Authors' Affiliations: School of Mathematical and Statistical Sciences; Department of Chemistry and Biochemistry, Arizona State University, Tempe; and
Authors' Affiliations: School of Mathematical and Statistical Sciences;
Cancer Res. 2014 Jul 15;74(14):3673-83. doi: 10.1158/0008-5472.CAN-13-3162. Epub 2014 May 22.
For progressive prostate cancer, intermittent androgen deprivation (IAD) is one of the most common and effective treatments. Although this treatment is usually initially effective at regressing tumors, most patients eventually develop castration-resistant prostate cancer (CRPC), for which there is no effective treatment and is generally fatal. Although several biologic mechanisms leading to CRPC development and their relative frequencies have been identified, it is difficult to determine which mechanisms of resistance are developing in a given patient. Personalized therapy that identifies and targets specific mechanisms of resistance developing in individual patients is likely one of the most promising methods of future cancer therapy. Prostate-specific antigen (PSA) is a biomarker for monitoring tumor progression. We incorporated a cell death rate (CDR) function into a previous dynamical PSA model that was highly accurate at fitting clinical PSA data for 7 patients. The mechanism of action of IAD is largely induction of apoptosis, and each mechanism of resistance varies in its CDR dynamics. Thus, we analyze the CDR levels and their time-dependent oscillations to identify mechanisms of resistance to IAD developing in individual patients.
对于进展期前列腺癌，间歇性雄激素剥夺（IAD）是最常见和最有效的治疗方法之一。尽管这种治疗通常最初能有效使肿瘤消退，但大多数患者最终会发展为去势抵抗性前列腺癌（CRPC），对此尚无有效治疗方法，且通常是致命的。尽管已经确定了导致 CRPC 发展的几种生物学机制及其相对频率，但很难确定在特定患者中哪种耐药机制正在发展。针对个体患者中正在发展的特定耐药机制的个性化治疗可能是未来癌症治疗最有前途的方法之一。前列腺特异性抗原（PSA）是监测肿瘤进展的生物标志物。我们将细胞死亡率（CDR）函数纳入之前的动态 PSA 模型中，该模型非常准确地拟合了 7 名患者的临床 PSA 数据。IAD 的作用机制主要是诱导细胞凋亡，而每种耐药机制的 CDR 动力学都不同。因此，我们分析 CDR 水平及其随时间的波动，以确定个体患者中对 IAD 产生耐药性的机制。
