Hashizume Rintaro, Zhang Ali, Mueller Sabine, Prados Michael D, Lulla Rishi R, Goldman Stewart, Saratsis Amanda M, Mazar Andrew P, Stegh Alexander H, Cheng Shi-Yuan, Horbinski Craig, Haas-Kogan Daphne A, Sarkaria Jann N, Waldman Todd, James C David
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (R.H., A.Z., C.D.J., A.M.S., C.H.); Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (R.H., C.D.J.); Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (A.H.S., S.-Y.C.), Northwestern Brain Tumor Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (R.H., R.R.L., S.G., A.M.S., A.P.M., A.H.S., S.-Y.C., C.H., C.D.J.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (R.H., R.R.L., S.G., A.P.M., A.H.S., S.-Y.C., C.H., C.D.J.); Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois (A.P.M., C.D.J.); Department of Pediatrics, Division of Hematology/Oncology, Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois (R.R.L., S.G.); Department of Neurological Surgery, University of California San Francisco, San Francisco, California (S.M., M.D.P.); Department of Pediatrics, University of California San Francisco, San Francisco, California (S.M.); Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts (D.A.H.-K.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.); Lombardi Cancer Center, Georgetown University, Washington, DC (T.W.).
Neuro Oncol. 2016 Nov;18(11):1519-1528. doi: 10.1093/neuonc/now106. Epub 2016 Jul 1.
Radiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM).
Evaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis.
For each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P < .05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis.
Our results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.
放射治疗是原发性恶性脑肿瘤术后最常用的治疗方法。因此，研究化疗药物与放疗联合治疗恶性脑肿瘤的疗效具有高度的临床相关性。在本研究中，我们研究了细胞周期蛋白依赖性激酶4/6抑制剂帕博西尼与放疗联合用于治疗人非典型畸胎样横纹肌样瘤（ATRT）和胶质母细胞瘤（GBM）的效果。
体外治疗抗肿瘤活性的评估基于细胞增殖试验、克隆形成试验、流式细胞术以及DNA双链断裂修复的免疫细胞化学结果。体内治疗抗肿瘤活性的解读基于生物发光成像、动物受试者生存分析以及肿瘤切片增殖和凋亡标志物染色。
对于所检测的每个视网膜母细胞瘤蛋白（RB）功能正常的肿瘤模型（2个ATRT和2个GBM），在动物受试者生存获益方面，一种或多种联合治疗方案显著（P < 0.05）优于两种单一疗法。在联合治疗方案中，帕博西尼与放疗同时使用以及放疗后使用帕博西尼的方案始终优于帕博西尼后放疗的顺序。体外研究表明，帕博西尼与放疗同时使用以及放疗后使用帕博西尼，均可抑制DNA双链断裂修复并促进肿瘤细胞凋亡增加。
我们的结果支持进一步研究帕博西尼作为保留RB表达的恶性脑肿瘤患者放疗辅助药物的可能性，并支持其可能的临床转化。
