Efficacy of Weekly Docetaxel and Bevacizumab in Mesenchymal Chondrosarcoma: A New Theranostic Method Combining Xenografted Biopsies with a Mathematical Model

被引:52
作者
Gorelik, Boris [2 ]
Ziv, Irit [2 ]
Shohat, Revital [2 ]
Wick, Michael [3 ]
Hankins, W. David [4 ,5 ]
Sidransky, David [5 ]
Agur, Zvia [1 ,2 ]
机构
[1] Inst Med Biomath, IL-60991 Bene Ataroth, Israel
[2] Optimata Ltd, Ramat Gan, Israel
[3] CTRC Inst Drug Dev, San Antonio, TX USA
[4] New Hope Pharmaceut Inc, Bethesda, MD USA
[5] Johns Hopkins Univ, Sch Med, Baltimore, MD USA
关键词
D O I
10.1158/0008-5472.CAN-08-1723
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The paucity of clinical treatment data on rare tumors, such as mesenchymal chondrosarcoma (MCS), emphasizes the need in theranostic tools for these diseases. We put forward and validated a new theranostic method, combining tumor xenografts and mathematical models, and used it to suggest an improved treatment schedule for a particular MCS patient. Growth curves and gene expression analysis of xenografts, derived from a patient's lung metastasis, served for creating a mathematical model of MCS progression and adapting it to the xenograft setting. The pharmacokinetics and pharmacodynamics of six drugs were modeled, with model variables being adjusted by patient-specific chemosensitivity tests. The xenografted animals were treated by various monotherapy and combination schedules, and the MCS xenograft model was computer simulated under the same treatment scenario. The mathematical model for xenograft growth was then up-scaled to retrieve the MCS patient's tumor progression under different treatment schedules. An average accuracy of 87.1% was obtained when comparing model predictions with the observed tumor growth inhibition in the xenografted animals. Simulation results suggested that a regimen containing bevacizumab applied i.v. in combination with once-weekly docetaxel would be more efficacious in the MCS patient than all other simulated schedules. Weekly docetaxel in the patient resulted in stable metastatic disease and relief of pancytopenia due to tumor infiltration. We suggest that the advantage of weekly docetaxel on the triweekly regimen is directly related to the angiogenesis rate of the tumor. Further validation of this conclusion, and the theranostic method we provide, may facilitate personalization of solid cancer pharmacotherapy. [Cancer Res 2008;68(21):9033-40]
引用
收藏
页码:9033 / 9040
页数:8
相关论文
共 50 条
[1]  
Agur Z, 2004, DISCRETE CONT DYN-B, V4, P29
[2]   REDUCTION OF CYTO-TOXICITY TO NORMAL-TISSUES BY NEW REGIMENS OF CELL-CYCLE PHASE-SPECIFIC DRUGS [J].
AGUR, Z ;
ARNON, R ;
SCHECHTER, B .
MATHEMATICAL BIOSCIENCES, 1988, 92 (01) :1-15
[3]   EFFECT OF THE DOSING INTERVAL ON MYELOTOXICITY AND SURVIVAL IN MICE TREATED BY CYTARABINE [J].
AGUR, Z ;
ARNON, R ;
SCHECHTER, B .
EUROPEAN JOURNAL OF CANCER, 1992, 28A (6-7) :1085-1090
[4]  
Agur Z., 2008, PRECLINICAL DEV HDB, P1229
[5]  
AGUR Z, 2006, AACR C MOL DIAGN CAN
[6]  
Agur Z., 1998, COMPUT MATH METHOD M, V1, P237
[7]   In vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer: General concepts and future perspectives [J].
Alexopoulos, A ;
Karamouzis, MV ;
Rigatos, G .
SEMINARS IN ONCOLOGY, 2004, 31 (02) :25-30
[8]   Vessel maturation effects on tumour growth: validation of a computer model in implanted human ovarian carcinoma spheroids [J].
Arakelyan, L ;
Merbl, Y ;
Agur, Z .
EUROPEAN JOURNAL OF CANCER, 2005, 41 (01) :159-167
[9]   A computer algorithm describing the process of vessel formation and maturation, and its use for predicting the effects of anti-angiogenic and anti-maturation therapy on vascular tumor growth [J].
Arakelyan L. ;
Vainstein V. ;
Agur Z. .
Angiogenesis, 2002, 5 (3) :203-214
[10]  
Arakelyan L, 2003, MATH COMP BIOL SER, P185