Developing targeted therapy with prostate cancer specific nanomedicine

描述(申请人提供)：前列腺癌(PCa)已超过肺癌成为美国男性的头号癌症。由于前列腺癌是一种雄激素依赖型(AD)疾病，大多数患者在最初的临床表现就已经发展为转移灶，雄激素消融术已经成为一种标准的治疗方法。由于去势耐药PCa细胞对常规化疗耐药，其复发不可避免地会导致患者死亡。此外，由于年龄较大，PCA患者往往没有良好的身体条件来耐受化疗的不良副作用。因此，开发一种新的安全有效的治疗方法成为当务之急。尽管新开发的治疗方案显著提高了前列腺癌患者的存活率，但前列腺癌仍然不治之症。解释癌症治疗复发和无效的可能理论之一是癌症干细胞(CSC)模型，在该模型中，肿瘤细胞亚群负责癌症的发生和发展以及癌症的复发。这些干细胞与正常干细胞具有自我更新、永生化和分化为多种细胞类型的特性，包括不同的癌细胞谱系。此外，CSC可以从治疗后留下的少数细胞重新生长，开发更专门针对CSCs的治疗方法将是重要的。因此，靶向肿瘤干细胞成为癌症治疗的一个活跃研究领域，以实现最终的治愈。为了靶向PCA，我们正在开发一种新的可生物降解和生物兼容的纳米颗粒，它可以靶向具有成像能力的PCA。利用这种独特的传递系统，我们建议设计一种独特的基因毒素，它可以优先杀死表达干细胞特性的PCa细胞，然后在临床前动物模型中评估分子成像监测的PCa的治疗效果。我们希望能够实时监测癌细胞的药物输送和/或反应。这种实验性疗法可能成为治疗CRPC的更好方案，因为这种药物具有PCA特异性，预计毒性低于化疗药物。最重要的是，这项建议是为了探索一种不同于传统治疗策略的量身定制治疗的新途径；我们预计这项研究的结果将对CRPC治疗产生直接的临床影响。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men. The majority of patients have already developed metastatic lesions at initial clinical presentation and androgen ablation has become a standard therapy because PCa is an androgen-dependent (AD) disease. Inevitably, the recurrence of castration resistant PCa (CRPC) will result in mortality of patients since CRPC cells are resistant to conventional chemotherapy. Moreover, because of high age, PCa patients often do not have favorable physical conditions to tolerate undesirable side effects of chemotherapy. Thus, developing a new, safe and effective therapy becomes a high priority. Although PCa patient survival with newly developed therapeutic regimens has been significantly improved, PCa remains incurable. One of the possible theories to explain the recurrence and ineffectiveness of cancer treatment is the cancer stem cell (CSC) model in which a subset of tumor cells is responsible for cancer initiation and progression as well as cancer recurrence. These CSCs share with normal stem cells the properties of self-renewal, immortal and differentiation into a variety of cell types including heterogeneous lineages of cancer cells. Also CSC can re-grow from a few cells left behind after therapy, it will be important to develop therapies that are more specifically directed against CSCs. Thus, targeting cancer stem cell is now becomes an active research area of cancer therapy to achieve the ultimate cure. In order to target PCa specifically, we are developing a new biodegradable and biocompatible nanoparticle that can target PCa specifically with imaging capabilities. Using this unique delivery system, we propose to engineer a unique genotoxin that can preferentially kill PCa cells expressing stem cell properties then evaluate the therapeutic efficacy of PCa monitored by molecular imaging in pre-clinical animal models. We expect be able to monitor the drug delivery and/or response of cancer cells in a real-time manner. This experimental therapy could become a better regimen for treating CRPC because this agent has a PCa specificity, which is expected to be less toxic than chemotherapeutic agents. Most importantly, this proposal is to explore a new avenue of tailored therapy in contrast to conventional therapeutic strategy; we expect that the outcome of this study should have an immediate clinical impact on CRPC therapy.