD3D、RAC2、ZAP70、GPR65、PRF1、ARHGAP15、NOTCH1、およびUBASH3Aの遺伝子配列、ならびに最も好ましくは、CD99、INSIG1、PRG1、MUF1、SLA、SSBP2、GNB5、MFNG、PSMB9、EVI2A、PTPN7、PTGER4、CXorf9、ZNFN1A1、CENTB1、NAP1L1、HLA-DRA、IFI16、ARHGEF6、PSCDBP、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、GZMB、SCN3A、RAFTLIN、DOCK2、CD3D、RAC2、ZAP70、GPR65、PRF1、ARHGAP15、NOTCH1、およびUBASH3Aの遺伝子配列。
e)発現が、アドリアマイシンに対する化学感受性を意味する、KIAA0220、B2M、TOP2A、CD99、SNRPE、RPS27、HNRPA1、CBX3、ANP32B、HNRPA1、DDX5、PPIA、SNRPF、およびUSP7の1つまたは複数の遺伝子配列、好ましくは、CD99、LAPTM5、ALDOC、HCLS1、CD53、SLA、SSBP2、IL2RG、GMFG、CXorf9、RHOH、PTPRCAP、ZNFN1A1、CENTB1、TCF7、CD1C、MAP4K1、CD1B、CD3G、PTPRC、CCR9、CORO1A、CXCR4、ARHGEF6、HEM1、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、CD1A、LAIR1、ITK、TRB@、CD3D、WBSCR20C、ZAP70、IFI44、GPR65、AIF1、ARHGAP15、NARF、およびPACAPの遺伝子配列、ならびに最も好ましくは、CD99、ALDOC、SLA、SSBP2、IL2RG、CXorf9、RHOH、ZNFN1A1、CENTB1、CD1C、MAP4K1、CD3G、CCR9、CXCR4、ARHGEF6、SELPLG、LAT、SEC31L2、CD3Z、SH2D1A、CD1A、LAIR1、TRB@、CD3D、WBSCR20C、ZAP70、IFI44、GPR65、AIF1、ARHGAP15、NARF、およびPACAPの遺伝子配列。
f)発現が、アクラルビシンに対する化学感受性を意味する、RPLP2、LAMR1、RPS25、EIF5A、TUFM、HNRPA1、RPS9、MYB、LAMR1、ANP32B、HNRPA1、HNRPA1、EIF4B、HMGB2、RPS15A、およびRPS7の1つまたは複数の遺伝子配列、好ましくは、RPL12、RPL32、RPLP2、MYB、ZNFN1A1、SCAP1、STAT4、SP140、AMPD3、TNFAIP8、DDX18、TAF5、FBL、RPS2、PTPRC、DOCK2、GPR65、HOXA9、FLJ12270、およびHNRPDの遺伝子配列、ならびに最も好ましくは、RPL12、RPLP2、MYB、ZNFN1A1、SCAP1、STAT4、SP140、AMPD3、TNFAIP8、DDX18、TAF5、RPS2、DOCK2、GPR65、HOXA9、FLJ12270、およびHNRPDの遺伝子配列。
g)発現が、ミトキサントロンに対する化学感受性を意味する、ARHGEF6、B2M、TOP2A、TOP2A、ELA2B、PTMA、LMNB1、TNFRSF1A、NAP1L1、B2M、HNRPA1、RPL9、C5orf13、NCOR2、ANP32B、OK/SW-cl.56、TUBA3、HMGN2、PRPS1、DDX5、PRG1、PPIA、G6PD、PSMB9、SNRPF、およびMAP1Bの1つまたは複数の遺伝子配列、好ましくは、PGAM1、DPYSL3、INSIG1、GJA1、BNIP3、PRG1、G6PD、BASP1、PLOD2、LOXL2、SSBP2、C1orf29、TOX、STC1、TNFRSF1A、NCOR2、NAP1L1、LOC94105、COL6A2、ARHGEF6、GATA3、TFPI、LAT、CD3Z、AF1Q、MAP1B、PTPRC、PRKCA、TRIM22、CD3D、BCAT1、IFI44、CCL2、RAB31、CUTC、NAP1L2、NME7、FLJ21159、およびCOL5A2の遺伝子配列、ならびに最も好ましくは、PGAM1、DPYSL3、INSIG1、GJA1、BNIP3、PRG1、G6PD、PLOD2、LOXL2、SSBP2、C1orf29、TOX、STC1、TNFRSF1A、NCOR2、NAP1L1、LOC94105、ARHGEF6、GATA3、TFPI、LAT、CD3Z、AF1Q、MAP1B、TRIM22、CD3D、BCAT1、IFI44、CUTC、NAP1L2、NME7、FLJ21159、およびCOL5A2の遺伝子配列。
h)発現が、マイトマイシンに対する化学感受性を意味する、GAPD、GAPD、GAPD、TOP2A、SUI1、TOP2A、FTL、HNRPC、TNFRSF1A、SHC1、CCT7、P4HB、CTSL、DDX5、G6PD、およびSNRPFの1つまたは複数の遺伝子配列、好ましくは、STC1、GPR65、DOCK10、COL5A2、FAM46A、およびLOC54103の遺伝子配列、ならびに最も好ましくは、STC1、GPR65、DOCK10、COL5A2、FAM46A、およびLOC54103の遺伝子配列。
i)発現が、パクリタキセルに対する化学感受性を意味する、RPS23、SFRS3、KIAA0114、RPL39、SFRS3、LOC51035、RPS6、EXOSC2、RPL35、IFRD2、SMN2、EEF1A1、RPS3、RPS18、およびRPS7の1つまたは複数の遺伝子配列、好ましくは、RPL10、RPS4X、NUDC、RALY、DKC1、DKFZP564C186、PRP19、RAB9P40、HSA9761、GMDS、CEP1、IL13RA2、MAGEB2、HMGN2、ALMS1、GPR65、FLJ10774、NOL8、DAZAP1、SLC25A15、PAF53、DXS9879E、PITPNC1、SPANXC、およびKIAA1393の遺伝子配列、ならびに最も好ましくは、RPL10、RPS4X、NUDC、DKC1、DKFZP564C186、PRP19、RAB9P40、HSA9761、GMDS、CEP1、IL13RA2、MAGEB2、HMGN2、ALMS1、GPR65、FLJ10774、NOL8、DAZAP1、SLC25A15、PAF53、DXS9879E、PITPNC1、SPANXC、およびKIAA1393の遺伝子配列。
j)発現が、ゲムシタビンに対する化学感受性を意味する、CSDA、LAMR1、およびTUBA3の1つまたは複数の遺伝子配列、好ましくは、PFN1、PGAM1、K-ALPHA-1、CSDA、UCHL1、PWP1、PALM2-AKAP2、TNFRSF1A、ATP5G2、AF1Q、NME4、およびFHOD1の遺伝子配列、ならびに最も好ましくは、PFN1、PGAM1、K-ALPHA-1、CSDA、UCHL1、PWP1、PALM2-AKAP2、TNFRSF1A、ATP5G2、AF1Q、NME4、FHOD1の遺伝子配列。
k)発現が、タキソテールに対する化学感受性を意味する、RPS23、SFRS3、KIAA0114、SFRS3、RPS6、DDX39、およびRPS7の1つまたは複数の遺伝子配列、好ましくは、ANP32B、GTF3A、RRM2、TRIM14、SKP2、TRIP13、RFC3、CASP7、TXN、MCM5、PTGES2、OBFC1、EPB41L4B、およびCALML4の遺伝子配列、ならびに最も好ましくは、ANP32B、GTF3A、RRM2、TRIM14、SKP2、TRIP13、RFC3、CASP7、TXN、MCM5、PTGES2、OBFC1、EPB41L4B、およびCALML4の遺伝子配列。
l)発現が、デキサメタゾンに対する化学感受性を意味する、IL2RG、H1FX、RDBP、ZAP70、CXCR4、TM4SF2、ARHGDIB、CDA、CD3E、STMN1、GNA15、AXL、CCND3、SATB1、EIF5A、LCK、NKX2-5、LAPTM5、IQGAP2、FLII、EIF3S5、TRB、CD3D、HOXB2、GATA3、HMGB2、PSMB9、ATP5G2、CORO1A、ARHGDIB、DRAP1、PTPRCAP、RHOH、およびATP2A3の1つまたは複数の遺伝子配列、好ましくは、IFITM2、UBE2L6、LAPTM5、USP4、ITM2A、ITGB2、ANPEP、CD53、IL2RG、CD37、GPRASP1、PTPN7、CXorf9、RHOH、GIT2、ADORA2A、ZNFN1A1、GNA15、CEP1、TNFRSF7、MAP4K1、CCR7、CD3G、PTPRC、ATP2A3、UCP2、CORO1A、GATA3、CDKN2A、HEM1、TARP、LAIR1、SH2D1A、FLII、SEPT6、HA-1、CREB3L1、ERCC2、CD3D、LST1、AIF1、ADA、DATF1、ARHGAP15、PLAC8、CECR1、LOC81558、およびEHD2の遺伝子配列、ならびに最も好ましくは、IFITM2、UBE2L6、USP4、ITM2A、IL2RG、GPRASP1、PTPN7、CXorf9、RHOH、GIT2、ZNFN1A1、CEP1、TNFRSF7、MAP4K1、CCR7、CD3G、ATP2A3、UCP2、GATA3、CDKN2A、TARP、LAIR1、SH2D1A、SEPT6、HA-1、ERCC2、CD3D、LST1、AIF1、ADA、DATF1、ARHGAP15、PLAC8、CECR1、LOC81558、およびEHD2の遺伝子配列。
m)発現が、Ara-Cに対する化学感受性を意味する、TM4SF2、ARHGDIB、ADA、H2AFZ、NAP1L1、CCND3、FABP5、LAMR1、REA、MCM5、SNRPF、およびUSP7の1つまたは複数の遺伝子配列、好ましくは、ITM2A、RHOH、PRIM1、CENTB1、GNA15、NAP1L1、ATP5G2、GATA3、PRKCQ、SH2D1A、SEPT6、PTPRC、NME4、RPL13、CD3D、CD1E、ADA、およびFHOD1の遺伝子配列、ならびに最も好ましくは、ITM2A、RHOH、PRIM1、CENTB1、NAP1L1、ATP5G2、GATA3、PRKCQ、SH2D1A、SEPT6、NME4、CD3D、CD1E、ADA、およびFHOD1の遺伝子配列。
n)発現が、メチルプレドニゾロンに対する化学感受性を意味する、
の1つまたは複数の遺伝子配列、好ましくは、
の遺伝子配列、ならびに最も好ましくは、
の遺伝子配列。
o)発現が、メトトレキセートに対する化学感受性を意味する、RPLP2、RPL4、HMGA1、RPL27、IMPDH2、LAMR1、PTMA、ATP5B、NPM1、NCL、RPS25、RPL9、TRAP1、RPL21、LAMR1、REA、HNRPA1、LDHB、RPS2、NME1、PAICS、EEF1B2、RPS15A、RPL19、RPL6、ATP5G2、SNRPF、SNRPG、およびRPS7の1つまたは複数の遺伝子配列、好ましくは、PRPF8、RPL18、RNPS1、RPL32、EEF1G、GOT2、RPL13A、PTMA、RPS15、RPLP2、CSDA、KHDRBS1、SNRPA、IMPDH2、RPS19、NUP88、ATP5D、PCBP2、ZNF593、HSU79274、PRIM1、PFDN5、OXA1L、H3F3A、ATIC、RPL13、CIAPIN1、FBL、RPS2、PCCB、RBMX、SHMT2、RPLP0、HNRPA1、STOML2、RPS9、SKB1、GLTSCR2、CCNB1IP1、MRPS2、FLJ20859、およびFLJ12270の遺伝子配列、ならびに最も好ましくは、PRPF8、RPL18、GOT2、RPL13A、RPS15、RPLP2、CSDA、KHDRBS1、SNRPA、IMPDH2、RPS19、NUP88、ATP5D、PCBP2、ZNF593、HSU79274、PRIM1、PFDN5、OXA1L、H3F3A、ATIC、CIAPIN1、RPS2、PCCB、SHMT2、RPLP0、HNRPA1、STOML2、SKB1、GLTSCR2、CCNB1IP1、MRPS2、FLJ20859、およびFLJ12270の遺伝子配列。
p)発現が、ブレオマイシンに対する化学感受性を意味する、ACTB、COL5A1、MT1E、CSDA、COL4A2、MMP2、COL1A1、TNFRSF1A、CFHL1、TGFBI、FSCN1、NNMT、PLAUR、CSPG2、NFIL3、C5orf13、NCOR2、TUBB4、MYLK、TUBA3、PLAU、COL4A2、COL6A2、COL6A3、IFITM2、PSMB9、CSDA、およびCOL1A1の1つまたは複数の遺伝子配列、好ましくは、
の遺伝子配列、ならびに最も好ましくは、
の遺伝子配列。
q)発現が、メチル-GAGに対する化学感受性を意味する、NOS2A、MUC1、TFF3、GP1BB、IGLL1、BATF、MYB、PTPRS、NEFL、AIP、CEL、DGKA、RUNX1、ACTR1A、およびCLCNKAの1つまたは複数の遺伝子配列、好ましくは、PTMA、SSRP1、NUDC、CTSC、AP1G2、PSME2、LBR、EFNB2、SERPINA1、SSSCA1、EZH2、MYB、PRIM1、H2AFX、HMGA1、HMMR、TK2、WHSC1、DIAPH1、LAMB3、DPAGT1、UCK2、SERPINB1、MDN1、BRRN1、G0S2、RAC2、MGC21654、GTSE1、TACC3、PLEK2、PLAC8、HNRPD、およびPNAS-4の遺伝子配列、ならびに最も好ましくは、SSRP1、NUDC、CTSC、AP1G2、PSME2、LBR、EFNB2、SERPINA1、SSSCA1、EZH2、MYB、PRIM1、H2AFX、HMGA1、HMMR、TK2、WHSC1、DIAPH1、LAMB3、DPAGT1、UCK2、SERPINB1、MDN1、BRRN1、G0S2、RAC2、MGC21654、GTSE1、TACC3、PLEK2、PLAC8、HNRPD、およびPNAS-4の遺伝子配列。
r)発現が、カルボプラチンに対する化学感受性を意味する、MSN、ITGA5、VIM、TNFAIP3、CSPG2、WNT5A、FOXF2、LOC94105、IFI16、LRRN3、FGFR1、DOCK10、LEPRE1、COL5A2、およびADAMTS1の1つまたは複数の遺伝子配列、ならびに最も好ましくは、ITGA5、TNFAIP3、WNT5A、FOXF2、LOC94105、IFI16、LRRN3、DOCK10、LEPRE1、COL5A2、およびADAMTS1の遺伝子配列。
s)発現が、5-FU(5-フルオロウラシル)に対する化学感受性を意味する、RPL18、RPL10A、RNPS1、ANAPC5、EEF1B2、RPL13A、RPS15、AKAP1、NDUFAB1、APRT、ZNF593、MRP63、IL6R、RPL13、SART3、RPS6、UCK2、RPL3、RPL17、RPS2、PCCB、TOMM20、SHMT2、RPLP0、GTF3A、STOML2、DKFZp564J157、MRPS2、ALG5、およびCALML4の1つまたは複数の遺伝子配列、ならびに最も好ましくは、RPL18、RPL10A、ANAPC5、EEF1B2、RPL13A、RPS15、AKAP1、NDUFAB1、APRT、ZNF593、MRP63、IL6R、SART3、UCK2、RPL17、RPS2、PCCB、TOMM20、SHMT2、RPLP0、GTF3A、STOML2、DKFZp564J157、MRPS2、ALG5、およびCALML4の遺伝子配列。
t)発現が、MABTHERA(商標)(リツキシマブ)に対する化学感受性を意味する、
の1つまたは複数の遺伝子配列、好ましくは、
の遺伝子配列、ならびに最も好ましくは、
の遺伝子配列。
u)発現が、放射線療法に対する感受性を意味する、CCL21、ANXA2、SCARB2、MAD2L1BP、CAST、PTS、NBL1、ANXA2、CD151、TRAM2、HLA-A、CRIP2、UGCG、PRSS11、MME、CBR1、LGALS1、DUSP3、PFN2、MICA、FTH1、RHOC、ZAP128、PON2、COL5A2、CST3、MCAM、IGFBP3、MMP2、GALIG、CTSD、ALDH3A1、CSRP1、S100A4、CALD1、CTGF、CAPG、HLA-A、ACTN1、TAGLN、FSTL1、SCTR、BLVRA、COPEB、DIPA、SMARCD3、FN1、CTSL、CD63、DUSP1、CKAP4、MVP、PEA15、S100A13、およびECE1の1つまたは複数の遺伝子配列、好ましくは、
の遺伝子配列、ならびに最も好ましくは、
の遺伝子配列。
v)発現が、HDAC阻害剤に対する感受性を意味する、
の1つまたは複数の遺伝子配列。
w)発現が、5-アザ-2'-デオキシシチジン(デシタビン)に対する感受性を意味する、CD99、SNRPA、CUGBP2、STAT5A、SLA、IL2RG、GTSE1、MYB、PTPN7、CXorf9、RHOH、ZNFN1A1、CENTB1、LCP2、HIST1H4C、CCR7、APOBEC3B、MCM7、LCP1、SELPLG、CD3Z、PRKCQ、GZMB、SCN3A、LAIR1、SH2D1A、SEPT6、CG018、CD3D、C18orf10、PRF1、AIF1、MCM5、LPXN、C22orf18、ARHGAP15、およびLEF1の1つまたは複数の遺伝子配列。
Microarrays containing oligonucleotide probes The microarray of the present invention is, for example, at least 5 residues, 8 residues, 12 residues, 20 residues, 30 residues, 40 residues, 60 residues of the biomarker genes listed below. One or more oligonucleotide probes having a nucleotide sequence that is identical to or complementary to 80, 100, 150, or 200 contiguous nucleotides (or nucleotide analogs) Including. An oligonucleotide probe can be, for example, 5-20 residues, 25 residues, 5-50 residues, 50-100 residues, or more than 100 nucleotides in length. The oligonucleotide probe may be deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). Contiguous nucleotides in oligonucleotide probes (e.g., 5-20 residues, 25 residues, 5-50 residues, 50-100 residues, or more than 100 residues) used as chemosensitive genetic biomarkers Nucleotides) of the nucleotides of the genes listed in Tables 1-21 or below, e.g., 1st residue, 10th residue, 20th residue, 30th residue, 40th residue, 50th residue, 60th residue, 70th residue, 80th residue, 90th residue, 100th residue, 150th residue, 200th residue, 500th residue, 1000th residue, or the vicinity thereof It may also exist as a contiguous nucleotide in one or more genes described herein, starting from. Column list_2006 in Tables 1-21 means preferred gene biomarkers for the compound list. The column list_Preferred in Tables 1-21 means the most preferred gene biomarker. The column list_2005 in Tables 1-21 refers to other biomarkers used in Examples 1-8. The column correlations in Tables 1-21 mean the correlation coefficient of biomarker gene expression for cancer cell growth inhibition. The following combinations of genetic biomarkers have been used to detect a subject's sensitivity to the described treatment:
a) Expression means chemosensitivity to vincristine, SFRS3, CCT5, RPL39, SLC25A5, UBE2S, EEF1A1, RPLP2, RPL24, RPS23, RPL39, RPL18, NCL, RPL9, RPL10A, RPS10, EIF3S2, SHFM1, RPS28, REA , RPL36A, GAPD, HNRPA1, RPS11, HNRPA1, LDHB, RPL3, RPL11, MRPL12, RPL18A, COX7B, and RPS7, one or more gene sequences, preferably UBB, RPS4X, S100A4, NDUFS6, B2M, C14orf139, MNA1 , SLC25A5, RPL10, RPL12, EIF5A, RPL36A, SUI1, BLMH, CTBP1, TBCA, MDH2, and DXS9879E gene sequences, and most preferably RPS4X, S100A4, NDUFS6, C14orf139, SLC25A5, RPL10, RPL12, EIF5, RPL5, EIF5 BLMH, CTBP1, TBCA, MDH2, and DXS9879E gene sequences.
b) One or more of B2M, ARHGDIB, FTL, NCL, MSN, SNRPF, XPO1, LDHB, SNRPF, GAPD, PTPN7, ARHGDIB, RPS27, IFI16, C5orf13, and HCLS1, whose expression means chemosensitivity to cisplatin Gene sequences, preferably C1QR1, HCLS1, CD53, SLA, PTPN7, PTPRCAP, ZNFN1A1, CENTB1, PTPRC, IFI16, ARHGEF6, SEC31L2, CD3Z, GZMB, CD3D, MAP4K1, GPR65, PRF1, ARHGAP15, TM6SF1, and TC6SF1 The gene sequence and most preferably the gene sequence of C1QR1, SLA, PTPN7, ZNFN1A1, CENTB1, IFI16, ARHGEF6, SEC31L2, CD3Z, GZMB, CD3D, MAP4K1, GPR65, PRF1, ARHGAP15, TM6SF1, and TCF4.
c) Expression means chemosensitivity to azaguanine, PRPS1, DDOST, B2M, SPARC, LGALS1, CBFB, SNRPB2, MCAM, MCAM, EIF2S2, HPRT1, SRM, FKBP1A, GYPC, UROD, MSN, HNRPA1, SND1, COPA , MAPRE1, EIF3S2, ATP1B3, EMP3, ECM1, ATOX1, NARS, PGK1, OK / SW-cl.56, FN1, EEF1A1, GNAI2, PRPS1, RPL7, PSMB9, GPNMB, PPP1R11, MIA, RAB7, VIM, and SMS One or more gene sequences, preferably MSN, SPARC, VIM, SRM, SCARB1, SIAT1, CUGBP2, GAS7, ICAM1, WASPIP, ITM2A, PALM2-AKAP2, ANPEP, PTPNS1, MPP1, LNK, FCGR2A, EMP3, RUNX3 , EVI2A, BTN3A3, LCP2, BCHE, LY96, LCP1, IFI16, MCAM, MEF2C, SLC1A4, BTN3A2, FYN, FN1, C1orf38, CHS1, CAPN3, FCGR2C, TNIK, AMPD2, SEPT6, RAFTLIN, SLC43LP -1, FLJ10539, FLJ35036, DOCK10, TRPV2, IFRG28, LEF1, and ADAMTS1 gene sequences, and most preferably SRM, SCARB1, SIAT1, CUGBP2, ICAM1, WASPIP, ITM2A, PALM2-AKAP2 , PTPNS1, MPP1, LNK, FCGR2A, RUNX3, EVI2A, BTN3A3, LCP2, BCHE, LY96, LCP1, IFI16, MCAM, MEF2C, SLC1A4, FYN, C1orf38, CHS1, FCGR2C, TNIK, AMPD2, SEPT6LC, FT3, SEPT6LC , LPXN, CKIP-1, FLJ10539, FLJ35036, DOCK10, TRPV2, IFRG28, LEF1, and ADAMTS1 gene sequences.
d) one or more gene sequences of B2M, MYC, CD99, RPS24, PPIF, PBEF1, and ANP32B, whose expression means chemosensitivity to etoposide, preferably CD99, INSIG1, LAPTM5, PRG1, MUF1, HCLS1 , CD53, SLA, SSBP2, GNB5, MFNG, GMFG, PSMB9, EVI2A, PTPN7, PTGER4, CXorf9, PTPRCAP, ZNFN1A1, CENTB1, PTPRC, NAP1L1, HLA-DRA, IFI16, CORO1A, ARHGEF6, PSCDBP, SELPLG, PSCDBP, SELPLG , CD3Z, SH2D1A, GZMB, SCN3A, ITK, RAFTLIN, DOCK2, CD3D, RAC2, ZAP70, GPR65, PRF1, ARHGAP15, NOTCH1, and UBASH3A gene sequences, and most preferably, CD99, INSIG1, PRG1, MUF1, SLA, SSBP2, GNB5, MFNG, PSMB9, EVI2A, PTPN7, PTGER4, CXorf9, ZNFN1A1, CENTB1, NAP1L1, HLA-DRA, IFI16, ARHGEF6, PSCDBP, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, GZMB, SC CD3D, RAC2, ZAP70, GPR65, PRF1, ARHGAP15, NOTCH1, and UBASH3A gene sequences.
e) one or more gene sequences of KIAA0220, B2M, TOP2A, CD99, SNRPE, RPS27, HNRPA1, CBX3, ANP32B, HNRPA1, DDX5, PPIA, SNRPF, and USP7, wherein expression means chemosensitivity to adriamycin, Preferably, CD99, LAPTM5, ALDOC, HCLS1, CD53, SLA, SSBP2, IL2RG, GMFG, CXorf9, RHOH, PTPRCAP, ZNFN1A1, CENTB1, TCF7, CD1C, MAP4K1, CD1B, CD3G, PTPRC, CCR9, CORO1AR, CEF4 , HEM1, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, CD1A, LAIR1, ITK, TRB @, CD3D, WBSCR20C, ZAP70, IFI44, GPR65, AIF1, ARHGAP15, NARF, and PACAP gene sequences, and most preferably CD99 , ALDOC, SLA, SSBP2, IL2RG, CXorf9, RHOH, ZNFN1A1, CENTB1, CD1C, MAP4K1, CD3G, CCR9, CXCR4, ARHGEF6, SELPLG, LAT, SEC31L2, CD3Z, SH2D1A, CD1A, LCD1, C ZAP70, IFI44, GPR65, AIF1, ARHGAP15, NARF, and PACAP gene sequences.
f) one or more of RPLP2, LAMR1, RPS25, EIF5A, TUFM, HNRPA1, RPS9, MYB, LAMR1, ANP32B, HNRPA1, HNRPA1, EIF4B, HMGB2, RPS15A, and RPS7, where expression means chemosensitivity to aclarubicin Gene sequences, preferably RPL12, RPL32, RPLP2, MYB, ZNFN1A1, SCAP1, STAT4, SP140, AMPD3, TNFAIP8, DDX18, TAF5, FBL, RPS2, PTPRC, DOCK2, GPR65, HOXA9, FLJ12270, and HNRPD And most preferably, gene sequences of RPL12, RPLP2, MYB, ZNFN1A1, SCAP1, STAT4, SP140, AMPD3, TNFAIP8, DDX18, TAF5, RPS2, DOCK2, GPR65, HOXA9, FLJ12270, and HNRPD.
g) ARHGEF6, B2M, TOP2A, TOP2A, ELA2B, PTMA, LMNB1, TNFRSF1A, NAP1L1, B2M, HNRPA1, RPL9, C5orf13, NCOR2, ANP32B, OK / SW-cl, whose expression means chemosensitivity to mitoxantrone One or more gene sequences of .56, TUBA3, HMGN2, PRPS1, DDX5, PRG1, PPIA, G6PD, PSMB9, SNRPF, and MAP1B, preferably PGAM1, DPYSL3, INSIG1, GJA1, BNIP3, PRG1, G6PD, BASP1 , PLOD2, LOXL2, SSBP2, C1orf29, TOX, STC1, TNFRSF1A, NCOR2, NAP1L1, LOC94105, COL6A2, ARHGEF6, GATA3, TFPI, LAT, CD3Z, AF1Q, MAP1B, PTPRC, PRKCA, TRIM22, CD3I, 44C , RAB31, CUTC, NAP1L2, NME7, FLJ21159, and COL5A2, and most preferably, PGAM1, DPYSL3, INSIG1, GJA1, BNIP3, PRG1, G6PD, PLOD2, LOXL2, SSBP2, C1orf29, TOX, STC1, TNFRSF1 NCOR2, NAP1L1, LOC94105, ARHGEF6, GATA3, TFPI, LAT, CD3Z, AF1Q, MAP1B, TRIM22, CD3D, BCAT1, IFI44, CUTC, NAP1L2, NME7, FLJ2115 9, and the gene sequence of COL5A2.
h) One or more of GAPD, GAPD, GAPD, TOP2A, SUI1, TOP2A, FTL, HNRPC, TNFRSF1A, SHC1, CCT7, P4HB, CTSL, DDX5, G6PD, and SNRPF, where expression means chemosensitivity to mitomycin Gene sequences of STC1, GPR65, DOCK10, COL5A2, FAM46A, and LOC54103, and most preferably gene sequences of STC1, GPR65, DOCK10, COL5A2, FAM46A, and LOC54103.
i) One or more genes of RPS23, SFRS3, KIAA0114, RPL39, SFRS3, LOC51035, RPS6, EXOSC2, RPL35, IFRD2, SMN2, EEF1A1, RPS3, RPS18, and RPS7 whose expression means chemosensitivity to paclitaxel Sequence, preferably RPL10, RPS4X, NUDC, RALY, DKC1, DKFZP564C186, PRP19, RAB9P40, HSA9761, GMDS, CEP1, IL13RA2, MAGEB2, HMGN2, ALMS1, GPR65, FLJ10774, NOL8, DAZAP1, E, SLC25DX1, E , SPANXC, and KIAA1393 gene sequences, and most preferably, RPL10, RPS4X, NUDC, DKC1, DKFZP564C186, PRP19, RAB9P40, HSA9761, GMDS, CEP1, IL13RA2, MAGEB2, HMGN2, ALMS1, GPR65, FLL10774, NOL8DA Gene sequences of SLC25A15, PAF53, DXS9879E, PITPNC1, SPNXC, and KIAA1393.
j) one or more gene sequences of CSDA, LAMR1, and TUBA3, wherein expression means chemosensitivity to gemcitabine, preferably PFN1, PGAM1, K-ALPHA-1, CSDA, UCHL1, PWP1, PALM2-AKAP2 , TNFRSF1A, ATP5G2, AF1Q, NME4, and FHOD1, and most preferably PFN1, PGAM1, K-ALPHA-1, CSDA, UCHL1, PWP1, PALM2-AKAP2, TNFRSF1A, ATP5G2, AF1Q, NME4, FHOD1 Gene sequence.
k) one or more gene sequences of RPS23, SFRS3, KIAA0114, SFRS3, RPS6, DDX39, and RPS7, preferably ANP32B, GTF3A, RRM2, TRIM14, SKP2, TRIP13, whose expression means chemosensitivity to taxotere , RFC3, CASP7, TXN, MCM5, PTGES2, OBFC1, EPB41L4B, and CALML4 gene sequences, and most preferably ANP32B, GTF3A, RRM2, TRIM14, SKP2, TRIP13, RFC3, CASP7, TXN, MCM5, PTGES2, OBFC1, EPB41L4B and CALML4 gene sequences.
l) Expression means chemosensitivity to dexamethasone, IL2RG, H1FX, RDBP, ZAP70, CXCR4, TM4SF2, ARHGDIB, CDA, CD3E, STMN1, GNA15, AXL, CCND3, SATB1, EIF5A, LCK, NKX2-5, LAPTM5 , IQGAP2, FLII, EIF3S5, TRB, CD3D, HOXB2, GATA3, HMGB2, PSMB9, ATP5G2, CORO1A, ARHGDIB, DRAP1, PTPRCAP, RHOH, and ATP2A3, preferably IFITM2, UBE2L6LA , USP4, ITM2A, ITGB2, ANPEP, CD53, IL2RG, CD37, GPRASP1, PTPN7, CXorf9, RHOH, GIT2, ADORA2A, ZNFN1A1, GNA15, CEP1, TNFRSF7, MAP4K1, CCR7, CD3G, PTPRC, ATP2RO3 , CDKN2A, HEM1, TARP, LAIR1, SH2D1A, FLII, SEPT6, HA-1, CREB3L1, ERCC2, CD3D, LST1, AIF1, ADA, DATF1, ARHGAP15, PLAC8, CECR1, LOC81558, and EHD2 gene sequences, and most preferred IFITM2, UBE2L6, USP4, ITM2A, IL2RG, GPRASP1, PTPN7, CXorf9, RHOH, GIT2, ZNFN1A1, CEP1, TNFRSF7, MAP4K1, CCR7, CD3 Gene sequences for G, ATP2A3, UCP2, GATA3, CDKN2A, TARP, LAIR1, SH2D1A, SEPT6, HA-1, ERCC2, CD3D, LST1, AIF1, ADA, DATF1, ARHGAP15, PLAC8, CECR1, LOC81558, and EHD2.
m) one or more gene sequences of TM4SF2, ARHGDIB, ADA, H2AFZ, NAP1L1, CCND3, FABP5, LAMR1, REA, MCM5, SNRPF, and USP7, wherein expression means chemosensitivity to Ara-C, preferably , ITM2A, RHOH, PRIM1, CENTB1, GNA15, NAP1L1, ATP5G2, GATA3, PRKCQ, SH2D1A, SEPT6, PTPRC, NME4, RPL13, CD3D, CD1E, ADA, and FHOD1, and most preferably ITM2A, RHOH, PRIM1, CENTB1, NAP1L1, ATP5G2, GATA3, PRKCQ, SH2D1A, SEPT6, NME4, CD3D, CD1E, ADA, and FHOD1 gene sequences.
n) expression means chemosensitivity to methylprednisolone,
One or more gene sequences, preferably
And most preferably,
Gene sequence.
o) Expression means chemosensitivity to methotrexate, RPLP2, RPL4, HMGA1, RPL27, IMPDH2, LAMR1, PTMA, ATP5B, NPM1, NCL, RPS25, RPL9, TRAP1, RPL21, LAMR1, REA, HNRPA1, LDHB, RPS2 One or more gene sequences of NME1, PAICS, EEF1B2, RPS15A, RPL19, RPL6, ATP5G2, SNRPF, SNRPG, and RPS7, preferably PRPF8, RPL18, RNPS1, RPL32, EEF1G, GOT2, RPL13A, PTMA, RPS15 , RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2, RPS19, NUP88, ATP5D, PCBP2, ZNF593, HSU79274, PRIM1, PFDN5, OXA1L, H3F3A, ATIC, RPL13, CIAPIN1, FBL, RPS2, PCCB, RBMX, SHMTH, RP , STOML2, RPS9, SKB1, GLTSCR2, CCNB1IP1, MRPS2, FLJ20859, and FLJ12270 gene sequences, and most preferably PRPF8, RPL18, GOT2, RPL13A, RPS15, RPLP2, CSDA, KHDRBS1, SNRPA, IMPDH2, RPS19, NPS ATP5D, PCBP2, ZNF593, HSU79274, PRIM1, PFDN5, OXA1L, H3F3A, ATIC, CIAPIN1, RPS2, PCCB, SHMT2, RPLP0, HN RPA1, STOML2, SKB1, GLTSCR2, CCNB1IP1, MRPS2, FLJ20859, and FLJ12270 gene sequences.
p) Expression means chemosensitivity to bleomycin, ACTB, COL5A1, MT1E, CSDA, COL4A2, MMP2, COL1A1, TNFRSF1A, CFHL1, TGFBI, FSCN1, NNMT, PLAUR, CSPG2, NFIL3, C5orf13, NCOR2, TUBB4, MYLK One or more gene sequences of TUBA3, PLAU, COL4A2, COL6A2, COL6A3, IFITM2, PSMB9, CSDA, and COL1A1, preferably
And most preferably,
Gene sequence.
q) One or more of NOS2A, MUC1, TFF3, GP1BB, IGLL1, BATF, MYB, PTPRS, NEFL, AIP, CEL, DGKA, RUNX1, ACTR1A, and CLCNKA, where expression means chemosensitivity to methyl-GAG Gene sequence, preferably PTMA, SSRP1, NUDC, CTSC, AP1G2, PSME2, LBR, EFNB2, SERPINA1, SSSCA1, EZH2, MYB, PRIM1, H2AFX, HMGA1, HMMR, TK2, WHSC1, DIAPH1, LAMB3, DPAGT1, UCK2 , SERPINB1, MDN1, BRRN1, G0S2, RAC2, MGC21654, GTSE1, TACC3, PLEK2, PLAC8, HNRPD, and PNAS-4 gene sequences, and most preferably SSRP1, NUDC, CTSC, AP1G2, PSME2, LBR, EFNB2, SERPINA1, SSSCA1, EZH2, MYB, PRIM1, H2AFX, HMGA1, HMMR, TK2, WHSC1, DIAPH1, LAMB3, DPAGT1, UCK2, SERPINB1, MDN1, BRRN1, G0S2, RAC2, MGC21654, GTSE1, TACC3, PLCK2, PD2 And the gene sequence of PNAS-4.
r) One or more genes of MSN, ITGA5, VIM, TNFAIP3, CSPG2, WNT5A, FOXF2, LOC94105, IFI16, LRRN3, FGFR1, DOCK10, LEPRE1, COL5A2, and ADAMTS1, whose expression means chemosensitivity to carboplatin The sequences, and most preferably the gene sequences of ITGA5, TNFAIP3, WNT5A, FOXF2, LOC94105, IFI16, LRRN3, DOCK10, LEPRE1, COL5A2, and ADAMTS1.
s) RPL18, RPL10A, RNPS1, ANAPC5, EEF1B2, RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, MRP63, IL6R, RPL13, SART3, whose expression means chemosensitivity to 5-FU (5-fluorouracil), One or more gene sequences of RPS6, UCK2, RPL3, RPL17, RPS2, PCCB, TOMM20, SHMT2, RPLP0, GTF3A, STOML2, DKFZp564J157, MRPS2, ALG5, and CALML4, and most preferably RPL18, RPL10A, ANAPC5, EEF1B2, RPL13A, RPS15, AKAP1, NDUFAB1, APRT, ZNF593, MRP63, IL6R, SART3, UCK2, RPL17, RPS2, PCCB, TOMM20, SHMT2, RPLP0, GTF3A, STOML2, DKFZp564J157, MRPS2, ALG5, and CAL4
t) expression means chemosensitivity to MABTHERA ™ (rituximab),
One or more gene sequences, preferably
And most preferably,
Gene sequence.
u) CCL21, ANXA2, SCARB2, MAD2L1BP, CAST, PTS, NBL1, ANXA2, CD151, TRAM2, HLA-A, CRIP2, UGCG, PRSS11, MME, CBR1, LGALS1, DUSP3 , PFN2, MICA, FTH1, RHOC, ZAP128, PON2, COL5A2, CST3, MCAM, IGFBP3, MMP2, GALIG, CTSD, ALDH3A1, CSRP1, S100A4, CALD1, CTGF, CAPG, HLA-A, ACTN1, TAGLN, FSTL1, SCTR One or more gene sequences of, BLVRA, COPEB, DIPA, SMARCD3, FN1, CTSL, CD63, DUSP1, CKAP4, MVP, PEA15, S100A13, and ECE1, preferably
And most preferably,
Gene sequence.
v) expression means sensitivity to HDAC inhibitors;
One or more gene sequences.
w) CD99, SNRPA, CUGBP2, STAT5A, SLA, IL2RG, GTSE1, MYB, PTPN7, CXorf9, RHOH, ZNFN1A1, CENTB1, LCP2 where expression means sensitivity to 5-aza-2'-deoxycytidine (decitabine) , HIST1H4C, CCR7, APOBEC3B, MCM7, LCP1, SELPLG, CD3Z, PRKCQ, GZMB, SCN3A, LAIR1, SH2D1A, SEPT6, CG018, CD3D, C18orf10, PRF1, AIF1, MCM5, LPXN, C22AP15, F1 Or multiple gene sequences.
本発明のマイクロアレイに使用可能なプローブは、上記の任意のバイオマーカー遺伝子の配列に相補的な配列を有するオリゴヌクレオチドプローブを含む。加えて、本発明のマイクロアレイに使用されるプローブは、任意のオリゴヌクレオチドプローブの配列、またはその相補的配列に選択的に結合するタンパク質、ペプチド、または抗体を含む場合もある。例示的なプローブを表22〜44に列挙する。これらの表には、列挙された各治療に関して、治療感受性の指標となる遺伝子バイオマーカー、成長阻害に対するバイオマーカー遺伝子の発現の相関、およびバイオマーカー遺伝子(表1〜21)の発現を検出するための例示的なプローブの配列(表22〜44)を示す。 Probes that can be used in the microarray of the present invention include oligonucleotide probes having a sequence complementary to the sequence of any of the above biomarker genes. In addition, the probes used in the microarrays of the invention may include proteins, peptides, or antibodies that selectively bind to the sequence of any oligonucleotide probe or its complementary sequence. Exemplary probes are listed in Tables 22-44. These tables show for each listed treatment to detect gene biomarkers that are indicative of treatment sensitivity, correlation of biomarker gene expression to growth inhibition, and expression of biomarker genes (Tables 1-21) The sequences of exemplary probes (Tables 22-44) are shown.
バイオマーカー遺伝子の同定
NCI60癌細胞株の遺伝子発現に関する測定結果は、米国立癌研究所およびマサチューセッツ工科大学(MIT)から得た。各データセットを、異なるチップによって測定された試料の発現が比較可能なように標準化した。標準化の好ましい方法は、各チップ上で各遺伝子yに対して行われるロジット変換である:
ロジット(y)=log[(y-「バックグラウンド」)/(「飽和」-y)]、
上式で「バックグラウンド」は、チップ上で測定される最小強度から、シグナル強度範囲の0.1%を差し引いた値:最小値-0.001*(最大値-最小値)として計算され:および「飽和」は、チップ上で測定される最大強度に、シグナル強度範囲の0.1%を加えた値:最大値+0.001*(最大値-最小値)として計算される。結果として得られたロジット変換後のデータを次に、平均を0、および標準偏差を1となるようにz変換する。
Identification of biomarker genes
Measurement results regarding gene expression of the NCI60 cancer cell line were obtained from the National Cancer Institute and the Massachusetts Institute of Technology (MIT). Each data set was normalized so that the expression of the samples measured by different chips was comparable. The preferred method of normalization is logit transformation performed on each chip for each gene y:
Logit (y) = log [(y- "background") / ("saturation" -y)],
In the above equation, "background" is calculated as the minimum intensity measured on the chip minus 0.1% of the signal intensity range: minimum -0.001 * (maximum-minimum): and "saturated" Is calculated as the maximum intensity measured on the chip plus 0.1% of the signal intensity range: maximum + 0.001 * (maximum-minimum). The resulting logit transformed data is then z transformed so that the mean is 0 and the standard deviation is 1.
次に遺伝子発現を、癌細胞の成長阻害と相関させる。数千種類の検討された化合物の任意の1つの存在下におけるNCI60細胞株の成長阻害データ(GI50)をNCIから得た。各細胞株における各遺伝子のロジット変換された発現レベルと、GI50(50%の成長阻害を生じる所定の化合物の濃度)の対数の間の相関は例えば、ピアソン相関係数、またはスピアマンの順位相関係数を用いて計算することができる。GI50を用いる代わりに、所定の化合物に対する患者の感受性の任意の他の尺度を、患者の遺伝子発現と相関させることができる。1つの遺伝子に関して複数の測定結果が存在する場合があるので、相関係数の最も正確な決定は、同じ遺伝子の発現を測定する全てのプローブに関して計算される相関係数の中央値であることが判明した。 Gene expression is then correlated with cancer cell growth inhibition. Growth inhibition data (GI50) of NCI60 cell line in the presence of any one of thousands of studied compounds was obtained from NCI. The correlation between the logit-converted expression level of each gene in each cell line and the logarithm of GI50 (concentration of a given compound that produces 50% growth inhibition) is, for example, Pearson correlation coefficient, or Spearman's rank correlation It can be calculated using a number. Instead of using a GI50, any other measure of a patient's sensitivity to a given compound can be correlated with the patient's gene expression. Since multiple measurements can exist for a gene, the most accurate determination of the correlation coefficient can be the median correlation coefficient calculated for all probes that measure the expression of the same gene. found.
成長阻害または患者の感受性に対してプローブに関して測定される遺伝子発現の相関係数の中央値は、全遺伝子に関して計算され、および0.3、0.4、0.5、0.6、0.7、0.8、0.9、0.95、もしくは0.99を上回る相関の中央値を有する遺伝子が、バイオマーカー遺伝子として保持される。好ましくは、バイオマーカー遺伝子の相関係数は0.3を上回る。この手順を、検討対象の全ての成分に関して繰り返す。その結果が、検討対象の各化合物に対する感受性と相関するマーカー遺伝子のリストである。 The median gene expression correlation coefficient measured for the probe to growth inhibition or patient sensitivity is calculated for all genes and 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, or 0.99 Genes with a median correlation greater than are retained as biomarker genes. Preferably, the biomarker gene correlation coefficient is greater than 0.3. This procedure is repeated for all components under consideration. The result is a list of marker genes that correlate with sensitivity to each compound under consideration.
医学的治療に対する患者の感受性もしくは抵抗性の推定
所定の化合物に関して、発現が化学感受性と相関することがわかっているバイオマーカー遺伝子を使用して、患者、例えば癌患者を、医学的治療、例えば化学療法剤または放射線の投与に感受性があると分類することができる。患者に由来する腫瘍試料または血液試料(例えば白血病もしくはリンパ腫の場合)を使用することで、治療薬剤の存在下における患者の細胞中におけるバイオマーカー遺伝子の発現が(例えば、RNA抽出キット、DNAマイクロアレイ、およびDNAマイクロアレイ用スキャナーを使用して)判定される。次に、遺伝子発現に関する測定結果が、上述の手順でロジット変換される。次に、マーカー遺伝子の発現に関する測定結果の和が、同じ腫瘍を有する患者のトレーニングセット集団に由来する和の中央値と比較される。仮に、患者における遺伝子発現の和が、トレーニングセットの生存構成員における発現の和の中央値に近い場合は、患者は、化合物または他の医学的治療に感受性を有すると推定される。仮に、患者における発現の和が、トレーニングセットの非生存構成員における発現の和の中央値に近い場合は、患者は化合物に抵抗性を有すると推定される。
Estimating a patient's susceptibility or resistance to medical treatment For a given compound, a biomarker gene whose expression is known to correlate with chemosensitivity is used to treat a patient, eg, a cancer patient, to a medical treatment, eg, a chemical It can be classified as sensitive to the administration of therapeutic agents or radiation. By using a tumor sample or blood sample from the patient (e.g. in the case of leukemia or lymphoma), the expression of the biomarker gene in the patient's cells in the presence of the therapeutic agent (e.g. RNA extraction kit, DNA microarray, And using a DNA microarray scanner). Next, the measurement result regarding the gene expression is logit converted by the above-described procedure. The sum of the measurement results for marker gene expression is then compared to the median sum from the training set population of patients with the same tumor. If the sum of gene expression in the patient is close to the median sum of expression in the surviving members of the training set, the patient is presumed to be sensitive to the compound or other medical treatment. If the sum of expression in the patient is close to the median sum of expression in non-surviving members of the training set, the patient is presumed to be resistant to the compound.
ニューラルネットワーク、サポートベクターマシン、K最近傍、および最近似重心などの機械学習法を、バイオマーカー遺伝子の発現を個々の患者を抵抗性または感受性として分類するモデル変数として使用した、治療に感受性を有する患者と治療に抵抗性を有する患者を区別するモデルの開発に使用することもできる。さまざまな測定結果を使用して、患者を分類するために使用される機械学習法は、それぞれの全体が参照により本明細書に組み入れられる、米国特許第5,822,715号;米国特許出願第2003/0073083号、第2005/0227266号、第2005/0208512号、第2005/0123945号、第2003/0129629号、および第2002/0006613号に;ならびにVapnik V N. Statistical Learning Theory, John Wiley & Sons, New York, 1998;Hastie et al., 2001, The Elements of Statistical Learning: Data Mining, Inference, and Prediction, Springer, N.Y.;Agresti, 1996, An Introduction to Categorical Data Analysis, John Wiley & Sons, New York;V. Tresp et al., 「Neural Network Modeling of Physiological Processes」, in Hanson S. J. et al. (Eds.), Computational Learning Theory and Natural Learning Systems 2, MIT Press, 1994に記載されている。 Sensitive to therapy using machine learning methods such as neural networks, support vector machines, K-nearest neighbors, and nearest centroids as model variables to classify individual biomarker genes as resistant or sensitive It can also be used to develop models that distinguish between patients and patients who are resistant to treatment. Machine learning methods used to classify patients using various measurements are described in US Pat. No. 5,822,715; US Patent Application No. 2003/0073083, each of which is incorporated herein by reference in its entirety. 2005/0227266, 2005/0208512, 2005/0123945, 2003/0129629, and 2002/0006613; and Vapnik V N. Statistical Learning Theory, John Wiley & Sons, New York, 1998; Hastie et al., 2001, The Elements of Statistical Learning: Data Mining, Inference, and Prediction, Springer, NY; Agresti, 1996, An Introduction to Categorical Data Analysis, John Wiley & Sons, New York; V. Tresp et al., “Neural Network Modeling of Physiological Processes”, Hanson SJ et al. (Eds.), Computational Learning Theory and Natural Learning Systems 2, MIT Press, 1994.
癌細胞の成長阻害に関する相関係数の中央値を生じる測定結果を有するオリゴヌクレオチドプローブのみを使用して、よりコンパクトなマイクロアレイを設計することができる。したがって、この態様では、1つのみのプローブが、各遺伝子の発現を測定する際に使用するために必要である。 More compact microarrays can be designed using only oligonucleotide probes with measurements that produce a median correlation coefficient for cancer cell growth inhibition. Thus, in this embodiment, only one probe is needed for use in measuring the expression of each gene.
癌の治療に感受性を有する患者の亜集団の同定
本発明は、過去に癌の治療に有効でないと考えられた化合物または他の医学的治療に感受性を有する患者、例えば癌患者の亜集団の同定に使用することもできる。この目的を達成するために、発現が化合物または他の治療に対する感受性と相関するバイオマーカー遺伝子を、化合物または他の治療に感受性を有する患者が同定可能なように同定することができる。このような遺伝子バイオマーカーを同定するためには、細胞株における遺伝子発現を、同じ化合物または他の治療の存在下で、そのような細胞株の成長と相関させるとよい。好ましくは、発現が細胞の成長と0.3を上回る相関係数で相関する遺伝子は、可能性のあるバイオマーカーと見なされ得る。
Identification of a Subpopulation of Patients Sensitive to Treatment of Cancer The present invention identifies compounds that have previously been considered ineffective in treating cancer or other medical treatment sensitive patients, eg, a subpopulation of cancer patients Can also be used. To achieve this goal, biomarker genes whose expression correlates with susceptibility to a compound or other treatment can be identified so that patients sensitive to the compound or other treatment can be identified. In order to identify such genetic biomarkers, gene expression in cell lines may be correlated with the growth of such cell lines in the presence of the same compound or other treatment. Preferably, genes whose expression correlates with cell growth with a correlation coefficient greater than 0.3 can be considered as potential biomarkers.
または遺伝子は、治療に感受性を有することが既知である患者を、抵抗性を有する患者と区別する能力にしたがって、バイオマーカーであると同定される場合がある。感受性患者と抵抗性患者間における遺伝子発現の差の有意性は、例えばt検定で測定できる。または単純ベイズ分類器を使用して、治療対象の患者集団内の感受性亜集団および抵抗性亜集団の遺伝子発現を考慮して、感受性患者亜集団と抵抗性患者亜集団を区別する遺伝子バイオマーカーを同定することができる。 Alternatively, a gene may be identified as a biomarker according to its ability to distinguish patients who are known to be sensitive to treatment from those who are resistant. The significance of the difference in gene expression between susceptible and resistant patients can be measured, for example, by t-test. Or use a naive Bayes classifier to identify genetic biomarkers that distinguish sensitive and resistant patient subpopulations, taking into account gene expression in sensitive and resistant subpopulations within the patient population being treated Can be identified.
検討対象の患者亜集団をさらに、治療なしに生存すると推定される患者、治療なしには死亡すると推定される患者、および治療なしには症状を有すると推定される患者に定義することができる。上記の方法は、癌の治療用の化合物または他の治療に対する対象の感受性を推定可能な遺伝子バイオマーカーを同定するために、このようなさらに定義された任意の患者亜集団に同様に適用することができる。 The patient subpopulations considered can be further defined as patients presumed to survive without treatment, patients presumed to die without treatment, and patients presumed to have symptoms without treatment. The above methods are equally applicable to any such further defined patient subpopulations to identify genetic biomarkers that can estimate a subject's susceptibility to cancer treatment compounds or other therapies. Can do.
化合物または他の医学的治療に対する感受性と相関するバイオマーカー遺伝子の発現が上昇した患者は、そのような化合物または他の医学的治療に感受性を有すると推定される場合がある。 Patients with increased expression of biomarker genes that correlate with susceptibility to a compound or other medical treatment may be presumed to be susceptible to such a compound or other medical treatment.
本発明は、臨床転帰の推定に使用可能な遺伝子バイオマーカーを同定するための、本明細書に記載された遺伝子発現法を使用して感受性を有する患者亜集団を同定することで、臨床試験で失敗した化合物または他の治療の回収に特に有用である。 The present invention provides a clinical trial by identifying sensitive patient subpopulations using the gene expression methods described herein to identify genetic biomarkers that can be used to estimate clinical outcomes. It is particularly useful for recovering failed compounds or other treatments.
臨床に使用されるキット、装置、およびソフトウェア
本発明は、腫瘍からRNAを抽出するためのキット(例えばInvitrogen社のトリゾール)、RNA増幅用のキット(例えばAmbion社のMessageAmp)、遺伝子発現の測定用のマイクロアレイ(例えばAffymetrix社のHG-U133A GeneChip)を含むキット、マイクロアレイハイブリダイゼーションステーションおよびスキャナー(例えばAffymetrix社のGeneChip System 3000Dx)、ならびに本明細書に記載されたマーカー遺伝子の発現解析用のソフトウェア(例えばInsightful社のR-ProjectまたはS-Plusに由来するRで実行されるソフトウェア)を使用することで、特定の治療に抵抗性または感受性を有する患者を推定するためにも使用することができる。
The present invention relates to a kit for extracting RNA from a tumor (e.g., Trizol from Invitrogen), a kit for RNA amplification (e.g., MessageAmp from Ambion), and gene expression measurement. A microarray (e.g., Affymetrix HG-U133A GeneChip), a microarray hybridization station and scanner (e.g., Affymetrix GeneChip System 3000Dx), and software for expression analysis of the marker genes described herein (e.g., Software running in R from Insightful's R-Project or S-Plus) can also be used to estimate patients who are resistant or sensitive to a particular treatment.
インビトロにおける癌の成長阻害のスクリーニング法
癌のスクリーニング用パネルのヒト腫瘍細胞株を、5%ウシ胎仔血清および2 mM L-グルタミンを含むRPMI 1640培地で成長させる。細胞を、96ウェルのマイクロタイタープレートに100μLで、個々の細胞株の倍加時間に応じて、5,000〜40,000細胞/ウェルのプレーティング密度で添加する。細胞の添加後にマイクロタイタープレートを、37℃、5% CO2、95%空気、および100%相対湿度で24時間インキュベートし、その後に実験化合物を添加する。
Screening Method for Inhibition of Cancer Growth In Vitro The human tumor cell line of the cancer screening panel is grown in RPMI 1640 medium containing 5% fetal calf serum and 2 mM L-glutamine. Cells are added at 100 μL to a 96-well microtiter plate at a plating density of 5,000-40,000 cells / well, depending on the doubling time of individual cell lines. Following the addition of cells, the microtiter plate is incubated for 24 hours at 37 ° C., 5% CO 2, 95% air, and 100% relative humidity, after which the experimental compounds are added.
24時間後に、各細胞株の2枚のプレートをTCAを用いてインサイチューで固定し、化合物の添加時(Tz)における各細胞株に対応する細胞集団に関する測定結果を得る。実験化合物を、ジメチルスルホキシド中に、所望の最終最大試験濃度の400倍となるように溶解し、および使用時まで凍結保存する。化合物の添加時に、凍結濃縮物のアリコートを溶解し、および所望の最終最大試験濃度の2倍に、50μg/mlのゲンタマイシンを含む完全培地で希釈する。さらに4倍、10倍、または1/2対数の段階希釈物を調製し、計5つの化合物濃度と対照を得る。これらの異なる化合物希釈物の100μlのアリコートを、事前に100μlの培地を含む適切なマイクロタイターウェルに添加して、必要な最終化合物濃度を得る。 After 24 hours, two plates of each cell line are fixed in situ using TCA, and measurement results regarding the cell population corresponding to each cell line at the time of compound addition (Tz) are obtained. Experimental compounds are dissolved in dimethyl sulfoxide to 400 times the desired final maximum test concentration and stored frozen until use. At the time of compound addition, an aliquot of the freeze concentrate is lysed and diluted in complete medium containing 50 μg / ml gentamicin to twice the desired final maximum test concentration. Prepare additional 4-fold, 10-fold, or 1/2 log serial dilutions for a total of 5 compound concentrations and controls. 100 μl aliquots of these different compound dilutions are added to appropriate microtiter wells containing 100 μl of media in advance to obtain the required final compound concentration.
化合物の添加後に、プレートをさらに48時間、37℃、5% CO2、95%空気、および100%相対湿度でインキュベートする。接着性の細胞の場合は、冷TCAを添加してアッセイ法を終了する。50μlの冷50%(w/v)TCA(最終濃度、10% TCA)を緩やかに添加し、4℃で60分間、インキュベートすることでインサイチューで細胞を固定する。上清を捨て、およびプレートを水道水で5回洗浄して風乾する。1%酢酸を溶媒とする0.4%(w/v)のスルホローダミンB(SRB)溶液(100μl)を各ウェルに添加し、およびプレートを室温で10分間インキュベートする。染色後に、結合しなかった色素を、1%酢酸で5回洗浄することで除去し、プレートを風乾する。次に結合した色素を、10 mMのトリズマ塩基で溶解し、および吸光度を自動プレートリーダーで515 nmの波長で読みとる。懸濁状の細胞の場合の方法は、アッセイ法が、沈殿した細胞を50μlの80% TCA(最終濃度、16% TCA)を緩やかに添加することでウェル底に固定することで終了される点以外は同じである。7つの吸光度の測定結果[ゼロ時間(Tz)、対照の成長(C)、および5つの濃度レベルにおける化合物の存在下における試験成長(Ti)]を使用して、個々の化合物濃度レベルにおける成長のパーセンテージを計算する。成長阻害のパーセンテージは、以下の式で計算される。
[(Ti-Tz)/(C-Tz)]x 100(濃度がTi>/=Tzの場合)
[(Ti-Tz)/Tz]x 100(濃度がTi<Tzの場合)
Following compound addition, the plates are incubated for an additional 48 hours at 37 ° C., 5% CO 2, 95% air, and 100% relative humidity. For adherent cells, cold TCA is added to terminate the assay. Fix cells in situ by gently adding 50 μl cold 50% (w / v) TCA (final concentration, 10% TCA) and incubating at 4 ° C. for 60 min. Discard the supernatant and wash the plate 5 times with tap water and air dry. 0.4% (w / v) sulforhodamine B (SRB) solution (100 μl) in 1% acetic acid as a solvent is added to each well and the plate is incubated at room temperature for 10 minutes. After staining, unbound dye is removed by washing 5 times with 1% acetic acid and the plates are air dried. The bound dye is then dissolved with 10 mM Trizma base and the absorbance is read at a wavelength of 515 nm with an automatic plate reader. In the case of suspended cells, the assay is terminated by fixing the pelleted cells to the bottom of the well by gently adding 50 μl of 80% TCA (final concentration, 16% TCA). Except for the same. Using the 7 absorbance measurements [Zero Time (Tz), Control Growth (C), and Test Growth in the Presence of Compound at 5 Concentration Levels (Ti)], the growth of individual compound concentration levels Calculate percentage. The percentage of growth inhibition is calculated by the following formula:
[(Ti-Tz) / (C-Tz)] x 100 (when the concentration is Ti> / = Tz)
[(Ti-Tz) / Tz] x 100 (when the concentration is Ti <Tz)
3つの用量反応パラメータが各実験薬剤に関して計算される。50%の成長阻害(GI50)は、[(Ti-Tz)/(C-Tz)]x 100=50から計算され、化合物濃度は、化合物のインキュベーション中に、対照細胞における正味のタンパク質の上昇(SRB染色で測定)の50%の低下を生じる。総成長阻害(TGI)を生じる化合物濃度は、Ti=Tzから計算される。治療後における細胞の正味の損失を意味するLC50(化合物による治療の開始時と比較して、化合物による治療の終了時に測定されるタンパク質の50%の低下を生じる化合物濃度)は、[(Ti-Tz)/Tz]x 100=-50から計算される。活性のレベルに達する場合は、値は、この3つのパラメータのそれぞれに関して計算されるが、仮に効果が達しないか、または上回る場合は、パラメータの値は、検討対象の最大濃度もしくは最小濃度を上回るか、または下回ると表現される。 Three dose response parameters are calculated for each experimental drug. 50% growth inhibition (GI50) is calculated from [(Ti-Tz) / (C-Tz)] x 100 = 50, and compound concentration is the net increase in protein in control cells during compound incubation ( Resulting in a 50% reduction in (measured with SRB staining). The compound concentration that results in total growth inhibition (TGI) is calculated from Ti = Tz. LC50, meaning net loss of cells after treatment (compound concentration that results in a 50% reduction in protein measured at the end of treatment with the compound compared to the start of treatment with the compound) is [(Ti- Calculated from Tz) / Tz] x 100 = -50. If the level of activity is reached, a value is calculated for each of the three parameters, but if the effect is not reached or exceeded, the value of the parameter exceeds the maximum or minimum concentration under consideration. Expressed as or below.
RNAの抽出および遺伝子発現に関する測定結果
細胞/組織試料を液体窒素中で瞬間凍結してから処理する。RNAは例えば、Invitrogen社のトリゾール試薬を製造業者の指示書に従って使用して抽出する。RNAは例えば、Ambion社のMessageAmpキットを製造業者の指示書に従って使用して増幅する。増幅されたRNAは例えば、Affymetrix社のHG-U133A GeneChipおよび同等の装置、例えばAffymetrix社のGCS3000Dxを製造業者の指示書に従って使用して定量する。
Results of RNA Extraction and Gene Expression Measurements Cell / tissue samples are snap frozen in liquid nitrogen before processing. RNA is extracted, for example, using Invitrogen's Trizol reagent according to the manufacturer's instructions. RNA is amplified, for example, using the Ambion MessageAmp kit according to the manufacturer's instructions. Amplified RNA is quantified using, for example, Affymetrix HG-U133A GeneChip and equivalent equipment, such as Affymetrix GCS3000Dx according to the manufacturer's instructions.
結果として得られた遺伝子発現に関する測定結果を、本文書に記載された手順でさらに処理する。記載された手順は、R-Projectから入手可能な、およびBioconductorから入手可能なパッケージに同梱されたRソフトウェアを使用して実施することができる。 The resulting measurement results regarding gene expression are further processed according to the procedures described in this document. The described procedure can be performed using R software available from R-Project and packaged with packages available from Bioconductor.
多くの薬剤について、10〜30個のバイオマーカーで適切な反応を得るのに十分であり、したがって、必要とされるバイオマーカーの数が比較的少数であることを考慮すれば、定量逆転写酵素ポリメラーゼ連鎖反応(qRT-PCR)などの手順で、試料中で発現されるバイオマーカー遺伝子の量を高精度で測定することができる。これはマイクロアレイに代わる方法、またはマイクロアレイを補う方法となり、本発明のバイオマーカーを使用する1つの付随的な試験、たいていはマイクロアレイ単独の場合より定量性に優れた試験で、新しい薬剤に対する感受性を推定することができる。qRT-PCRは単独で実施可能なほか、または本明細書に記載されたマイクロアレイと組み合わせて実施可能である。qRT-PCRを実施する際の手順は例えば、米国特許第7,101,663号、ならびに米国特許出願第2006/0177837号および第2006/0088856号に記載されている。本発明の方法は容易に、新たに発見された薬剤、ならびに本明細書に記載された薬剤に応用可能である。 For many drugs, 10-30 biomarkers are sufficient to obtain an appropriate response, and therefore given the relatively small number of biomarkers required, quantitative reverse transcriptase The amount of biomarker gene expressed in a sample can be measured with high accuracy by a procedure such as polymerase chain reaction (qRT-PCR). This is an alternative to or supplementing microarrays, and is an additional test that uses the biomarkers of the present invention, usually more quantitative than microarrays alone, to estimate sensitivity to new drugs can do. qRT-PCR can be performed alone or in combination with the microarrays described herein. Procedures for performing qRT-PCR are described, for example, in US Pat. No. 7,101,663 and US Patent Applications 2006/0177837 and 2006/0088856. The methods of the present invention are readily applicable to newly discovered drugs as well as those described herein.
以下の実施例は、当業者が本発明の方法およびキットの使用法を確認するために提供される。実施例には、発明者らが本発明と見なす範囲を制限する意図はない。 The following examples are provided to enable those skilled in the art to determine how to use the methods and kits of the invention. The examples are not intended to limit the scope of what the inventors regard as the present invention.
実施例
実施例1:一般的な化学療法剤に対する化学感受性に関する遺伝子バイオマーカーの同定
NCI60データセットの60の癌細胞株を対象としたDNAチップによる測定結果をブロード研究所(Broad Institute)からダウンロードしてロジット基準化した。同じ細胞株に対する数千種類の化合物の成長阻害データは米国立癌研究所からダウンロードした。50%の成長阻害(GI50)に達する濃度の差が1 log未満の化合物は、得られる情報はないと見なして退けた。各細胞株における各遺伝子の発現は、所定の化合物の存在下で、細胞株における、その成長(-log(GI50))に相関していた。多数の発現に関する測定結果が所定の遺伝子に関して利用可能な場合には、ピアソン相関係数の中央値を使用し、および0.3を上回る相関係数の中央値を有する遺伝子が、所定の化合物用のバイオマーカーとして同定された。
Examples Example 1: Identification of genetic biomarkers for chemosensitivity to common chemotherapeutic agents
The results of DNA chip measurements on 60 cancer cell lines from the NCI60 data set were downloaded from the Broad Institute and logit-standardized. Data on the growth inhibition of thousands of compounds against the same cell line were downloaded from the National Cancer Institute. Compounds with a concentration difference of less than 1 log reaching 50% growth inhibition (GI50) were dismissed assuming no information was available. The expression of each gene in each cell line correlated with its growth (-log (GI50)) in the cell line in the presence of a given compound. If multiple expression measurements are available for a given gene, the median Pearson correlation coefficient is used, and a gene with a median correlation coefficient greater than 0.3 is the bio for a given compound. Identified as a marker.
実施例2:脳腫瘍患者の治療感受性の推定
60人の脳腫瘍患者の腫瘍における遺伝子発現のDNAチップによる測定結果を、ブロード研究所からダウンロードした。全てのデータファイルをロジット基準化した。一般的な化学療法剤であるシスプラチン、ビンクリスチン、アドリアマイシン、エトポシド、アクラルビシン、ミトキサントロン、およびアザグアニンのそれぞれについて、マーカー遺伝子の遺伝子発現を合計した。和を全患者の標準偏差で割って標準化し、生存患者の和の中央値、および死亡患者の和の中央値と比較した。
標準化された和(化合物)=和(化合物に対するマーカー遺伝子)/標準偏差(全患者の和)
感受性(化合物)=[標準化された和(化合物)-中央値(死亡患者の標準化された和(化合物))]2-[標準化された和(化合物)-中央値(生存患者の標準化された和(化合物))]2
Example 2: Estimation of therapeutic sensitivity of brain tumor patients
The results of measurement of gene expression in tumors of 60 brain tumor patients using a DNA chip were downloaded from the Broad Institute. All data files were logit standardized. For each of the common chemotherapeutic agents cisplatin, vincristine, adriamycin, etoposide, aclarubicin, mitoxantrone, and azaguanine, the gene expression of the marker genes was summed. The sum was normalized by dividing by the standard deviation of all patients and compared to the median sum of surviving patients and the median sum of dead patients.
Standardized sum (compound) = sum (marker gene for compound) / standard deviation (sum of all patients)
Sensitivity (compound) = [standardized sum (compound)-median (standardized sum of dead patients (compound))] 2- [standardized sum (compound)-median (standardized sum of surviving patients) (Compound))] 2
図2および図3は、60人の患者のうちの2人について推定された、結果として得られた治療感受性を示す。全患者がシスプラチンの投与を受け、およびシスプラチンに対する化学感受性に基づく60人の患者を対象とした生存率の推定から、図4に示すカプラン-マイヤー生存曲線を得た。最初に、16のシスプラチンバイオマーカー遺伝子の発現を、独立成分解析(fastICA)で5成分(次元)に分けた。5つのさまざまな分類法を、60人の患者に由来する、K最近傍(K=1)、K最近傍(K=3)、最近似重心、サポートベクターマシン、およびニューラルネットワークの5成分を対象にトレーニングを行った。化学感受性、または放射線療法に対する感受性を、5つの方法の分類を組み合わせることで推定し、各分類法あたり一票を割り当てた:一致する化学感受性/治療感受性の推定から、化学感受性/治療感受性が推定された。他の全ての推定から、化学抵抗性/治療抵抗性が推定された。組み合わされた分類器の性能を、1つ抜き相互検証で検証し、および2つの推定グループの生存率を図4に示す。化学感受性を有すると推定された患者の生存率は、化学抵抗性を有すると推定された患者より高かった。 Figures 2 and 3 show the resulting therapeutic sensitivity estimated for two of the 60 patients. Kaplan-Meier survival curves shown in FIG. 4 were obtained from all patients receiving cisplatin and from survival estimates for 60 patients based on chemosensitivity to cisplatin. First, the expression of 16 cisplatin biomarker genes was divided into 5 components (dimensions) by independent component analysis (fastICA). Five different taxonomies for five components from 60 patients: K nearest neighbor (K = 1), K nearest neighbor (K = 3), nearest centroid, support vector machine, and neural network I trained. Chemosensitivity, or sensitivity to radiation therapy, was estimated by combining the classifications of the five methods, and a vote was assigned for each classification method: Estimating chemosensitivity / treatment sensitivity from the estimated chemosensitivity / treatment sensitivity It was done. From all other estimates, chemical resistance / treatment resistance was estimated. The performance of the combined classifier is verified with one cross-validation, and the survival rates of the two estimated groups are shown in FIG. Survival of patients estimated to have chemosensitivity was higher than patients estimated to have chemoresistance.
実施例3:リンパ腫(DLBCL)患者を対象とした化学感受性の推定
56人のDLBCL(びまん性大細胞型B細胞リンパ腫)患者に由来する腫瘍を対象とした、遺伝子発現のDNAチップによる測定結果をブロード研究所からダウンロードした。全てのデータファイルをロジット基準化した。全ての患者がビンクリスチンおよびアドリアマイシンの投与を受け、ならびにビンクリスチンおよびアドリアマイシンに対する化学感受性に基づく56人の患者の生存率の推定から、図5に示すカプラン-マイヤー生存曲線を得た。33人のビンクリスチン遺伝子、および16人のアドリアマイシン遺伝子の発現を最初に、独立成分解析(fastICA)で3成分(次元)に分割した。K最近傍(K=1)、K最近傍(K=3)、最近似重心、サポートベクターマシン、およびニューラルネットワークの5つの異なる分類法のトレーニングを、56人の患者に由来する独立成分に関して行った。化学感受性を、各分類法あたり一票を割り当てた5つの方法の分類を組み合わせることで推定し:一致する化学感受性の推定から、化学感受性が推定された。他の全ての推定から、化学抵抗性が推定された。組み合わされた分類器の性能を、1つ抜き相互検証で検証し、および2つの推定グループの生存率を図5に示す。化学感受性を有すると推定された患者の生存率は、化学抵抗性を有すると推定された患者より高かった。
Example 3: Estimation of chemosensitivity for patients with lymphoma (DLBCL)
The results of measurement of gene expression using a DNA chip for tumors derived from 56 DLBCL (diffuse large B-cell lymphoma) patients were downloaded from the Broad Institute. All data files were logit standardized. All patients received vincristine and adriamycin, and an estimate of survival of 56 patients based on chemosensitivity to vincristine and adriamycin yielded the Kaplan-Meier survival curve shown in FIG. The expression of 33 vincristine genes and 16 adriamycin genes were first divided into 3 components (dimensions) by independent component analysis (fastICA). Training of five different taxonomies for K nearest neighbor (K = 1), K nearest neighbor (K = 3), nearest centroid, support vector machine, and neural network on independent components from 56 patients It was. The chemosensitivity was estimated by combining the classifications of the five methods assigned one vote for each taxonomy: the chemosensitivity was estimated from the matching chemosensitivity estimates. From all other estimates, chemical resistance was estimated. The performance of the combined classifier is verified with one cross-validation, and the survival rates of the two estimated groups are shown in FIG. Survival of patients estimated to have chemosensitivity was higher than patients estimated to have chemoresistance.
実施例4:肺癌患者の化学感受性の推定
86人の肺癌(腺癌)患者に由来する腫瘍を対象とした遺伝子発現のDNAチップによる測定結果をミシガン大学アナーバー校からダウンロードした。86人の患者のうち19人が第III期の癌であり、およびアジュバント化学療法を受けていた。生データをロジット基準化した。上述の脳腫瘍およびリンパ腫の例に関して説明された統合分類器に代えて、バイオマーカー遺伝子の発現の和を各患者に関して計算し、ならびに化学感受性の患者と化学抵抗性の患者の区別に使用した。各患者について、シスプラチン感受性に関する16のマーカー遺伝子の遺伝子発現(手術後にシスプラチンが投与された第III期の全患者)を合計した。この和が、生存患者の和の中央値に近ければ、患者はシスプラチンに対する感受性を有すると推定された。仮に和が、非生存患者の和の中央値に近ければ、患者はシスプラチンに対する抵抗性を有すると推定された。2つの推定グループの生存率を図6に示す。化学感受性を有すると推定された患者の生存率は、化学抵抗性を有すると推定された患者より高かった。
Example 4: Estimation of chemosensitivity in lung cancer patients
The results of DNA expression measurements of tumors derived from 86 lung cancer (adenocarcinoma) patients were downloaded from the University of Michigan Ann Arbor. Of the 86 patients, 19 had stage III cancer and received adjuvant chemotherapy. Raw data was logit standardized. Instead of the integrated classifier described for the brain tumor and lymphoma example above, the sum of biomarker gene expression was calculated for each patient and used to distinguish between chemosensitive and chemoresistant patients. For each patient, the gene expression of 16 marker genes for cisplatin sensitivity (all patients in stage III who received cisplatin after surgery) was summed. If this sum was close to the median sum of surviving patients, it was estimated that the patient was sensitive to cisplatin. If the sum was close to the median sum of non-surviving patients, the patient was estimated to be resistant to cisplatin. The survival rates of the two estimated groups are shown in FIG. Survival of patients estimated to have chemosensitivity was higher than patients estimated to have chemoresistance.
実施例5:リンパ腫(DLBCL)患者のリツキシマブ感受性の推定
この方法は、細胞毒性薬剤に制限されない。また、この方法は、癌の治療用に承認されたモノクローナル抗体などのタンパク性治療薬の効果の推定にも応用できる。例えば、モノクローナル抗体MABTHERA(商標)(リツキシマブ、RITUXAN(商標))について検討した。インビトロにおける細胞株におけるリツキシマブの細胞毒性に関するデータは、公開された報告書(Ghetie et al., Blood, 97(5):1392-1398, 2001)から得た。各細胞株における細胞毒性は、これらの細胞株における遺伝子の発現と相関していた(アクセッション番号GSE2350、GSE1880、GDS181を使用して、NCBI Gene Expression Omnibusデータベースからダウンロードした)。同定されたマーカー遺伝子を使用して、リツキシマブおよびCHOP(R-CHOP)が投与された患者14人の小さなセットにおける、リツキシマブに対するDLBCLの感受性を推定した(アクセッション番号GSE4475の下でNCBI Gene Expression Omnibusからダウンロードした)。異なるチップのタイプ間の変換を、Affymetrix社から入手可能なマッチング表を使用して実施した。
Example 5: Estimating Rituximab Sensitivity in Lymphoma (DLBCL) Patients This method is not limited to cytotoxic drugs. This method can also be applied to estimate the effects of proteinaceous therapeutics such as monoclonal antibodies approved for the treatment of cancer. For example, the monoclonal antibody MABTHERA ™ (Rituximab, RITUXAN ™) was studied. Data on cytotoxicity of rituximab in cell lines in vitro was obtained from a published report (Ghetie et al., Blood, 97 (5): 1392-1398, 2001). Cytotoxicity in each cell line correlated with gene expression in these cell lines (downloaded from NCBI Gene Expression Omnibus database using accession numbers GSE2350, GSE1880, GDS181). The identified marker genes were used to estimate the sensitivity of DLBCL to rituximab in a small set of 14 patients receiving rituximab and CHOP (R-CHOP) (NCBI Gene Expression Omnibus under accession number GSE4475 Downloaded from). Conversion between different chip types was performed using a matching table available from Affymetrix.
R-CHOPに感受性を有すると推定された患者の生存率を、R-CHOPに抵抗性を有すると推定された患者の生存率と図7で比較する。化学感受性を有すると推定された患者の生存率は、化学抵抗性を有すると推定された患者より高かった。 The survival rate of patients estimated to be sensitive to R-CHOP is compared in FIG. 7 with the survival rate of patients estimated to be resistant to R-CHOP. Survival of patients estimated to have chemosensitivity was higher than patients estimated to have chemoresistance.
びまん性大細胞型B細胞リンパ腫(DLBCL)の治療に使用されるような組み合わせ療法に対する感受性を推定するためには、特定の組み合わせ療法に対する患者の感受性は、組み合わせに使用される各化合物に関するマーカー遺伝子を組み合わせることで推定される。この例を図8に示す。DLBCLに対して使用されるいくつかの組み合わせ療法に対する、1人の患者の推定された感受性(頭文字で表示)を以下に示す:R-CHOPは、リツキシマブ(MABTHERA(商標))、ビンクリスチン、ドキソルビシン(アドリアマイシン)、シクロホスファミド、およびプレドニゾロンを含み;R-ICEは、リツキシマブ、イホスファミド、カルボプラチン、およびエトポシドを含み;R-MIMEは、リツキシマブ、ミトグアゾン、イホスファミド、メトトレキセート、およびエトポシドを含み;CHOEPは、シクロホスファミド、ドキソルビシン、エトポシド、ビンクリスチン、およびプレドニゾンを含み;DHAPは、デキサメタゾン、シタラビン(Ara C)、およびシスプラチンを含み;ESHAPは、エトポシド、メチルプレドニゾロン(ソルメドロール)、シタラビン(Ara-C)、およびシスプラチンを含み;ならびにHOAP-Bleoは、ドキソルビシン、ビンクリスチン、Ara C、プレドニゾン、およびブレオマイシンを含む。 To estimate susceptibility to a combination therapy such as that used in the treatment of diffuse large B-cell lymphoma (DLBCL), the patient's susceptibility to a particular combination therapy is determined by the marker gene for each compound used in the combination. It is estimated by combining. An example of this is shown in FIG. The estimated susceptibility (in acronym) of one patient to several combination therapies used for DLBCL is shown below: R-CHOP is rituximab (MABTHERA ™), vincristine, doxorubicin (Adriamycin), including cyclophosphamide, and prednisolone; R-ICE includes rituximab, ifosfamide, carboplatin, and etoposide; R-MIME includes rituximab, mitoguazone, ifosfamide, methotrexate, and etoposide; CHOEP DHAP contains dexamethasone, cytarabine (Ara C), and cisplatin; ESHAP contains etoposide, methylprednisolone (solmedrol), cytarabine (Ara-C) ), And cisplatin Wherein; and HOAP-bleo include doxorubicin, vincristine, Ara C, prednisone, and bleomycin.
実施例6:脳腫瘍(髄芽腫)患者の放射線感受性の推定
バイオマーカーを同定する方法は、放射線療法などの他の治療にも応用できる。例えば、脳腫瘍患者に関して、放射線療法に対する感受性が推定された。腫瘍に対する線量が5,300〜7,200センチグレイ(cGy)となる2,400〜3,600 cGyを生じる、脳脊髄へ照射する放射線療法が脳腫瘍患者に、放射線のビームを放出する医学的装置を使用して照射された。放射線療法に対する、NCI60データセットに使用された60の癌細胞株の感受性を、公開済みの報告書から得た。この感受性は、マーカー遺伝子を同定するために上述した細胞株における遺伝子の発現と相関していた。後に放射線療法による治療を受ける患者から得られた脳腫瘍における遺伝子発現をDNAマイクロアレイで測定した結果をブロード研究所から入手した。同定された遺伝子バイオマーカーを使用して、患者を放射線療法に感受性または抵抗性に分類した。2つの推定カテゴリーにおける患者の生存率を図9に示す。放射線療法に対する感受性を有すると推定された患者の生存率は、放射線療法に抵抗性を有すると推定された患者より高かった。
Example 6: Estimation of radiosensitivity of patients with brain tumors (medulloblastoma) The method of identifying biomarkers can be applied to other treatments such as radiotherapy. For example, sensitivity to radiation therapy has been estimated for brain tumor patients. Radiation therapy applied to the brain and spinal cord, which produces 2,400-3,600 cGy with a dose to the tumor of 5,300-7,200 centimeter gray (cGy), was applied to brain tumor patients using a medical device that emits a beam of radiation. The sensitivity of the 60 cancer cell lines used in the NCI60 data set to radiation therapy was obtained from published reports. This sensitivity correlated with gene expression in the cell lines described above to identify marker genes. The results of measuring gene expression in a brain tumor obtained from a patient who was later treated with radiation therapy using a DNA microarray were obtained from the Broad Institute. The identified genetic biomarkers were used to classify patients as sensitive or resistant to radiation therapy. The patient survival rates in the two estimated categories are shown in FIG. Survival of patients estimated to be sensitive to radiation therapy was higher than patients estimated to be resistant to radiation therapy.
実施例7:薬剤の救済
集団の全ての構成員は、特定の治療に同等に反応しない場合がある。例えば新規化合物は、検討対象集団における効果の欠如のために、後期臨床試験でしばしば失敗する。このような化合物は、集団全体には有効ではない可能性はあるが、遺伝子発現に固有の差を含む多様な理由のために、失敗した化合物に感受性を有する亜集団が存在する可能性がある。本明細書に記載された方法で、遺伝子発現を指標として使用して、化合物に感受性を有する患者の亜集団を同定することで、失敗した化合物を救済することができる。感受性を有する患者の亜集団を限定した、続いて行われる臨床試験で、特定の患者亜集団における過去に失敗した化合物の効果が確認される可能性があり、化合物が、対象亜集団における使用の承認に向かって進むことになる。
Example 7: Drug Remedy All members of a population may not respond equally to a particular treatment. For example, new compounds often fail in late clinical trials due to lack of efficacy in the study population. Such compounds may not be effective across the population, but there may be subpopulations that are sensitive to failed compounds for a variety of reasons, including differences inherent in gene expression. . The methods described herein can be used to rescue failed compounds by identifying a subpopulation of patients that are sensitive to the compound using gene expression as an indicator. Subsequent clinical trials limiting the subpopulation of susceptible patients may confirm the effects of previously failed compounds in a particular patient subpopulation, and the compound may be Proceed towards approval.
このために、上述の手順で回収された反応患者亜集団に由来する、さまざまな癌細胞試料に対する化合物の阻害効果のインビトロにおける測定結果、または治療対象患者の臨床反応の尺度を、このような患者に由来する細胞の遺伝子発現と比較する。癌細胞試料の成長は、上述した遺伝子発現に関する測定結果と相関する場合がある。これによって、失敗した化合物に対する患者の感受性の推定に使用可能なマーカー遺伝子が同定される。好ましくはバイオマーカー遺伝子は、失敗した化合物に感受性を有することが判明済みの患者集団内で同定される。バイオマーカーが同定されれば、患者におけるバイオマーカー遺伝子の発現を、上述の手順に従って測定できる。患者は、それらの遺伝子のバイオマーカーの発現に従って、化合物による治療に対して反応性を有するか、または反応性を有さないと推定される。臨床効果は後に、失敗した化合物に感受性を有すると推定された患者のグループで示されなければならない。 To this end, in vitro measurements of the compound's inhibitory effect on various cancer cell samples derived from the response patient subpopulations collected in the above procedure, or a measure of the clinical response of the treated patient, can be used for such patients. Compared to the gene expression of cells derived from. The growth of the cancer cell sample may correlate with the measurement results regarding gene expression described above. This identifies marker genes that can be used to estimate patient susceptibility to failed compounds. Preferably, the biomarker gene is identified in a patient population that has been found to be sensitive to the failed compound. Once the biomarker is identified, the expression of the biomarker gene in the patient can be measured according to the procedure described above. Patients are presumed to be responsive or not responsive to treatment with compounds according to the expression of biomarkers of their genes. The clinical effect must later be shown in a group of patients presumed to be sensitive to the failed compound.
このような方法はさらに、仮に化合物による治療に反応する患者がさらに、化合物なしに生存すると推定される患者、および化合物なしには死亡するか再発すると推定される患者に分割されると洗練され得る。死亡するか再発すると推定される亜集団における臨床効果がさらに明らかにされる可能性がある。簡単に説明すると、後に疾患によって死亡する患者の診断時における遺伝子発現を、5年後も生存している患者の診断時における遺伝子発現と比較する。2つのグループ間で異なって発現される遺伝子が、見込みのあるバイオマーカーとして同定され、および治療効果を推定するために、そのような遺伝子バイオマーカーを使用したモデルが構築される。 Such a method can be further refined if patients who respond to treatment with a compound are further divided into patients who are presumed to survive without the compound and those who are presumed to die or relapse without the compound. . Clinical effects in subpopulations estimated to die or recur may be further clarified. Briefly, gene expression at the time of diagnosis for patients who later die from disease is compared to gene expression at the time of diagnosis for patients who are still alive after 5 years. Genes that are differentially expressed between the two groups are identified as potential biomarkers, and models using such gene biomarkers are constructed to estimate therapeutic effects.
臨床試験で失敗した化合物の例には、難治性の進行性非小細胞肺癌(NSCLC)に対するイレッサ(ゲフィニチブ、AstraZeneca)、進行性膵臓癌を対象とする第一選択治療におけるアバスチン(ベバシズマブ、Genentech)、難治性の転移性乳癌患者に対するアバスチン(ベバシズマブ、Genentech)、および転移性非小細胞肺癌(NSCLC)に対するタルセバ(エルロチニブ、Genentech)などがある。本発明に記載された方法を、化合物に反応する感受性患者亜集団が同定可能なように、これらの化合物などに応用することができる。 Examples of compounds that failed clinical trials include Iressa (Gefinitib, AstraZeneca) for refractory advanced non-small cell lung cancer (NSCLC), Avastin (bevacizumab, Genentech) in first-line treatment for advanced pancreatic cancer And Avastin (bevacizumab, Genentech) for patients with refractory metastatic breast cancer, and Tarceva (erlotinib, Genentech) for metastatic non-small cell lung cancer (NSCLC). The methods described in this invention can be applied to these compounds and the like so that sensitive patient subpopulations responsive to the compounds can be identified.
実施例8:中央値の相関に対する相関の中央値
本発明で使用される癌細胞の成長に対する個々のプローブによる測定結果の相関の中央値を、プローブの測定結果の中央値の相関と比較した:この比較によって、中央値の計算を行うべき方法の段階がわかる。前期の場合は、複数の相関が各遺伝子に関して計算される。なぜなら、多数のプローブが任意の遺伝子の発現を測定するが、相関係数の中央値のみが最終的に、バイオマーカーを同定するために保持されるからである。後期の場合は、各遺伝子に対して1つの相関のみが計算される。なぜなら、遺伝子発現に関する測定結果の中央値のみが各遺伝子に対して考慮されるからである。図10は、60人の脳腫瘍患者の生存率を推定する放射線感受性のバイオマーカー遺伝子を同定するために、発現に関する測定結果の中央値を使用した場合の結果を示す。図10に示す、放射線感受性を有すると推定されるグループと、放射線抵抗性を有すると推定されるグループの間の生存率の差は、相関係数の中央値を使用する図9に示される差よりかなり小さく、図9に使用される本発明の相関の中央値が、図10に示した中央値の相関より優れていることが示唆される。
Example 8: Median correlation to median correlation The median correlation of measurement results with individual probes to the growth of cancer cells used in the present invention was compared to the median correlation of probe measurement results: This comparison reveals the stage of the method on which the median should be calculated. In the first half, multiple correlations are calculated for each gene. This is because many probes measure the expression of any gene, but only the median correlation coefficient is ultimately retained to identify the biomarker. In the late case, only one correlation is calculated for each gene. This is because only the median measurement result for gene expression is considered for each gene. FIG. 10 shows the results when using the median measurement of expression for identifying radiosensitive biomarker genes that estimate survival of 60 brain tumor patients. The difference in survival rate between the group estimated to be radiosensitive and the group presumed to be radioresistant as shown in FIG. 10 is the difference shown in FIG. 9 using the median correlation coefficient. It is much smaller, suggesting that the median correlation of the present invention used in FIG. 9 is superior to the median correlation shown in FIG.
OMDのような個々のマーカー遺伝子に注目すると、インビトロにおける細胞株の測定された放射線感受性に対する相関の中央値は0.32である。しかしながら、中央値の相関は0.39である。しかしながら、差を補うためにカットオフ値を0.3から0.4に調節しても、図10に示すように改善しない。 Focusing on individual marker genes such as OMD, the median correlation for measured radiosensitivity of cell lines in vitro is 0.32. However, the median correlation is 0.39. However, adjusting the cut-off value from 0.3 to 0.4 to compensate for the difference does not improve as shown in FIG.
発明者らは、Staunton et al., PNAS 98(19):10787-10792, (2001)によって提案されている、重み付け投票(weighted voting)に対する中央値の相関も比較した。重み付け投票は、図10の結果と同等の低い結果を生じ、P値は0.11であった。 The inventors also compared the median correlation to weighted voting proposed by Staunton et al., PNAS 98 (19): 10787-10792, (2001). The weighted voting yielded a low result comparable to that of FIG. 10, with a P value of 0.11.
他の態様
本明細書で言及された全ての出版物および特許出願は、個々の独立した出版物または特許出願が特異的かつ個別に参照により組み入れられると示されたように、同様の規模で参照により本明細書に組み入れられる。
Other Embodiments All publications and patent applications mentioned in this specification are referenced on a similar scale, as each individual publication or patent application is shown to be specifically and individually incorporated by reference. Is incorporated herein by reference.
本発明は、本発明の特定の態様と関連して記載されているが、さらなる修飾が可能であり、ならびに本出願は、一般に本発明の原理に従って、本発明の任意の変形、使用、または改変を含むこと、および本発明が関する当技術分野の既知の、または慣行の範囲内にある本開示からの逸脱を含み、ならびに本明細書に記載された本質的な特徴に応用可能なことが意図されると理解されたい。 While this invention has been described in connection with specific embodiments of this invention, further modifications are possible, and this application generally follows any principles of the invention, including any variation, use, or modification of the invention. And is intended to be applicable to the essential features described herein, including deviations from this disclosure that are within the scope of known or practiced in the art to which this invention pertains. I want to be understood.
レジェンド:
リスト_2006:新しいU133Aチップによる測定結果によって2006年に同定されたバイオマーカー
リスト_2005:2005年の特許申請に列挙されたバイオマーカー
HU6800:旧式のHU6800チップによる測定結果によって得られたバイオマーカー
リスト_Prior:先行技術におけるマッチング用のバイオマーカー
リスト_Preferr:好ましいバイオマーカーのリスト
相関:化合物に対する感受性に対するバイオマーカーの相関
legend:
List_2006: List of biomarkers identified in 2006 based on measurement results from new U133A chip_2005: Biomarkers listed in 2005 patent application
HU6800: Biomarker list obtained from the measurement results of the old HU6800 chip _Prior: Biomarker list for matching in the prior art _Preferr: List of preferred biomarkers Correlation: Correlation of biomarkers with sensitivity to compounds
(表1) ビンクリスチンのバイオマーカー
(Table 1) Vincristine biomarkers
(表2)シスプラチンのバイオマーカー (Table 2) Biomarkers of cisplatin
(表3) アザグアニンのバイオマーカー
(Table 3) Biomarkers of azaguanine
(表4) エトポシドのバイオマーカー
(Table 4) Biomarkers of etoposide
(表5) アドリアマイシンのバイオマーカー
(Table 5) Adriamycin biomarkers
(表6) アクラルビシンのバイオマーカー
(Table 6) Biomarkers for aclarubicin
(表7) ミトキサントロンのバイオマーカー
(Table 7) Biomarkers of mitoxantrone
(表8) マイトマイシンのバイオマーカー
(Table 8) Mitomycin biomarkers
(表9) パクリタキセル(タキソール)のバイオマーカー
(Table 9) Biomarkers of paclitaxel (Taxol)
(表10) ゲムシタビン(Gemzar)のバイオマーカー
(Table 10) Biomarkers of gemcitabine (Gemzar)
(表11) タキソテール(ドセタキセル)のバイオマーカー
(Table 11) Taxotere (docetaxel) biomarker
(表12) デキサメタゾンのバイオマーカー
(Table 12) Dexamethasone Biomarker
(表13) Ara-C(塩酸シタラビン)のバイオマーカー
(Table 13) Biomarkers of Ara-C (cytarabine hydrochloride)
(表14) メチルプレドニゾロンのバイオマーカー
(Table 14) Biomarkers of methylprednisolone
(表15) メトトレキセートのバイオマーカー
(Table 15) Biomarkers for methotrexate
(表16) ブレオマイシンのバイオマーカー
Table 16: Biomarkers of bleomycin
(表17) メチル-GAG(メチルグリオキサールビス(アミジノヒドラゾン)二塩酸塩)のバイオマーカー
Table 17: Biomarkers of methyl-GAG (methylglyoxal bis (amidinohydrazone) dihydrochloride)
(表18) カルボプラチンのバイオマーカー
Table 18: Carboplatin biomarkers
(表19) 5-FU(5-フルオロウラシル)のバイオマーカー
Table 19: Biomarkers of 5-FU (5-fluorouracil)
(表20) リツキシマブ(マブセラ)のバイオマーカー
(Table 20) Rituximab (Mabsela) biomarker
(表21) 放射線感受性のバイオマーカー
Table 21: Biomarkers for radiation sensitivity
(表22) ビンクリスチンのバイオマーカー
(Table 22) Vincristine biomarkers
(表23) シスプラチンのバイオマーカー
Table 23: Biomarkers of cisplatin
(表24) エトポシドのバイオマーカー
Table 24: Etoposide biomarkers
(表25) アザグアニンのバイオマーカー
Table 25: Azaguanine biomarkers
(表26) カルボプラチンのバイオマーカー
Table 26: Carboplatin biomarkers
(表27) アドリアマイシンのバイオマーカー
Table 27: Adriamycin biomarkers
(表28) アクラルビシンのバイオマーカー
(Table 28) Biomarkers for aclarubicin
(表29) ミトキサントロンのバイオマーカー
Table 29: Biomarkers for mitoxantrone
(表30) マイトマイシンのバイオマーカー
Table 30: Mitomycin biomarkers
(表31) パクリタキセル(タキソール)のバイオマーカー
(Table 31) Biomarkers of paclitaxel (Taxol)
(表32) ゲムシタビン(Gemzar)のバイオマーカー
(Table 32) Biomarkers of gemcitabine (Gemzar)
(表33) タキソテール(ドセタキセル)のバイオマーカー
(Table 33) Taxotere (docetaxel) biomarker
(表34) デキサメタゾンのバイオマーカー
Table 34: Dexamethasone biomarkers
(表35) Ara-C(塩酸シタラビン)のバイオマーカー
(Table 35) Biomarkers of Ara-C (cytarabine hydrochloride)
(表36) メチルプレドニゾロンのバイオマーカー
Table 36: Methylprednisolone biomarkers
(表37) メトトレキセートのバイオマーカー
(Table 37) Biomarkers for methotrexate
(表38) ブレオマイシンのバイオマーカー
Table 38: Biomarkers of bleomycin
(表39) メチル-GAG(メチルグリオキサールビスアミジノヒドラゾン二塩酸塩)のバイオマーカー
Table 39: Biomarkers of methyl-GAG (methylglyoxal bisamidinohydrazone dihydrochloride)
(表40) HDAC阻害剤のバイオマーカー
Table 40: HDAC inhibitor biomarkers
(表41) 5-フルオロウラシルのバイオマーカー
Table 41: 5-Fluorouracil biomarkers
(表42) 放射線感受性のバイオマーカー
Table 42: Radiosensitive biomarkers
(表43) マブセラ(リツキシマブ)のバイオマーカー
(Table 43) Biomarkers for Mabusera (Rituximab)
(表44) 5-アザ-2'-デオキシシチジン(デシタビン)のバイオマーカー
Table 44: 5-aza-2'-deoxycytidine (decitabine) biomarkers
Claims (94)
からなる群より選択される遺伝子の少なくとも1つの遺伝子の発現のレベルを決定する段階を含み、遺伝子の発現のレベルの変化が、患者が治療に感受性を有することを意味する、癌の治療に対する癌患者の感受性を推定する方法。 In the patient's cells,
Determining the level of expression of at least one gene selected from the group consisting of: wherein the change in the level of expression of the gene means that the patient is sensitive to the treatment A method for estimating patient sensitivity.
からなる群より選択されるか、または方法がさらに、SRRM1、LAPTM5、ITGB2、CD53、CD37、GMFG、PTPRCAP、GNA15、BLM、PTPRC、CORO1A、PRKCB1、HEM1、およびUGT2B17からなる群より選択される少なくとも1つの遺伝子の発現のレベルを測定する段階を含み、遺伝子の発現のレベルの上昇が、患者がメチルプレドニゾロンに感受性を有することを意味する、請求項1記載の方法。 At least one gene
At least selected from the group consisting of SRRM1, LAPTM5, ITGB2, CD53, CD37, GMFG, PTPRCAP, GNA15, BLM, PTPRC, CORO1A, PRKCB1, HEM1, and UGT2B17 2. The method of claim 1, comprising measuring the level of expression of one gene, wherein increasing the level of expression of the gene means that the patient is sensitive to methylprednisolone.
からなる群より選択されるか、または方法がさらに、MSN、ACTR2、AKR1B1、VIM、ITGA3、OPTN、M6PRBP1、COL1A1、BASP1、ANPEP、TGFB1、NFIL3、NK4、CSPG2、PLAU、COL6A2、UBC、FGFR1、BAX、COL4A2、およびRAB31からなる群より選択される少なくとも1つの遺伝子の発現のレベルを測定する段階を含み、遺伝子の発現のレベルの上昇が、患者がブレオマイシンに感受性を有することを意味する、請求項1記載の方法。 At least one gene
Or a method is further selected from the group consisting of MSN, ACTR2, AKR1B1, VIM, ITGA3, OPTN, M6PRBP1, COL1A1, BASP1, ANPEP, TGFB1, NFIL3, NK4, CSPG2, PLAU, COL6A2, UBC, FGFR1, Measuring the level of expression of at least one gene selected from the group consisting of BAX, COL4A2, and RAB31, wherein increasing the level of expression of the gene means that the patient is sensitive to bleomycin, Item 1. The method according to Item 1.
からなる群より選択されるか、または方法がさらに、ITK、RALY、PSMC5、MYL6、CD1B、STMN1、GNA15、MDK、CAPG、ACTN1、CTNNA1、FARSLA、E2F4、CPSF1、SEPW1、TFRC、ABL1、TCF7、FGFR1、NUCB2、SMA3、FAT、VIM、およびATP2A3からなる群より選択される少なくとも1つの遺伝子の発現のレベルを測定する段階を含み、遺伝子の発現のレベルの上昇が、患者がリツキシマブに感受性を有することを意味する、請求項1記載の方法。 At least one gene
Or selected from the group consisting of ITK, RALY, PSMC5, MYL6, CD1B, STMN1, GNA15, MDK, CAPG, ACTN1, CTNNA1, FARSLA, E2F4, CPSF1, SEPW1, TFRC, ABL1, TCF7, Including measuring the level of expression of at least one gene selected from the group consisting of FGFR1, NUCB2, SMA3, FAT, VIM, and ATP2A3, wherein the increased level of gene expression makes the patient sensitive to rituximab The method of claim 1, which means
からなる群より選択されるか、または方法がさらに、WARS、CD81、CTSB、PKM2、PPP2CB、CNN3、ANXA2、JAK1、EIF4G3、COL1A1、DYRK2、NFIL3、ACTN1、CAPN2、BTN3A2、IGFBP3、FN1、COL4A2、およびKPNB1からなる群より選択される少なくとも1つの遺伝子の発現のレベルを測定する段階を含み、遺伝子の発現のレベルの上昇が、患者が放射線療法に感受性を有することを意味する、請求項1記載の方法。 At least one gene
Or selected from the group consisting of WARS, CD81, CTSB, PKM2, PPP2CB, CNN3, ANXA2, JAK1, EIF4G3, COL1A1, DYRK2, NFIL3, ACTN1, CAPN2, BTN3A2, IGFBP3, FN1, COL4A2, And measuring the level of expression of at least one gene selected from the group consisting of KPNB1, wherein increasing the level of expression of the gene means that the patient is sensitive to radiation therapy. the method of.
からなる群より選択され、遺伝子の発現のレベルの上昇が、患者がヒストンデアセチラーゼ(HDAC)阻害剤に感受性を有することを意味する、請求項1記載の方法。 At least one gene
2. The method of claim 1, wherein the increased level of gene expression is selected from the group consisting of: wherein the patient is sensitive to a histone deacetylase (HDAC) inhibitor.
からなる群より選択される少なくとも1つの遺伝子の少なくとも5残基の連続したヌクレオチドに相補的であるか、または同一である1本鎖核酸を含み、1本鎖核酸が、遺伝子の発現のレベルの検出に十分であり、および1本鎖核酸と、遺伝子またはその相補物にコードされる核酸間の特異的なハイブリダイゼーションを可能とし、キットが、さらに、癌患者に由来する試料から回収された核酸を適用するための指示書、1本鎖核酸とハイブリダイズする遺伝子の発現のレベルを決定するための指示書、ならびに癌の治療に対する患者の感受性を推定するための指示書を含むキット。 Kit
A single-stranded nucleic acid that is complementary to or identical to at least 5 consecutive nucleotides of at least one gene selected from the group consisting of: Nucleic acids that are sufficient for detection and that allow specific hybridization between a single-stranded nucleic acid and a nucleic acid encoded by a gene or its complement, and the kit is further recovered from a sample from a cancer patient A kit comprising: instructions for applying, instructions for determining the level of expression of a gene that hybridizes with a single-stranded nucleic acid, and instructions for estimating a patient's susceptibility to cancer treatment.
からなる群より選択されるか、またはキットがさらに、SRRM1、LAPTM5、ITGB2、CD53、CD37、GMFG、PTPRCAP、GNA15、BLM、PTPRC、CORO1A、PRKCB1、HEM1、およびUGT2B17からなる群より選択される遺伝子の少なくとも5残基の連続したヌクレオチドに相補的であるか、または同一である1つもしくは複数の1本鎖核酸を含み、遺伝子の発現のレベルの上昇が、患者が治療に感受性を有することを意味し、ならびに治療がメチルプレドニゾロンによる治療である、請求項34記載のキット。 Gene
A gene selected from the group consisting of SRRM1, LAPTM5, ITGB2, CD53, CD37, GMFG, PTPRCAP, GNA15, BLM, PTPRC, CORO1A, PRKCB1, HEM1, and UGT2B17 One or more single-stranded nucleic acids that are complementary to or identical to at least 5 consecutive nucleotides of the gene, wherein increased levels of gene expression indicate that the patient is susceptible to treatment. 35. A kit according to claim 34, which means and wherein the treatment is treatment with methylprednisolone.
からなる群より選択されるか、またはキットがさらに、MSN、ACTR2、AKR1B1、VIM、ITGA3、OPTN、M6PRBP1、COL1A1、BASP1、ANPEP、TGFB1、NFIL3、NK4、CSPG2、PLAU、COL6A2、UBC、FGFR1、BAX、COL4A2、およびRAB31からなる群より選択される遺伝子の少なくとも5残基の連続したヌクレオチドに相補的であるか、または同一である1つもしくは複数の1本鎖核酸を含み、遺伝子の発現のレベルの上昇が、患者が治療に感受性を有することを意味し、ならびに治療がブレオマイシンによる治療である、請求項34記載のキット。 Gene
Or selected from the group consisting of MSN, ACTR2, AKR1B1, VIM, ITGA3, OPTN, M6PRBP1, COL1A1, BASP1, ANPEP, TGFB1, NFIL3, NK4, CSPG2, PLAU, COL6A2, UBC, FGFR1, One or more single-stranded nucleic acids that are complementary to or identical to at least 5 consecutive nucleotides of a gene selected from the group consisting of BAX, COL4A2, and RAB31, and 35. The kit of claim 34, wherein increased levels mean that the patient is sensitive to treatment, and wherein the treatment is treatment with bleomycin.
からなる群より選択されるか、またはキットがさらに、ITK、RALY、PSMC5、MYL6、CD1B、STMN1、GNA15、MDK、CAPG、ACTN1、CTNNA1、FARSLA、E2F4、CPSF1、SEPW1、TFRC、ABL1、TCF7、FGFR1、NUCB2、SMA3、FAT、VIM、およびATP2A3からなる群より選択される遺伝子の少なくとも5残基の連続したヌクレオチドに相補的であるか、または同一である1つもしくは複数の1本鎖核酸を含み、遺伝子の発現のレベルの上昇が、患者が治療に感受性を有することを意味し、ならびに治療がリツキシマブによる治療である、請求項34記載のキット。 Gene
Or selected from the group consisting of ITK, RALY, PSMC5, MYL6, CD1B, STMN1, GNA15, MDK, CAPG, ACTN1, CTNNA1, FARSLA, E2F4, CPSF1, SEPW1, TFRC, ABL1, TCF7, One or more single-stranded nucleic acids that are complementary to or identical to at least 5 consecutive nucleotides of a gene selected from the group consisting of FGFR1, NUCB2, SMA3, FAT, VIM, and ATP2A3 35. The kit of claim 34, wherein the increased level of expression of the gene means that the patient is susceptible to treatment, and the treatment is treatment with rituximab.
からなる群より選択されるか、またはキットがさらに、WARS、CD81、CTSB、PKM2、PPP2CB、CNN3、ANXA2、JAK1、EIF4G3、COL1A1、DYRK2、NFIL3、ACTN1、CAPN2、BTN3A2、IGFBP3、FN1、COL4A2、およびKPNB1からなる群より選択される遺伝子の少なくとも5残基の連続したヌクレオチドに相補的であるか、または同一である1つもしくは複数の1本鎖核酸を含み、遺伝子の発現のレベルの上昇が、患者が治療に感受性を有することを意味し、ならびに治療が放射線療法による治療である、請求項34記載のキット。 Gene
Or a kit is further selected from the group consisting of WARS, CD81, CTSB, PKM2, PPP2CB, CNN3, ANXA2, JAK1, EIF4G3, COL1A1, DYRK2, NFIL3, ACTN1, CAPN2, BTN3A2, IGFBP3, FN1, COL4A2, And one or more single-stranded nucleic acids that are complementary to or identical to at least five consecutive nucleotides of a gene selected from the group consisting of KPNB1, and have an increased level of expression of the gene 35. The kit of claim 34, wherein the patient is sensitive to treatment and the treatment is treatment with radiation therapy.
からなる群より選択され、遺伝子の発現のレベルの上昇が、患者が治療に感受性を有することを意味し、ならびに治療がヒストンデアセチラーゼ(HDAC)阻害剤による治療である、請求項34記載のキット。 Gene
35. The method of claim 34, wherein the increased level of expression of the gene is selected from the group consisting of that means that the patient is susceptible to treatment, and the treatment is treatment with a histone deacetylase (HDAC) inhibitor. kit.
a.さまざまな細胞タイプにおける遺伝子の発現レベルに関する複数の測定結果、および癌に対する該治療の非存在下における該細胞タイプの成長に対する、癌に対する治療の存在下における同細胞タイプの成長に関する測定結果を得る段階;
b.該細胞における該遺伝子の発現レベルの個々の複数の測定結果を、該細胞の成長と相関させて相関係数を得る段階;
c.該遺伝子に関して計算された相関係数の中央値を選択する段階;ならびに
d.該相関係数の中央値が0.3を上回る場合は、該遺伝子が、癌の該治療に対する癌患者の感受性を判定するために使用されるバイオマーカーとして同定される段階。 A method for identifying biomarkers useful for determining a cancer patient's susceptibility to cancer treatment, comprising the following steps:
a. Obtaining multiple measurements of gene expression levels in various cell types, and measurements of growth of the same cell type in the presence of treatment for cancer versus growth of the cell type in the absence of the treatment for cancer ;
b. Correlating individual measurements of the expression level of the gene in the cell with the growth of the cell to obtain a correlation coefficient;
c. Selecting the median correlation coefficient calculated for the gene; and
d. If the median correlation coefficient is greater than 0.3, the gene is identified as a biomarker used to determine the susceptibility of a cancer patient to the treatment for cancer.
からなる群より選択される、請求項65記載の方法。 Gene
66. The method of claim 65, wherein the method is selected from the group consisting of:
a.該癌患者に由来する試料中におけるバイオマーカー遺伝子の発現のレベルに関する測定結果を得る段階;
b.線形和、最近傍、最近似重心(nearest centroid)、線形判別分析、サポートベクタマシン、およびニューラルネットワークからなる群より選択されるアルゴリズムを使用して開発される、癌の治療に対する感受性を推定するモデルを、該測定結果に適用する段階;ならびに
c.該癌患者が癌の該治療に反応するか否かを推定する段階。 A method for estimating the susceptibility of a cancer patient to treatment for cancer comprising the following steps:
a. Obtaining a measurement result relating to the level of expression of a biomarker gene in a sample derived from the cancer patient;
b. A model for estimating cancer susceptibility to treatment developed using an algorithm selected from the group consisting of linear sum, nearest neighbor, nearest centroid, linear discriminant analysis, support vector machine, and neural network Applying to the measurement results; and
c. Estimating whether the cancer patient responds to the treatment for cancer.
からなる群より選択される、請求項77記載の方法。 Gene
78. The method of claim 77, selected from the group consisting of:
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JP2009523011A (en) | 2009-06-18 |
JP2014147386A (en) | 2014-08-21 |
JP5984324B2 (en) | 2016-09-06 |
CN101365806B (en) | 2016-11-16 |
WO2007072225A8 (en) | 2008-11-06 |
CA2631236C (en) | 2019-10-29 |
WO2007072225A2 (en) | 2007-06-28 |
EP1960551A2 (en) | 2008-08-27 |
CN101365806A (en) | 2009-02-11 |
WO2007072225A3 (en) | 2008-07-10 |
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