Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib.
Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib.
复制标题
DOI：
10.1126/sciadv.abl5838
复制
发表时间：
2022-01-28
期刊：
影响因子：
13.6
通讯作者：
Sokolsky-Papkov M
中科院分区：
文献类型：
--
作者：
Lim C;Dismuke T;Malawsky D;Ramsey JD;Hwang D;Godfrey VL;Kabanov AV;Gershon TR;Sokolsky-Papkov M
CDK4/6抑制剂对脑肿瘤的治疗潜力因复发而受到限制。为了应对复发，我们测试了CDK4/6抑制剂palbociclib的纳米制剂(POX-PALBO)，在基因工程小鼠中单独或与我们分析建议的特定药物联合使用，以发展SHH驱动的髓母细胞瘤。纳米粒胶囊降低了帕波西利的毒性，使非肠道给药成为可能，改善了中枢神经系统的药代动力学，并延长了小鼠的存活时间，但复发仍然存在。ScRNA-seq发现，在POX-PALBO治疗的小鼠髓母细胞瘤细胞中，谷氨酸转运体SLC1a2的表达上调，多种核糖体基因的表达下调，这表明mTORC1信号受到抑制，随后4EBP1磷酸化的降低证实了这一点。与单独使用任何一种药物相比，POX-PABO与mTORC1抑制剂Sapanisertib联合使用产生了相互增强的效果，并延长了小鼠的存活时间，与其他受试药物组合形成了显著对比。我们的数据表明，纳米颗粒制剂和耐药的scRNA-seq分析有可能改善脑肿瘤的治疗，并确定POX-PALBO+Sapanisertib是SHH髓母细胞瘤的有效联合治疗方法。通过纳米粒给药及与沙培林联合应用，可提高帕波西利治疗髓母细胞瘤的疗效。
The therapeutic potential of CDK4/6 inhibitors for brain tumors has been limited by recurrence. To address recurrence, we tested a nanoparticle formulation of CDK4/6 inhibitor palbociclib (POx-Palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma, alone or in combination with specific agents suggested by our analysis. Nanoparticle encapsulation reduced palbociclib toxicity, enabled parenteral administration, improved CNS pharmacokinetics, and extended mouse survival, but recurrence persisted. scRNA-seq identified up-regulation of glutamate transporter Slc1a2 and down-regulation of diverse ribosomal genes in proliferating medulloblastoma cells in POx-Palbo–treated mice, suggesting mTORC1 signaling suppression, subsequently confirmed by decreased 4EBP1 phosphorylation. Combining POx-Palbo with the mTORC1 inhibitor sapanisertib produced mutually enhancing effects and prolonged mouse survival compared to either agent alone, contrasting markedly with other tested drug combinations. Our data show the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment and identify POx-Palbo + Sapanisertib as effective combinatorial therapy for SHH medulloblastoma. The efficacy of palbociclib for medulloblastoma is improved by nanoparticle delivery and combination with sapanisertib.
登录
查看更多内容
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
16.1
作者：
Hwang D;Ramsey JD;Kabanov AV
通讯作者：
Kabanov AV
DOI：
10.1016/j.nano.2020.102345
发表时间：
2021-03
期刊：
Nanomedicine : nanotechnology, biology, and medicine
影响因子：
--
作者：
Hwang D;Dismuke T;Tikunov A;Rosen EP;Kagel JR;Ramsey JD;Lim C;Zamboni W;Kabanov AV;Gershon TR;Sokolsky-Papkov PhD M
通讯作者：
Sokolsky-Papkov PhD M
影响因子：
64.8
作者：
Northcott PA;Shih DJ;Peacock J;Garzia L;Morrissy AS;Zichner T;Stütz AM;Korshunov A;Reimand J;Schumacher SE;Beroukhim R;Ellison DW;Marshall CR;Lionel AC;Mack S;Dubuc A;Yao Y;Ramaswamy V;Luu B;Rolider A;Cavalli FM;Wang X;Remke M;Wu X;Chiu RY;Chu A;Chuah E;Corbett RD;Hoad GR;Jackman SD;Li Y;Lo A;Mungall KL;Nip KM;Qian JQ;Raymond AG;Thiessen NT;Varhol RJ;Birol I;Moore RA;Mungall AJ;Holt R;Kawauchi D;Roussel MF;Kool M;Jones DT;Witt H;Fernandez-L A;Kenney AM;Wechsler-Reya RJ;Dirks P;Aviv T;Grajkowska WA;Perek-Polnik M;Haberler CC;Delattre O;Reynaud SS;Doz FF;Pernet-Fattet SS;Cho BK;Kim SK;Wang KC;Scheurlen W;Eberhart CG;Fèvre-Montange M;Jouvet A;Pollack IF;Fan X;Muraszko KM;Gillespie GY;Di Rocco C;Massimi L;Michiels EM;Kloosterhof NK;French PJ;Kros JM;Olson JM;Ellenbogen RG;Zitterbart K;Kren L;Thompson RC;Cooper MK;Lach B;McLendon RE;Bigner DD;Fontebasso A;Albrecht S;Jabado N;Lindsey JC;Bailey S;Gupta N;Weiss WA;Bognár L;Klekner A;Van Meter TE;Kumabe T;Tominaga T;Elbabaa SK;Leonard JR;Rubin JB;Liau LM;Van Meir EG;Fouladi M;Nakamura H;Cinalli G;Garami M;Hauser P;Saad AG;Iolascon A;Jung S;Carlotti CG;Vibhakar R;Ra YS;Robinson S;Zollo M;Faria CC;Chan JA;Levy ML;Sorensen PH;Meyerson M;Pomeroy SL;Cho YJ;Bader GD;Tabori U;Hawkins CE;Bouffet E;Scherer SW;Rutka JT;Malkin D;Clifford SC;Jones SJ;Korbel JO;Pfister SM;Marra MA;Taylor MD
通讯作者：
Taylor MD
DOI：
10.2217/17435889.3.5.703
发表时间：
2008-10
期刊：
Nanomedicine (London, England)
影响因子：
--
作者：
Longmire M;Choyke PL;Kobayashi H
通讯作者：
Kobayashi H