Delivering Glioblastoma a Kick-DGKα Inhibition as a Promising Therapeutic Strategy for GBM.
Delivering Glioblastoma a Kick-DGKα Inhibition as a Promising Therapeutic Strategy for GBM.
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DOI：
10.3390/cancers14051269
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发表时间：
2022-03-01
期刊：
影响因子：
5.2
通讯作者：
Purow B
中科院分区：
文献类型：
--
作者：
Purow B
胶质母细胞瘤是最常见和最具侵袭性的脑癌，迫切需要针对这种无法治愈的癌症的新治疗策略。抑制二酰基甘油激酶α提供了针对胶质母细胞瘤细胞的新的直接机制，但也提供了同时增强针对胶质母细胞瘤的免疫细胞活性的潜力。本文综述了二酰基甘油激酶α抑制剂对胶质母细胞瘤的潜力，以及对其他癌症的潜在影响。二酰基甘油激酶α（DGKα）抑制可能与胶质母细胞瘤（GBM）的治疗特别相关，GBM是一种相对常见的脑恶性肿瘤，目前的治疗方法无法治愈。先前的报道表明，DGKα抑制对GBM细胞具有多种直接活性，包括抑制致癌途径mTOR和HIF-1α。它还抑制与正常治疗耐药间充质表型相关的途径，产生对间充质GBM的优先活性;这表明可能将DGKα抑制与放射和间充质表型促进耐药性的其他疗法结合使用。DGKα抑制阻断或逆转T细胞无反应性的潜力也表明DGKα抑制促进针对GBM的免疫治疗的潜力，GBM通常被认为是免疫学上的“冷”肿瘤。最近的一份报告表明，DGKα缺乏增加了巨噬细胞的反应性，表明DGKα抑制也可能具有增强巨噬细胞和小胶质细胞对GBM的活性的潜力-鉴于这些细胞在GBM中的严重浸润，这可能是一种特别有前途的方法。因此，DGKα抑制可能提供对GBM的有希望的多管齐下的攻击，具有多种直接抗GBM活性，并且还具有增强针对GBM的适应性和先天性免疫应答的能力。然而，DGKα抑制对GBM的直接和间接获益可能需要与其他疗法联合使用才能获得有意义的疗效。此外，GBM为DGKα抑制剂的应用带来了其他挑战，包括血脑屏障（BBB）的可及性降低。理想的GBM DGKα抑制剂将结合联合收割机效力、特异性和BBB穿透性。目前还没有已知的抑制剂满足所有这些标准，但DGKα抑制这种致命脑癌的强大潜力应该有助于推动药物的开发和测试，将这种有前途的策略应用于GBM患者的临床。
Glioblastoma is the most common and aggressive brain cancer, and there is a desperate need for new therapeutic strategies for this incurable cancer. Inhibition of Diacylglycerol kinase α provides novel direct mechanisms against glioblastoma cells, but also offers the potential to simultaneously boost immune cell activities against glioblastoma. This review provides an updated summary of the promising potential of Diacylglycerol kinase α inhibition against glioblastoma, with potential implications for other cancers as well. Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways mTOR and HIF-1α. It also inhibits pathways associated with the normally treatment-resistant mesenchymal phenotype, yielding preferential activity against mesenchymal GBM; this suggests possible utility in combining DGKα inhibition with radiation and other therapies for which the mesenchymal phenotype promotes resistance. The potential for DGKα inhibition to block or reverse T cell anergy also suggests the potential of DGKα inhibition to boost immunotherapy against GBM, which is generally considered an immunologically “cold” tumor. A recent report indicates that DGKα deficiency increases responsiveness of macrophages, indicating that DGKα inhibition could also have the potential to boost macrophage and microglia activity against GBM—which could be a particularly promising approach given the heavy infiltration of these cells in GBM. DGKα inhibition may therefore offer a promising multi-pronged attack on GBM, with multiple direct anti-GBM activities and also the ability to boost both adaptive and innate immune responses against GBM. However, both the direct and indirect benefits of DGKα inhibition for GBM will likely require combinations with other therapies to achieve meaningful efficacy. Furthermore, GBM offers other challenges for the application of DGKα inhibitors, including decreased accessibility from the blood-brain barrier (BBB). The ideal DGKα inhibitor for GBM will combine potency, specificity, and BBB penetrability. No existing inhibitor is known to meet all these criteria, but the strong potential of DGKα inhibition against this lethal brain cancer should help drive development and testing of agents to bring this promising strategy to the clinic for patients with GBM.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
8
作者：
Baldanzi, G.;Cutrupi, S.;Graziani, A.
通讯作者：
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影响因子：
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作者：
Han J;Chu J;Keung Chan W;Zhang J;Wang Y;Cohen JB;Victor A;Meisen WH;Kim SH;Grandi P;Wang QE;He X;Nakano I;Chiocca EA;Glorioso Iii JC;Kaur B;Caligiuri MA;Yu J
通讯作者：
Yu J
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth
影响因子：
6.2
作者：
Hess, KR;Broglio, KR;Bondy, ML
通讯作者：
Bondy, ML