Developing targeted therapy with prostate cancer specific nanomedicine

描述（由申请人提供）：前列腺癌（PCa）已超过肺癌，成为美国男性的头号癌症。大多数患者在最初的临床表现时已经出现转移性病变，并且雄激素消融已成为标准治疗方法，因为 PCa 是一种雄激素依赖性 (AD) 疾病。由于去势抵抗性PCa（CRPC）细胞对常规化疗具有抵抗力，其复发将不可避免地导致患者死亡。此外，由于PCa患者年龄较大，身体状况往往较差，无法耐受化疗带来的不良副作用。因此，开发一种新的、安全且有效的疗法成为当务之急。 尽管新开发的治疗方案使 PCa 患者的生存率得到显着改善，但 PCa 仍然无法治愈。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，其中肿瘤细胞的子集负责癌症的发生和进展以及癌症复发。这些CSC与正常干细胞一样具有自我更新、永生和分化成多种细胞类型（包括异质癌细胞谱系）的特性。此外，CSC 可以从治疗后留下的一些细胞中重新生长，因此开发更专门针对 CSC 的疗法非常重要。因此，靶向癌症干细胞现已成为癌症治疗的一个活跃研究领域，以实现最终治愈。为了专门针对 PCa，我们正在开发一种新的可生物降解且生物相容性纳米颗粒，它可以专门针对 PCa 并具有成像功能。利用这种独特的递送系统，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，然后评估临床前动物模型中通过分子成像监测的 PCa 的治疗效果。我们期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，因为该药物具有 PCa 特异性，预计其毒性低于化疗药物。最重要的是，该提案旨在探索一种与传统治疗策略不同的定制治疗新途径；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.