CN114712515A - 一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 - Google Patents
一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 Download PDFInfo
- Publication number
- CN114712515A CN114712515A CN202210328805.3A CN202210328805A CN114712515A CN 114712515 A CN114712515 A CN 114712515A CN 202210328805 A CN202210328805 A CN 202210328805A CN 114712515 A CN114712515 A CN 114712515A
- Authority
- CN
- China
- Prior art keywords
- dll4
- inhibitor
- ovarian cancer
- parp
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010033128 Ovarian cancer Diseases 0.000 title claims abstract description 32
- 206010061535 Ovarian neoplasm Diseases 0.000 title claims abstract description 32
- 239000012661 PARP inhibitor Substances 0.000 title claims abstract description 26
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 239000003112 inhibitor Substances 0.000 title claims abstract description 16
- 101000872077 Homo sapiens Delta-like protein 4 Proteins 0.000 title claims abstract 7
- 102100033553 Delta-like protein 4 Human genes 0.000 title claims abstract 6
- 238000011282 treatment Methods 0.000 claims description 11
- 230000035945 sensitivity Effects 0.000 claims description 10
- 230000002195 synergetic effect Effects 0.000 claims description 3
- 230000008685 targeting Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 8
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 description 18
- 229940079593 drug Drugs 0.000 description 12
- 108091033409 CRISPR Proteins 0.000 description 8
- 238000010354 CRISPR gene editing Methods 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 108020004459 Small interfering RNA Proteins 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000003197 gene knockdown Methods 0.000 description 5
- 230000002452 interceptive effect Effects 0.000 description 5
- 108010068097 Rad51 Recombinase Proteins 0.000 description 4
- 102000002490 Rad51 Recombinase Human genes 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 101150038500 cas9 gene Proteins 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- -1 DLL4 Proteins 0.000 description 3
- 230000005971 DNA damage repair Effects 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- 102100024829 DNA polymerase delta catalytic subunit Human genes 0.000 description 2
- 102100038795 E3 ubiquitin-protein ligase TRIM4 Human genes 0.000 description 2
- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 description 2
- 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 description 2
- 101000664604 Homo sapiens E3 ubiquitin-protein ligase TRIM4 Proteins 0.000 description 2
- 101001001473 Homo sapiens Importin subunit alpha-4 Proteins 0.000 description 2
- 101001025967 Homo sapiens Lysine-specific demethylase 6A Proteins 0.000 description 2
- 101000652226 Homo sapiens Suppressor of cytokine signaling 6 Proteins 0.000 description 2
- 102100036187 Importin subunit alpha-4 Human genes 0.000 description 2
- 102100037462 Lysine-specific demethylase 6A Human genes 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 102100030529 Suppressor of cytokine signaling 7 Human genes 0.000 description 2
- 102000002258 X-ray Repair Cross Complementing Protein 1 Human genes 0.000 description 2
- 108010000443 X-ray Repair Cross Complementing Protein 1 Proteins 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- GUDJFFQZIISQJB-UHFFFAOYSA-N 4-cyano-5-(3,5-dichloropyridin-4-yl)sulfanyl-n-(4-methylsulfonylphenyl)thiophene-2-carboxamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1NC(=O)C(S1)=CC(C#N)=C1SC1=C(Cl)C=NC=C1Cl GUDJFFQZIISQJB-UHFFFAOYSA-N 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 101100227322 Caenorhabditis elegans fli-1 gene Proteins 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 102000009506 Cyclin-Dependent Kinase Inhibitor p19 Human genes 0.000 description 1
- 108010009361 Cyclin-Dependent Kinase Inhibitor p19 Proteins 0.000 description 1
- 102100022477 DNA repair protein complementing XP-C cells Human genes 0.000 description 1
- 102100039328 Endoplasmin Human genes 0.000 description 1
- 101000618535 Homo sapiens DNA repair protein complementing XP-C cells Proteins 0.000 description 1
- 101000812663 Homo sapiens Endoplasmin Proteins 0.000 description 1
- 101001014553 Homo sapiens MRG/MORF4L-binding protein Proteins 0.000 description 1
- 101001094700 Homo sapiens POU domain, class 5, transcription factor 1 Proteins 0.000 description 1
- 101001124867 Homo sapiens Peroxiredoxin-1 Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101000759994 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 47 Proteins 0.000 description 1
- 101000743488 Homo sapiens V-set and immunoglobulin domain-containing protein 4 Proteins 0.000 description 1
- 102100032521 MRG/MORF4L-binding protein Human genes 0.000 description 1
- 101100281205 Mus musculus Fli1 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100035423 POU domain, class 5, transcription factor 1 Human genes 0.000 description 1
- 102100029139 Peroxiredoxin-1 Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- 102100025029 Ubiquitin carboxyl-terminal hydrolase 47 Human genes 0.000 description 1
- 102100038296 V-set and immunoglobulin domain-containing protein 4 Human genes 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000012350 deep sequencing Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 210000004996 female reproductive system Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 1
- 229950011068 niraparib Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000011518 platinum-based chemotherapy Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000007482 whole exome sequencing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种DLL4抑制剂联合PARP抑制剂在制备治疗卵巢癌药物中的应用，有增效、逆转耐药作用，具有显著的效果。
Description
技术领域
本发明属于药物领域，特别涉及一种DLL4抑制剂联合PARP抑制剂在制备治疗卵巢癌药物中的应用。
背景技术
卵巢癌是病死率最高的女性生殖系统恶性肿瘤，70％的卵巢癌患者就诊时已是临床晚期。卵巢癌首选治疗模式为手术联合以铂类为基础的化疗。虽然，大多数患者经过初始治疗可获得临床缓解，但仍有70％的患者在3年内复发，部分患者会经历多次复发，且复发间歇期越来越短，5年生存率只有40％左右。
发明内容
本发明所要解决的技术问题是提供一种DLL4抑制剂联合PARP抑制剂在制备治疗卵巢癌药物中的应用。
本发明的一种DLL4抑制剂联合PARP抑制剂在制备治疗卵巢癌药物中的应用。
本发明的一种所述DLL4抑制剂联合PARP抑制剂在制备治疗BRCA野生型卵巢癌药物中的应用。
本发明的一种所述DLL4抑制剂联合PARP抑制剂在制备协同治疗BRCA野生型卵巢癌药物中的应用。
本发明的一种DLL4在制备治疗BRCA卵巢癌药物的增敏剂或逆转耐药剂中的应用。
所述DLL4抑制剂为DLL4为靶标的抑制剂。
DLL4基因增强PARP抑制剂的敏感性。
所述药物为的制剂剂型包括口服液、胶囊剂、油滴剂、粉剂、片剂或注射剂。
有益效果
本发明中表明敲低Delta样配体(DLL4)基因能显著增加卵巢癌PARP抑制剂的敏感性，DLL4抑制剂联合PARP抑制剂作为新的多靶点联合治疗药物，有增效、逆转耐药作用、两者联合应用有增效作用，具有显著的效果。
附图说明
图1为CRISPR/cas9初步筛选PARP抑制剂(尼拉帕利)耐药相关基因；A:SKOV3-GeCKO细胞系构建成功；B:CRISPR/cas9筛选模式图；C：DNA凝胶示PCR产物位置正确；
图2为CRISPR/cas9文库阴性筛选结果。A，RIGER分析图，排名靠前的基因，包括MRGBP、KPNA3、DLL4、USP47、POLD1、BRD2等；B，气泡图，差异大的基因已被标注出来；
图3为qPCR验证各个候选基因的siRNA敲除效率；
图4中A-F为CCK-8验证干扰候选基因后SKOV3细胞对PARP抑制剂尼拉帕利敏感性变化；
图5为DLL4在卵巢癌中表达升高。A，realtime PCR检测13例正常卵巢组织和27例卵巢癌组织中DLL4的mRNA水平；B，western blot检测5例正常卵巢组织和5例卵巢癌组织中DLL4的蛋白水平；C，qPCR检测7株卵巢癌细胞系中DLL4 mRNA表达水平；D，Western blot检测7株卵巢癌细胞系中DLL4蛋白表达水平。N代表正常的卵巢；T代表卵巢癌；
图6中A，在高表达DLL4的A2780及SKOV3细胞中，用siRNA干扰DLL4表达后，CCK8法测定细胞生长，检测细胞对尼拉帕利的敏感性，发现干扰DLL4后，IC50值降低；B，在SKOV3细胞中，干扰DLL4或PARP抑制剂处理后，细胞的凋亡增加，联合应用对细胞凋亡有叠加作用；C，在A2780细胞中，干扰DLL4或应用PARP抑制剂后，能抑制细胞克隆形成，联合应用对细胞克隆形成抑制作用更显著。*P<0.05。**P<0.01。D，DLL4在SKOV3尼拉帕利耐药株中表达升高；E，在SKOV3耐药株中干扰DLL4表达后，尼拉帕尼的IC50值明显降低；F，在SKOV3耐药株中干扰DLL4表达后，能促进细胞凋亡，再加尼拉帕尼处理后，对细胞凋亡有进一步促进作用；
图7为调降DLL4后卵巢癌细胞DNA损伤修复功能受损。A，SKOV3细胞尼拉帕尼处理后，敲低DLL4，细胞免疫荧光检测到γ-H2AX foci增加；B，SKOV3细胞中，干扰DLL4联合尼拉帕尼处理后，DNA损伤修复蛋白RAD51 foci形成显著减少。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
卵巢癌PARP抑制剂耐药相关基因筛选的细胞模型构建方法。
利用CRISPR/Cas9文库系统，从全基因组水平筛选BRCAWT卵巢癌细胞中影响PARP抑制剂敏感性的分子靶点。GeCKO v2文库包含123,411个sgRNA，靶向19,050个基因，平均每个基因6个位点。选取的SKOV3细胞已进行全外显子组测序，证实为BRCAWT且HRD阴性；在低感染复数(MOI＝0.3)下转染SKOV3细胞并进行嘌呤霉素选择，构建稳定CRISPR/cas9敲除细胞系SKOV3-GeCKO。用临床试验中证实对全人群有效的PARP抑制剂尼拉帕利(Niraparib)4μM处理48h后撤药，继续扩增细胞至14天，以进行阴性筛选。分别收取Day7、Day14的细胞全基因组DNA，深度测序筛选出与对照组相比减少的sgRNA，整个筛选流程如图1所示。
从CRISPR/Cas9基因敲除文库筛选中，鉴定了靶向1238个基因的sgRNA的子集，这些基因在尼拉帕利处理后的细胞中显著消耗(Z评分＞1.4),表明这些基因可能与PARP抑制剂敏感性相关(如图2所示)。选取排名靠前的17个基因：VSIG4、XPC、XRCC1、SOCS6、RET、TRIM4、RAD51、PRDX1、POU5F1、POLD1、KPNA3、KDM6A、HSP90B1、DLL4、CDKN2D、BRD2和FLI1，进行初步验证。首先验证siRNA的敲除效率，可以看到敲低候选基因后，其mRNA均显著下调(如图3所示)。利用siRNA敲低候选基因后，CCK-8检测细胞生长情况，可以看到发现敲低TRIM4、DLL4、KDM6A、XRCC1、RAD51后，SKOV3细胞对尼拉帕利的IC50值均显著降低，其中DLL4的作用最为显著；而敲低SOCS6后，细胞对尼拉帕利的IC50值增加了(如图4)。
qPCR和western blot分析DLL4在人卵巢癌组织中的表达情况，发现DLL4的mRNA和蛋白水平在卵巢癌组织中明显上调(如图5A和B)。还分析了7株卵巢癌细胞中DLL4的表达情况，可以看到DLL4在SKOV3和A2780两株细胞中表达最高(图5C和D)。
选取DLL4高表达的卵巢癌细胞株SKOV3和A2780，进行siRNA干扰试验，验证敲低DLL4是否影响卵巢癌细胞对PARP抑制剂，观察到敲低DLL4后细胞对尼拉帕尼的敏感性增加(图6A)。且敲低DLL4和PARP抑制剂联合应用后，对卵巢癌细胞的凋亡促进作用更显著，对细胞的克隆形成抑制作用更显著(图6B和6C)。
进一步建立尼拉帕尼耐药细胞株：选取卵巢癌细胞系SKOV3，采用尼拉帕利低浓度逐步加量诱导法历时9个月成功构建SKOV3尼拉帕利耐药株(SKOV3-NR)，耐药指数为22.5。发现DLL4在耐药株中表达明显升高(图6D)，而敲低SKOV3-NR中DLL4后，SKOV3-NR细胞对尼拉帕尼的敏感性明显增加。(图6E)。
在SKOV3细胞中，尼拉帕利处理后，进一步干扰DLL4表达，我们发现DNA损伤标志物γ-H2AX表达显著增强(图7A)，DNA损伤修复蛋白RAD51集落形成显著减少，提示下调DLL4可能通过减少DNA损伤修复增加了尼拉帕利的敏感性(图7B)。
Claims (6)
1.一种DLL4抑制剂联合PARP抑制剂在制备治疗卵巢癌药物中的应用。
2.一种权利要求1所述DLL4抑制剂联合PARP抑制剂在制备治疗BRCA野生型卵巢癌药物中的应用。
3.一种权利要求1所述DLL4抑制剂联合PARP抑制剂在制备协同治疗BRCA野生型卵巢癌药物中的应用。
4.根据权利要求1所述应用，其特征在于，所述DLL4抑制剂为DLL4为靶标的抑制剂。
5.根据权利要求1所述应用，其特征在于，DLL4基因增强PARP抑制剂的敏感性。
6.根据权利要求1所述应用，其特征在于，所述药物为的制剂剂型包括口服液、胶囊剂、油滴剂、粉剂、片剂或注射剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210328805.3A CN114712515A (zh) | 2022-03-30 | 2022-03-30 | 一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210328805.3A CN114712515A (zh) | 2022-03-30 | 2022-03-30 | 一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114712515A true CN114712515A (zh) | 2022-07-08 |
Family
ID=82239540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210328805.3A Pending CN114712515A (zh) | 2022-03-30 | 2022-03-30 | 一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114712515A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116716349A (zh) * | 2023-08-01 | 2023-09-08 | 江苏集萃药康生物科技股份有限公司 | 一种dll4人源化小鼠模型的构建方法及其应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581679A (zh) * | 2016-10-21 | 2017-04-26 | 同济大学 | 用于治疗卵巢癌的药物组合物及其制备方法 |
| US20200306236A1 (en) * | 2017-10-06 | 2020-10-01 | Tesaro, Inc. | Combination therapies and uses thereof |
| CN111979290A (zh) * | 2020-09-04 | 2020-11-24 | 大连医科大学附属第二医院 | Spp1基因在制备增强卵巢癌患者对parp抑制剂敏感性的药物中的应用 |
-
2022
- 2022-03-30 CN CN202210328805.3A patent/CN114712515A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581679A (zh) * | 2016-10-21 | 2017-04-26 | 同济大学 | 用于治疗卵巢癌的药物组合物及其制备方法 |
| US20200306236A1 (en) * | 2017-10-06 | 2020-10-01 | Tesaro, Inc. | Combination therapies and uses thereof |
| CN111979290A (zh) * | 2020-09-04 | 2020-11-24 | 大连医科大学附属第二医院 | Spp1基因在制备增强卵巢癌患者对parp抑制剂敏感性的药物中的应用 |
Non-Patent Citations (1)
| Title |
|---|
| 罗荣城等主编: "《肿瘤综合诊疗新进展》", vol. 2, 30 September 2006, 人民军医出版社, pages: 345 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116716349A (zh) * | 2023-08-01 | 2023-09-08 | 江苏集萃药康生物科技股份有限公司 | 一种dll4人源化小鼠模型的构建方法及其应用 |
| CN116716349B (zh) * | 2023-08-01 | 2023-10-31 | 江苏集萃药康生物科技股份有限公司 | 一种dll4人源化小鼠模型的构建方法及其应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Huang et al. | Genome‐Wide CRISPR‐Cas9 Screening Identifies NF‐κB/E2F6 Responsible for EGFRvIII‐Associated Temozolomide Resistance in Glioblastoma | |
| Stimson et al. | HDAC inhibitor-based therapies and haematological malignancy | |
| Li et al. | Identification of miR-29c and its target FBXO31 as a key regulatory mechanism in esophageal cancer chemoresistance: functional validation and clinical significance | |
| Duan et al. | IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and DNA repair associated molecules | |
| Hsu et al. | Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer | |
| Varkaris et al. | Ligand‐independent activation of MET through IGF‐1/IGF‐1R signaling | |
| US20150219624A1 (en) | Methods for identifying anti-cancer compounds | |
| Nagel et al. | Inhibition of the replication stress response is a synthetic vulnerability in SCLC that acts synergistically in combination with cisplatin | |
| Rominiyi et al. | DDRugging glioblastoma: Understanding and targeting the DNA damage response to improve future therapies | |
| WO2021028081A1 (en) | New treatments involving mirna-193a | |
| Mudianto et al. | Yap1 mediates trametinib resistance in head and neck squamous cell carcinomas | |
| EP2376081A2 (en) | Enzastaurin for the treatment of cancer | |
| CN114712515A (zh) | 一种dll4抑制剂联合parp抑制剂在制备治疗卵巢癌药物中的应用 | |
| Lee et al. | Genome‐scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib‐resistant lung cancer | |
| Criscione et al. | The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells | |
| CA3066350A1 (en) | Induction of synthetic lethality with epigenetic therapy | |
| CN115054605B (zh) | G9a抑制剂在制备治疗葡萄膜黑色素瘤的药物中的应用 | |
| CN114712507B (zh) | 一种trim4在制备治疗卵巢癌药物的增敏剂或逆转耐药剂中的应用 | |
| Yin et al. | Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy | |
| Lai et al. | Overcoming EGFR T790M-based tyrosine kinase inhibitor resistance with an allele-specific DNAzyme | |
| Martin et al. | Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma | |
| Amir et al. | Role of long noncoding RNA in regulating HIV infection—a comprehensive review | |
| US10941403B2 (en) | Microrna inhibitors as anti-cancer therapeutics | |
| US20240189450A1 (en) | Methods for treating cancers | |
| US20210322417A1 (en) | Gastric cancer treatments |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |