JP2021519302A - 微小残存がんを治療する方法 - Google Patents
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Abstract
Description
本開示は、対象内の微小残存がんを治療する方法に関する。
小胞体(「ER」)管腔におけるタンパク質の折り畳み不全は、3つの主要経路、PERK、IRE1α、およびATF6を活性化し、それは小胞体ストレス応答(「UPR」)としても知られ、細胞がこのストレスを補正して生存することを可能にする(Walter et al., “The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation,” Science 334:1081-1086 (2011)およびRon et al., “Signal Integration In the Endoplasmic Reticulum Unfolded Protein Response,” Nat. Rev. Mol. Cell Biol. 8:519-529 (2007))。最近のエビデンスによれば、さまざまなタイプのがんにおいて、各種シグナルのなかでもUPRはとくに、腫瘍細胞ががん遺伝子および低酸素を原因とする増大した転写負荷により課されるERへの要求および酸化条件に応答するのを可能にする機構である(Blais et al., “Activating Transcription Factor 4 is Translationally Regulated by Hypoxic Stress,” Mol. Cell. Biol. 24:7469-7482 (2004); Chevet et al., “Endoplasmic Reticulum Stress-Activated Cell Reprogramming in Oncogenesis,” Cancer Discov. 5:586-597 (2015); Tameire et al., “Cell Intrinsic and Extrinsic Activators of the Unfolded Protein Response in Cancer: Mechanisms and Targets for Therapy,” Semin. Cancer Biol. 33:3-15 (2015); Hart et al., “ER Stress-Mediated Autophagy Promotes Myc-Dependent Transformation and Tumor Growth,” J. Clin. Invest. 122:4621-4634 (2012); Martin-Perez et al., “Activated ERBB2/HER2 Licenses Sensitivity to Apoptosis Upon Endoplasmic Reticulum Stress Through a PERK-Dependent Pathway,” Cancer Res. 74:1766-1777 (2014); Rajasekhar et al., “Postgenomic Global Analysis of Translational Control Induced by Oncogenic Signaling,” Oncogene 23:3248-3264 (2004); Rajasekhar et al., “Oncogenic Ras and Akt Signaling Contribute to Glioblastoma Formation by Differential Recruitment of Existing mRNAs to Polysomes,” Mol. Cell 12:889-901 (2003); Rojo et al., “4E-Binding Protein 1, A Cell Signaling Hallmark in Breast Cancer that Correlates With Pathologic Grade and Prognosis,” Clin. Cancer Res. 13:81-89 (2007);およびSequeira et al., “Inhibition of eIF2alpha Dephosphorylation Inhibits ErbB2-Induced Deregulation of Mammary Acinar Morphogenesis,” BMC Cell Biol. 10:64 (2009))。がん遺伝子により活性化した経路は、mTORシグナリングの活性化および翻訳開始によって、ERクライアントタンパク質負荷を増加させる(Hart et al., “ER Stress-Mediated Autophagy Promotes Myc-Dependent Transformation and Tumor Growth,” J. Clin. Invest. 122:4621-4634 (2012); Ozcan et al., “Loss of the Tuberous Sclerosis Complex Tumor Suppressors Triggers the Unfolded Protein Response to Regulate Insulin Signaling and Apoptosis,” Mol. Cell 29:541-551 (2008);およびTameire et al., “Cell Intrinsic and Extrinsic Activators of the Unfolded Protein Response in Cancer: Mechanisms and Targets for Therapy,” Semin. Cancer Biol. 33:3-15 (2015))。PERKおよびIRE1α-XBP-1経路は、低酸素および微小環境ストレスへの適応に寄与することがさらにわかっており(Bi et al., “ER Stress-Regulated Translation Increases Tolerance to Extreme Hypoxia and Promotes Tumor Growth,” EMBO J. 24:3470-3481 (2005); Blais et al., “Activating Transcription Factor 4 is Translationally Regulated by Hypoxic Stress,” Mol. Cell. Biol. 24:7469-7482 (2004); Chen et al., “XBP1 Promotes Triple-Negative Breast Cancer by Controlling the HIF1alpha Pathway,” Nature 508:103-107 (2014); Romero-Ramirez et al., “X box-Binding Protein 1 Regulates Angiogenesis in Human Pancreatic Adenocarcinomas,” Transl. Oncol. 2:31-38 (2009); Rouschop et al., “The Unfolded Protein Response Protects Human Tumor Cells During Hypoxia Through Regulation of the Autophagy Genes MAP1LC3B and ATG5,” J. Clin. Invest. 120:127-141 (2010); Schewe et al., “ATF6alpha-Rheb-mTOR Signaling Promotes Survival of Dormant Tumor Cells In Vivo,” Proc. Nat’l. Acad. Sci. U.S.A. 105:10519-10524(2008);およびYe et al., “The GCN2-ATF4 Pathway is Critical for Tumour Cell Survival and Proliferation in Response to Nutrient Deprivation,” EMBO J. 29:2082-2096 (2010))、UPRが変化する環境への適応を可能にし得ることが示唆される。
本開示の一局面は、対象内の微小残存がんを治療する方法に関する。この方法は、対象内の播種性がん細胞(DCC)を骨形成タンパク質7(「BMP7」)誘導体タンパク質と接触させる段階であって、対象の接触させたDCCの休眠を誘導または維持して対象内の微小残存がんを治療する、段階を含む。この局面の方法は、微小残存がんを対象内で侵襲性増殖へと進行させないために用いられ得る。
本明細書において、対象内の微小残存がんを治療する方法を開示する。本開示の一局面は、対象内の微小残存がんを治療する方法に関する。この方法は、対象内の播種性がん細胞(DCC)を骨形成タンパク質7(BMP7)誘導体タンパク質と接触させる段階を含む。対象内の播種性がん細胞(DCC)を骨形成タンパク質7(BMP7)誘導体タンパク質と接触させる段階により、対象の接触させたDCCの休眠を誘導または維持して、対象内の微小残存がんを治療する。
。当業者であれば、シグナルペプチドがタンパク分解性切断により除去されて、pro-BMP7と呼ばれるインタクトなプロドメイン/成熟ペプチドができることを理解されよう。
に示すアミノ酸配列を有する。
に示すコンセンサス配列に示される特定のアミノ酸の変更を有する。本開示のヒト成熟BMP7タンパク質の特定のバリアントは、野生型成熟ヒトBMP7タンパク質と比べて、比活性の増加、可溶性特徴の改善、生物利用性の改善、内在性循環阻害物質との結合の減少、および/またはEBF活性の低下を有する。
の化合物、またはその薬学的に許容される塩であり、
式中、Rは、
からなる群より選択され;
XはCHまたはNであり;
R1は水素またはハロゲン(たとえばフルオロ)であり;
R2はC1〜C3アルキルである。
の化合物、またはその薬学的に許容される塩であり、
式中、Rは、
からなる群より選択され;
XはCHまたはNであり;
R1は水素またはハロゲン(たとえばフルオロ)であり;
R2はC1〜C3アルキルである。
試薬、細胞培養、および処置:PeproTech(ニュージャージー州ロッキーヒル)からEGFを入手し、100 ng/mlを用いた。Sigma(ミズーリ州セントルイス)からタプシガルジンを入手し、2 nM用いた。H2B-Dendra2プラスミドの安定トランスフェクションによりZR75.1-H2B-Dendra2細胞株を作った(Gurskaya et al., “Engineering of a Monomeric Green-to-Red Photoactivatable Fluorescent Protein Induced by Blue Light,” Nat. Biotechnol. 24:461-465 (2006)、参照により全文が本明細書に組み入れられる)。3D培養のために、MCF10A-HER2、SKBR3、およびZR75.1-H2B-Dendra2細胞を、先述のように増殖因子低減マトリゲル(NY州コーニング、Corning)に蒔き、増殖させた(Avivar-Valderas et al., “Regulation of Autophagy during ECM Detachment is Linked to a Selective Inhibition of mTORC1 by PERK,” Oncogene 32(41):4932-40 (2013)、参照により全文が本明細書に組み入れられる)。「低密度」に言及する場合、細胞3500個/8ウェルを播種し、「高密度」は細胞2万個/8ウェルを播種した。ビヒクル(DMSO)またはLY4(2 μM)での処置は、2Dの場合は24時間おきに、3D培養の場合は48時間おきに交換した。
PERK経路活性化は、UPR誘導性増殖停止、および休眠表現型と関連付けられる生存の重要なエフェクターであることがわかっている(Brewer et al., “PERK Mediates Cell-Cycle Exit During the Mammalian Unfolded Protein Response,” Proc. Natl. Acad. Sci. U.S.A. 97:12625-30 (2000); Ranganathan et al., “Dual Function of Pancreatic Endoplasmic Reticulum Kinase in Tumor Cell Growth Arrest and Survival,” Cancer Res. 68:3260-3268 (2008);およびRanganathan et al., “Functional Coupling of p38-Induced Up-Regulation of BiP and Activation of RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells,” Cancer Res. 66:1702-1711 (2006)、それぞれ参照により全文が本明細書に組み入れられる)。MMTV-HER2動物では、高パーセンテージのマウスが肺への転移を生じ、それは初期DCCまたは後期DCCにより開始し得る(Guy et al., “Expression of the Neu Protooncogene in the Mammary Epithelium of Transgenic Mice Induces Metastatic Disease,” Proc. Nat’l. Acad. Sci. U.S.A. 89:10578-10582 (1992); Husemann et al., “Systemic Spread Is an Early Step in Breast Cancer,” Cancer Cell 13:58-68 (2008); Harper et al., “Mechanism of Early Dissemination and Metastasis in Her2+ Mammary Cancer,” Nature 540:588-592 (2016); Hosseini et al., “Early Dissemination Seeds Metastasis in Breast Cancer,” Nature 540:552-558 (2016)、参照により全文が本明細書に組み入れられる)。休眠DCCはE-カドヘリンの喪失およびTwist1の発現を示すが(Harper et al., “Mechanism of Early Dissemination and Metastasis in Her2+ Mammary Cancer,” Nature 540:588-592 (2016)、参照により全文が本明細書に組み入れられる)、膵臓がんモデルのE-カドヘリン陰性DCCも、無活動であり、かつPERK誘導遺伝子CHOPの上向き調節を示すことがわかっている(Pommier et al., “Unresolved Endoplasmic Reticulum Stress Engenders Immune-Resistant, Latent Pancreatic Cancer Metastases,” Science 360(6394):eaao4908 (2018)、参照により全文が本明細書に組み入れられる)。これと同じPERK経路活性化レベルと細胞周期停止との相関関係が、MMTV-HER2自然転移モデルにも存在するかどうかを評価するために、免疫蛍光(IF)を用いる高解像度撮影、ならびにDCCおよび転移の単一細胞解像度の遺伝子発現分析、の2つの異なるアプローチを用いた。大きな腫瘍を有し、したがって休眠および増殖性DCCを有する動物の、MMTV-HER2肺組織切片のIFを実施した(Harper et al., “Mechanism of Early Dissemination and Metastasis in Her2+ Mammary Cancer,” Nature 540:588-592 (2016)、参照により全文が本明細書に組み入れられる)。次に、組織を同時染色してHER2、Ki67(増殖マーカーとして)、およびGADD34(またはPPP1r15A)陽性DCCを検出した。GADD34は、(eIF2αリン酸化による)翻訳抑制からストレス誘導性遺伝子発現へのプログラムされたシフトを担うPERK誘導性ストレス遺伝子である(Novoa et al., “Stress-Induced Gene Expression Requires Programmed Recovery from Translational Repression,” EMBO J. 22:1180-7 (2003)、参照により全文が本明細書に組み入れられる)。画像分析によると、低増殖性指数(ki67low)のHER2+転移病変またはDCCは、高レベルのGADD34発現により示されるように、高レベルのERストレスを呈した(図1A、上パネルおよびグラフ)。他方で、高増殖性DCCまたは病変では、非常に低レベルのGADD34染色が示された(図1A、下パネルおよびグラフ)。2つのマーカー、Ki67とGADD34とは、100%の細胞で逆相関しており、GADD34検出が、UPRhigh、無活動DCC、および転移病変の生物指標となり得ることを裏付けている。
上記の結果を受け、選択的PERK阻害物質が休眠DCC運命および転移形成に及ぼす効果の評価を行った。LY2、LY3、およびLY4(LYシリーズの阻害物質)は、インビボの研究をサポートする、適切な薬物様の特性をもつ強力かつ選択的なPERK阻害物質とされている(Pytel et al., “PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma,” PLoS Genet. 12:1-22 (2016)、参照により全文が本明細書に組み入れられる)。LYシリーズの阻害物質をインビトロのキナーゼアッセイ(eIF2αを基質として用いる)および細胞ベースのアッセイで試験し、eIF2αリン酸化およびその下流のATF4出量を調べた(表6)。3種類の阻害物質すべてがGSK2656157と比べて同等または優れた効力を示し(Axten et al., “Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development,” ACS Med. Chem. Lett. 4:964-968 (2013)、参照により全文が本明細書に組み入れられる);HER2発現MCF10A細胞でP-PERK(P-T980)レベルおよびその下流の標的ATF4を有効に減少させ(図2Cおよび図3A);これらの同じ細胞を低用量タプシガルジン処理に対し感受性とし、かくしてこれらのPERK阻害物質がいかに選択的にERストレス適応に影響するかを示した(図2D)。
a 精製eIF2aを基質として用いたPERK生化学的アッセイ。
b 293個の細胞におけるツニカマイシン誘導性eIF2aリン酸化の細胞ベースのアッセイ。
c 293個の細胞におけるツニカマイシン誘導性ATF4-Luc活性の細胞ベースのアッセイ。
d 精製eIF2aを基質として用いたGCN2生化学的アッセイ。
e 活性部位プローブの置換を用いた結合データに基づくDiscoveRx scanMAX(商標)キナーゼプロファイリング、456種類のキナーゼを試験。
f Atkins et al., “Characterization of a Novel PERK Kinase Inhibitor with Antitumor and Antiangiogenic Activity,” Cancer Res. 73(6):1993-2002 (2013)、参照により全文が本明細書に組み入れられる。
a 活性部位プローブの置換を用いた結合データに基づくDiscoveRx scanMAX(商標)キナーゼプロファイリング、456種類のキナーゼを試験。
b Atkins et al.、 “Characterization of a Novel PERK Kinase Inhibitor with Antitumor and Antiangiogenic Activity,” Cancer Res. 73(6):1993-2002 (2013)、参照により全文が本明細書に組み入れられる。
最も休眠と関連のある無活動UPRhigh DCCにおいてPERK依存性が存在することを実証したのに続き、腫瘍病変を評価した。HER2誘発性の増悪は、MMTV-HER2モデルでは遺伝子的にPERKキナーゼに依存することが見出されており(Bobrovnikova-Marjon et al., “PERK-Dependent Regulation of Lipogenesis During Mouse Mammary Gland Development and Adipocyte Differentiation,” Proc. Nat’l. Acad. Sci. U.S.A. 105:16314-16319 (2008)、参照により全文が本明細書に組み入れられる)、またHER2+腫瘍はタンパク質毒性に感受性であり、かつERAD依存性であることがわかっている(Singh et al., “HER2-mTOR Signaling-Driven Breast Cancer Cells Require ER-Associated Degradation to Survive,” Sci. Signal. 8:ra52 (2015)、参照により全文が本明細書に組み入れられる)。さらに、cBIOデータベース(Cerami et al., “The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data,” Cancer Discovery 2:401-404 (2012)、参照により全文が本明細書に組み入れられる)の分析によると、HER2増幅ヒト乳腺腫瘍のおよそ14%が、PERKに関するmRNAの上向き調節を示すことがわかった(図5A)。したがって、過形成乳腺からDCISおよび浸潤性がんまで種々のステージの増悪が分析され得る原発病変において、LY4がHER2誘導性乳腺腫瘍増悪に影響したかどうかを調査した(Lu et al., “Mechanism of Inhibition of MMTV-neu and MMTV-wnt1 Induced Mammary Oncogenesis by RARalpha agonist AM580,” Oncogene 29(25):3665-76 (2010); Muller et. al., “Single-Step Induction of Mammary Adenocarcinoma in Transgenic Mice Bearing the Activated c-neu Oncogene,” Cell 54(1):105-115 (1988); Harper et al., “Mechanism of Early Dissemination and Metastasis in Her2+ Mammary Cancer,” Nature 540:588-592 (2016) ; Hosseini et al., “Early Dissemination Seeds Metastasis in Breast Cancer,” Nature 540:552-558 (2016)、参照により全文が本明細書に組み入れられる)。
HER2+腫瘍はタンパク質毒性に対し感受性であるため(Singh et al., “HER2-mTOR Signaling-Driven Breast Cancer Cells Require ER-Associated Degradation to Survive,” Sci. Signal. 8:ra52 (2015)、参照により全文が本明細書に組み入れられる)、PERK阻害物質が、ERクライアントタンパク質負荷の増加により最適なHER2活性に影響し得るかどうかを評価した。腫瘍内の残基Y1221/1222のHER2リン酸化の検出は、他の研究で報告されているP-HER2陽性面積(DiGiovanna et al., “Active Signaling by Neu in Transgenic Mice,” Oncogene 17:1877-1884 (1998)、参照により全文が本明細書に組み入れられる)がP-PERKおよびP-eIF2αの染色と重なったことを示した(図9A)。この知見は、PERK経路およびHER2経路の活性化が同時局在することを示した。同様に、原発腫瘍細胞の単一細胞を標的とする遺伝子発現プロファイリングでも、高レベルのERストレス遺伝子発現を有する原発腫瘍細胞集団(約25%)が示され(図9B)、これはP-HER2活性化を示す集団に対応した可能性がある。重要なことに、染色の面積および強度の両方を考慮して腫瘍のP-HER2レベルをスコア付けすると(図10A)、LY4処置腫瘍は対照動物よりも有意に低いレベルのP-HER2を示したことが見出された(図9C)。HER2は、EGFRおよびHER3とのホモ二量体またはヘテロ二量体としてシグナル伝達する(Moasser MM, “The Oncogene HER2: Its Signaling and Transforming Functions and its Role in Human Cancer Pathogenesis,” Oncogene 26(45):6469-87 (2007)およびNegro et al., “Essential Roles of Her2/erbB2 in Cardiac Development and Function,” Recent Prog. Horm. Res. 59:1-12 (2014)、それぞれ参照により全文が本明細書に組み入れられる)。飢餓状態にし、そしてLY4(2 μM)の存在下または非存在下でEGF(100 ng/ml、15分)で処理したMCF10A-HER2細胞のインビトロ処理は、PERK阻害物質が、基底およびEGFの両方が誘導するP-EGFRおよびP-HER2のレベルを減少させたこと、ならびに生存経路P-AKT、P-S6、およびP-ERK1/2レベルの下向き調節を明らかにした(図9Dおよびグラフ、ならびに図10B)。表面ビオチン化および同時免疫沈降を調べて決定したところ、これらの条件下では、全HER2レベルまたはEGFRとのヘテロ二量体化に対する明白な効果は観測されなかった。LY4は、どのHERファミリーメンバーの活性部位、AKTまたはS6キナーゼに対しても直接の阻害効果がないので(表8)、この効果はHER2シグナリングに対する間接的なPERK阻害効果によるものであろう。他のHERファミリーメンバーと違って、HER2は、リガンドとの結合および二量体化後も細胞膜に留まることが知られている(Hommelgaard et al., “Association with Membrane Protrusions Makes ErbB2 an Internalization-Resistant Receptor,” Mol Biol Cell. 15(4):1557-67 (2004); Bertelsen et al., “The Mysterious Ways of ErbB2/HER2 Trafficking,” Membranes (Basel) 4:424-446 (2014)、それぞれ参照により全文が本明細書に組み入れられる)。LY4がHER2受容体の活性化機構を妨害し得るかどうかを試験するために、表面ビオチン化アッセイを実施して、細胞表面の受容体の存在を測定し、かつ可逆的表面ビオチン化を測定して、受容体エンドサイトーシスを測定した(Cihil et al., “The Cell-Based L-Glutathione Protection Assays to Study Endocytosis and Recycling of Plasma Membrane Proteins,” J. Vis. Exp. e50867 (2013)、参照により全文が本明細書に組み入れられる)。データは、LY4処理が、細胞表面のP-HER2および全HER2の量を減少させ(図9Eおよび図10C)、またそれに付随してホスホ-HER2および全HER2のエンドサイトーシスを増加させたこと示した(図9F)。このデータは、Singh et al., “HER2-mTOR Signaling-Driven Breast Cancer Cells Require ER-Associated Degradation to Survive,” Sci. Signal. 8:ra52 (2015)(参照により全文が本明細書に組み入れられる)のデータとともに、PERKシグナリングおよび適当なUPR機能が、最適な受容体局在化および活性化に影響することにより、適当なHER2下流シグナリングの維持に必要であることを示唆している。
1 活性部位プローブの置換を用いた結合データに基づくDiscoveRx scanMAX(商標)キナーゼプロファイリング、456種類のキナーゼを試験。
原発病変に対する薬理学的PERK阻害の効果が確立され、また、極めて重要なことに、LY4が休眠DCCの根絶により転移を阻害できることも確立された。この情報を踏まえ、休眠を模倣するような臨床的に利用可能な薬物を用いて、休眠性がん細胞をUPRhighおよびLY4感受性にできるかどうかを評価した。この基本原理を裏付けるのは、UPRhigh DCCがより高いレベルのCDK阻害物質を発現したという知見である(図1C)。したがって次に、CDK4/6阻害物質アベマシクリブ(50 mpk、4週)で動物を前処置することにより、無活動DCCのプールを基底の50%よりも増加させること(図11A)によって、LY4の抗転移効果がさらに増強されるかどうかを問うた。実際、MMTV-HER2雌をアベマシクリブ単剤で前処置すると、本来(対照)はGADD34染色の非常に低い、かつ局在化したレベルを示す原発腫瘍切片において、GADD34+細胞が急増した(図11B)。原発腫瘍での測定を、アベマシクリブがもたらす無活動関連UPRの代用バイオマーカーとした。予想どおり、LY4での処置により、処置動物の原発腫瘍におけるGADD34の発現はなくなった(図11B)。アベマシクリブ(休眠様誘導フェーズ)に続きLY4(休眠DCC根絶フェーズ)でマウスを連続処置した結果、LY4単剤処置で観測されたのと同じマクロ転移負荷の減少が得られた(図11C)。しかし、併用によりミクロ転移の存在もほぼ完全に消え(図11D)、また、単剤でも見られたように、無活動の単一播種性がん細胞の数が大きく減少した(図11E)。まとめると、これらの結果は、再活性化してこれらの病変を播種する無活動DCCを標的とすることにより転移を防止する有望な治療ストラテジーとしての、CDK阻害物質などの細胞分裂阻害物質とそれに続くLY4の連続的併用の基本原理を裏付けている。
HER2+乳がんモデルの複数の研究が、HER2+乳がんの腫瘍発生は、PERKシグナリングに生存および適応を依存していると結論付けている(Bobrovnikova-Marjon et al., “PERK Promotes Cancer Cell Proliferation and Tumor Growth by Limiting Oxidative DNA Damage,” Oncogene 29(27):3881-95 (2010); Singh et al., “HER2-mTOR Signaling-Driven Breast Cancer Cells Require ER-Associated Degradation to Survive,” Sci. Signal. 8:ra52 (2015); Avivar-Valderas et al., “PERK Integrates Autophagy and Oxidative Stress Responses to Promote Survival During Extracellular Matrix Detachment,” Mol. Cell. Biol. 31:3616-3629 (2011);およびAvivar-Valderas et al., “Regulation of Autophagy During ECM Detachment is Linked to a Selective Inhibition of mTORC1 by PERK,” Oncogene 32(41):4932-40 (2013)、それぞれ参照により全文が本明細書に組み入れられる)。興味深いことに、手術マージンに存在する、そして標的器官にも休眠播種性がん細胞として存在する無活動腫瘍細胞(Bragado et al., “TGF-Beta2 Dictates Disseminated Tumour Cell Fate in Target Organs Through TGF-Beta-RIII and P38Alpha/Beta Signalling,” Nat. Cell. Biol. 15:1351-1361 (2013); Chery et al., “Characterization of Single Disseminated Prostate Cancer Cells Reveals Tumor Cell Heterogeneity and Identifies Dormancy Associated Pathways,” Oncotarget 5(20):9939-51 (2014); Sosa et al., “Mechanisms of Disseminated Cancer Cell Dormancy: An Awakening Field,” Nat. Rev. Cancer 14:611-622 (2014);およびSosa et al., “NR2F1 Controls Tumour Cell Dormancy Via SOX9- and RARbeta-Driven Quiescence Programmes,” Nat. Commun. 6:6170 (2015)、それぞれ参照により全文が本明細書に組み入れられる)が、生存のために他のERストレス経路とともにPERKシグナリングを活性化したことも見出されている(Adomako et al., “Identification of Markers that Functionally Define a Quiescent Multiple Myeloma Cell Sub-Population Surviving Bortezomib Treatment,” BMC Cancer 15:444 (2015); Ranganathan et al., “Dual Function of Pancreatic Endoplasmic Reticulum Kinase in Tumor Cell Growth Arrest and Survival,” Cancer Res. 68:3260-3268 (2008); Ranganathan et al., “Functional Coupling of p38-Induced Up-Regulation of BiP and Activation of RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells,” Cancer Res. 66:1702-1711 (2006); Schewe et al., “ATF6alpha-Rheb-mTOR Signaling Promotes Survival of Dormant Tumor Cells In Vivo,” Proc. Nat’l. Acad. Sci. U.S.A. 105:10519-10524(2008); Schewe et al., “Inhibition of eIF2alpha Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy,” Cancer Res. 69:1545-1552 (2009);およびChery et al., “Characterization of Single Disseminated Prostate Cancer Cells Reveals Tumor Cell Heterogeneity and Identifies Dormancy Associated Pathways,” Oncotarget 5(20):9939-51 (2014)、それぞれ参照により全文が本明細書に組み入れられる)。最近、Pommier et al., “Unresolved Endoplasmic Reticulum Stress Engenders Immune-Resistant, Latent Pancreatic Cancer Metastases,” Science 360(6394):eaao4908 (2018)(参照により全文が本明細書に組み入れられる)が、肝臓内の膵臓DCC(および他のモデル)が無活動中にUPRを活性化することを示して、本件を実証した。種々のがんおよびモデルに及ぶこの再現性レベルは、この生態の高度な生物学的妥当性を示唆している。
CDK4/6阻害物質は細胞周期停止を誘導することがわかっており、また、LY4は休眠性の細胞周期停止DTCの細胞死を誘導するので(図12A)、CDK4/6阻害物質とLY4の併用がインビトロ細胞株の細胞生存率を低下させるかどうかを、次に調査した。CDK4/6阻害物質アベマシクリブは、2Dおよび3Dインビトロ細胞培養のどちらでも、WM35メラノーマ細胞の増殖を阻害することがわかっている。1週間の50 nMのアベマシクリブの前処理に続くインビトロの2 μMのLY4での短時間処理(48時間)(2D)により、Braf変異メラノーマWM35細胞の生存率は、2 μMのLY4単剤で処理した細胞よりも低下する(図12B)。インビトロ3D培養では、1週間のアベマシクリブ前処理に続く2 μMのLY4の添加が、細胞生存率の低下にさらなる効果を有した(図12C)。図12Cに示すこれらの結果は、3D細胞培養で、アベマシクリブ前処理が増殖停止および一部の細胞死を誘導し得ることを示唆している。そうであればLY4の添加は、その細胞死の効果を増強していると考えられる。このことは、アベマシクリブで停止させた細胞が、GADD34の上向き調節からわかるようにERストレス応答を上向き調節させ得(図12G)、そしてLY4感受性となり得るという概念と合致する。
BMP7-F9は、ERK/p38活性比を低下させ、かつ休眠シグネチャーのさまざまなmRNAを誘導する(図13A〜13C)。図13Aは、2 ng/ml、5 ng/ml、および10 ng/mlのBMP7-F9処理(それぞれ2つめ、3つめ、および4つめのグレーのバー:対照は1つめの黒いバー)によりERK/p38活性比が対照よりも低下したことを示し、これはHEp3 HNSCC細胞のウェスタンブロットで決定した。ERK/p38活性比に対する効果は、2〜6および24時間後に観測される(縦の2つめから4つめの群)。最初の30分で、ERK活性をBMP7により刺激する(縦1つめのセット)。図13Bは、BMP7-F9処理(10 ng/ml BMP7-F9、24時間)により、休眠シグネチャー遺伝子をコードするDEC2、p53、およびp27 mRNAが誘導されることを示す。図13Cは、同じ細胞のBMP7-F9処理により、強力な休眠誘導性転写因子NR2F1の核集積が誘導されることを示し、これは免疫蛍光により決定した(10 ng/ml、24時間)。図13Aおよび図13Bでは差はp<0.05であり、スチューデントのt検定により計算した。
Claims (47)
- 対象内の播種性がん細胞(DCC)を骨形成タンパク質7(「BMP7」)誘導体タンパク質と接触させる段階であって、該対象の接触させた該DCCの休眠を誘導または維持して該対象内の微小残存がんを治療する、該段階
を含む、対象内の微小残存がんを治療する方法。 - 前記対象が、乳がん、多発性骨髄腫、肺がん、非小細胞肺がん、脳がん、子宮頸がん、マントル細胞リンパ腫、白血病、肝細胞がん、前立腺がん、メラノーマ、皮膚がん、頭頸部がん、甲状腺がん、グリオブラストーマ、ニューロブラストーマ、または結腸直腸がんと診断されている、請求項1に記載の方法。
- 前記がんが、浸潤性乳がん、乳管内上皮内がん(DCIS)、非浸潤性小葉がん(LCIS)、および炎症性乳がんから選択される乳がんである、請求項2に記載の方法。
- 前記乳がんがHER2+乳がんである、請求項3に記載の方法。
- 前記対象が、播種性腫瘍細胞および/または非転移性がんと診断されている、請求項1〜4のいずれか一項に記載の方法。
- 前記BMP7誘導体がBMP7-F9である、請求項1〜5のいずれか一項に記載の方法。
- 前記対象に化学療法剤、免疫療法剤、エピジェネティック作用物質、または電離放射線を投与する段階
をさらに含む、請求項1〜6のいずれか一項に記載の方法。 - 前記対象に化学療法剤が投与され、かつ該化学療法剤が、トラスツズマブ(ハーセプチン(登録商標))およびラパチニブ(タイケルブ(登録商標))から選択される抗HER2化学療法剤である、請求項7に記載の方法。
- 前記対象に化学療法剤が投与され、かつ該化学療法剤が、アントラサイクリン、タキサン、キナーゼ阻害物質、抗体、フルオロピリミジン、および白金薬物から選択される、請求項7に記載の方法。
- 前記対象に免疫療法剤が投与され、かつ該免疫療法剤が、免疫チェックポイント阻害物質、インターフェロン、または腫瘍ワクチンから選択される、請求項7に記載の方法。
- 前記対象にエピジェネティック作用物質が投与され、かつ該エピジェネティック作用物質が、ヒストンデアセチラーゼ(HDAC)阻害物質、5-アザシチジン、レチノイン酸、三酸化ヒ素、Zeste2エンハンサーポリコーム抑制複合体2サブユニット(EZH2)阻害物質、ブロモドメイン(BRD)阻害物質、およびそれらの誘導体から選択される、請求項7に記載の方法。
- 前記接触させる段階が、前記BMP7誘導体タンパク質を前記対象に投与することにより実行される、請求項1〜11のいずれか一項に記載の方法。
- 前記接触させる段階の前に、前記対象内のDCCの存在を検出する段階
をさらに含む、請求項1〜12のいずれか一項に記載の方法。 - 前記DCCがNR2F1+である、請求項13に記載の方法。
- 前記DCCが骨形成タンパク質受容体陽性(「BMPR+」)である、請求項13または請求項14に記載の方法。
- 前記DCCがホスホ-PERK活性である、請求項13〜15のいずれか一項に記載の方法。
- 前記対象内のDCCを、プロテインキナーゼRNA様小胞体キナーゼ(PERK)阻害物質、MEK阻害物質、CDK4/6阻害物質、またはそれらの任意の組み合わせと接触させる段階
をさらに含む、請求項1〜16のいずれか一項に記載の方法。 - 前記接触させる段階が、PERK阻害物質を前記対象に投与することにより実行される、請求項17に記載の方法。
- 前記接触させる段階が、LY2、LY3、LY4、およびそれらの組み合わせから選択されるPERK阻害物質を用いて実行される、請求項17または請求項18に記載の方法。
- 前記接触させる段階が、EIF2AK1もEIF2AK2もEIF2AK4も阻害しないPERK阻害物質を用いて実行される、請求項17〜19のいずれか一項に記載の方法。
- 前記接触させる段階が、MEK阻害物質を前記対象に投与することにより実行される、請求項17に記載の方法。
- 前記MEK阻害物質が、PD184352、PD318088、PD98059、PD334581、RDEA119/BAY 869766から選択される、請求項21に記載の方法。
- 前記接触させる段階が、CDK4/6阻害物質を前記対象に投与することにより実行される、請求項17に記載の方法。
- 前記CDK4/6阻害物質が、アベマシクリブ(LY2835219)、パルボシクリブ(PD0332991)、およびリボシクリブ(LEE011)から選択される、請求項23に記載の方法。
- 前記対象がヒトである、請求項1〜24のいずれか一項に記載の方法。
- 前記接触させる段階の前に、がん寛解状態の対象を選択する段階
をさらに含む、請求項1〜25のいずれか一項に記載の方法。 - 対象内の播種性がん細胞(DCC)を、LY2、LY3、およびLY4から選択されるプロテインキナーゼRNA様小胞体キナーゼ(PERK)阻害物質と接触させる段階であって、該対象内のDCCを根絶して該対象内の微小残存がんを治療する、該段階
を含む、対象内の微小残存がんを治療する方法。 - 前記対象が、乳がん、多発性骨髄腫、肺がん、非小細胞肺がん、脳がん、子宮頸がん、マントル細胞リンパ腫、白血病、肝細胞がん、前立腺がん、メラノーマ、皮膚がん、頭頸部がん、甲状腺がん、グリオブラストーマ、ニューロブラストーマ、または結腸直腸がんと診断されている、請求項27に記載の方法。
- 前記がんが、浸潤性乳がん、乳管内上皮内がん(DCIS)、非浸潤性小葉がん(LCIS)、および炎症性乳がんから選択される乳がんである、請求項28に記載の方法。
- 前記乳がんがHER2+乳がんである、請求項29に記載の方法。
- 前記対象が、播種性腫瘍細胞および/または非転移性がんと診断されている、請求項27に記載の方法。
- 前記対象に化学療法剤、免疫療法剤、エピジェネティック作用物質、または電離放射線を投与する段階
をさらに含む、請求項27〜31のいずれか一項に記載の方法。 - 前記対象に化学療法剤が投与され、かつ該化学療法剤が、トラスツズマブ(ハーセプチン(登録商標))およびラパチニブ(タイケルブ(登録商標))から選択される抗HER2化学療法剤である、請求項32に記載の方法。
- 前記対象に化学療法剤が投与され、かつ該化学療法剤が、アントラサイクリン、タキサン、キナーゼ阻害物質、抗体、フルオロピリミジン、および白金薬物から選択される、請求項32に記載の方法。
- 前記対象に免疫療法剤が投与され、かつ該免疫療法剤が、免疫チェックポイント阻害物質、インターフェロン、または腫瘍ワクチンから選択される、請求項32に記載の方法。
- 前記対象にエピジェネティック作用物質が投与され、かつ該エピジェネティック作用物質が、ヒストンデアセチラーゼ(HDAC)阻害物質、5-アザシチジン、レチノイン酸、三酸化ヒ素、Zeste2エンハンサーポリコーム抑制複合体2サブユニット(EZH2)阻害物質、ブロモドメイン(「BRD」)阻害物質、およびそれらの誘導体から選択される、請求項32に記載の方法。
- 前記接触させる段階が、前記PERK阻害物質を前記対象に投与することにより実行される、請求項27〜36のいずれか一項に記載の方法。
- 前記接触させる段階の前に、前記対象内のDCCの存在を検出する段階
をさらに含む、請求項27〜37のいずれか一項に記載の方法。 - 前記DCCがNR2F1+である、請求項38に記載の方法。
- 前記DCCがホスホ-PERK活性である、請求項38または請求項39に記載の方法。
- 前記DCCが骨形成タンパク質受容体陽性(「BMPR+」)である、請求項38〜40のいずれか一項に記載の方法。
- 前記対象内のDCCを骨形成タンパク質7(BMP7)誘導体タンパク質と接触させる段階
をさらに含む、請求項41に記載の方法。 - 前記対象内のDCCをBMP7誘導体タンパク質と接触させる段階が、該BMP7誘導体タンパク質を該対象に投与することにより実行される、請求項42に記載の方法。
- 前記BMP7誘導体タンパク質がBMP7-F9である、請求項42または請求項43に記載の方法。
- 前記PERK阻害物質が、EIF2AK1もEIF2AK2もEIF2AK4も阻害しない、請求項27〜44のいずれか一項に記載の方法。
- 前記対象がヒトである、請求項27〜45のいずれか一項に記載の方法。
- 前記接触させる段階の前に、がん寛解状態の対象を選択する段階
をさらに含む、請求項27〜46のいずれか一項に記載の方法。
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