Choline Metabolism in Prostate Cancers: Response to Dietary Soy Phytochemicals

描述(申请人提供)：许多前列腺癌患者希望将以饮食为基础的治疗纳入他们的治疗计划，大豆强化饮食和大豆膳食补充剂被广泛倡导为标准前列腺癌治疗的潜在有益补充。然而，由于前列腺癌的生物异质性，我们没有一个可靠的战略来设计和监测将使个体患者受益(或至少不会损害)的大豆饮食干预措施。最近，在前列腺癌的小鼠模型中，我们发现了基因表达的变化，这表明抑制肿瘤生长的大豆膳食补充剂也会改变肿瘤胆碱代谢。这一发现对我们对前列腺癌的基本了解以及将其转化为监测人类前列腺癌的大豆饮食疗法的非侵入性策略具有潜在的重要意义。该项目是开发一种方案的重要临床前阶段，该方案利用MRI/MRS，这是一种强大的非侵入性成像技术，已在许多医疗中心使用，以监测前列腺癌对大豆饮食干预的反应。前列腺癌MR波谱的代谢变化特征包括胆碱增加和柠檬酸共振峰降低，并且这些MRS变化的大小与肿瘤的分级(侵袭性)成正比。我们自己对人类前列腺组织的分析表明，胆碱激酶(胆碱激酶：含膜脂类胆碱从头合成途径中的第一个，也可能是第一个调节酶)的过度表达模式与已建立的前列腺癌标志物的过度表达模式密切相关。最近，在一个已建立的前列腺癌动物模型(LNCaP-SCID模型)中，我们发现可靠地抑制前列腺癌生长和转移的大豆植物化学(SPC)膳食补充剂也减少了肿瘤中胆碱激酶的表达。在这个R21项目中，我们将使用这个前列腺癌模型来测试这样一个假设，即可以通过肿瘤胆碱代谢的变化来监测前列腺癌生长对大豆膳食补充剂的反应的变化。在一系列实验中，我们将比较早期和晚期SPC饮食干预与标准对照饮食；我们将分析参与胆碱代谢的基因在肿瘤中表达的变化，以及MRI/MRS可见胆碱光谱的相关变化。考虑到有报道称，在一些雄激素非依赖性前列腺癌模型中，大豆类膳食补充剂可以增强肿瘤侵袭性，我们将把雄激素反应型和雄激素非依赖性LNCaP-SCID前列腺癌纳入我们的研究。值得注意的是，这一努力与BIDMC在临床MRI/MRS前列腺癌成像、基于饮食的补充癌症治疗和前列腺癌生物标记物开发方面的强大研究计划密切相关。因此，我们处于有利地位，可以利用这个R21项目的结果来设计扩展的后续研究工作，如果合适的话，包括人体临床试验。许多前列腺癌患者希望将基于饮食的治疗纳入他们的治疗计划，大豆强化饮食和大豆膳食补充剂被广泛倡导为标准前列腺癌治疗的潜在有益补充。然而，由于前列腺癌的生物异质性，我们没有一个可靠的战略来设计和监测将使个体患者受益(或至少不会损害)的大豆饮食干预措施。该项目代表着利用磁共振成像和磁共振波谱(MRI/MRS)的方案开发的重要临床前阶段；磁共振成像和磁共振波谱(MRI/MRS)是一种强大的非侵入性成像技术，已在许多医疗中心提供，用于监测前列腺癌对大豆饮食干预的反应。

DESCRIPTION (provided by applicant): Many prostate cancer patients would like to incorporate diet-based therapies into their treatment plan, and soy enriched diets and soy dietary supplements are widely advocated as potentially beneficial complements to standard prostate cancer management. However, because of the biological heterogeneity of prostate cancer, we do not have a reliable strategy for designing and monitoring soy based dietary interventions that will benefit (or at least not harm) individual patients. Recently, in a mouse model of prostate cancer, we have identified changes in gene expression that suggest that soy dietary supplements that inhibit tumor growth also alter tumor choline metabolism. This finding is potentially important for our basic understanding of this disease and for its potential translation into a non-invasive strategy for monitoring of soy based dietary therapies for human prostate cancer. This project represents an important pre-clinical stage in the development of a protocol to utilize MRI/MRS, a powerful non-invasive imaging technology already available in many medical centers, to monitor the response of prostate cancer to soy based dietary interventions. The metabolic changes characteristic of MR spectra of prostate cancer include increased choline and decreased citrate resonance peaks, and the magnitude of these MRS changes is proportional to the grade (aggressiveness) of the tumor. Our own analyses of human prostate tissues shows that patterns of over-expression of choline kinase (choline kinase: the first and probably regulatory enzyme in the pathway for de novo synthesis of choline containing membrane lipids) are strongly correlated with the patterns of over-expression of established prostate cancer markers. Recently, in an established animal model of prostate cancer (the LNCaP-SCID model), we have found that soy phytochemical (SPC) dietary supplements that reliably inhibit prostate cancer growth and metastasis also decrease the expression of choline kinase in the tumors. In this R21 project, we will use this model of prostate cancer to test the hypothesis that changes in prostate cancer growth in response to soy dietary supplements can be monitored by changes in tumor choline metabolism. In a series of experiments, we will compare early and late SPC dietary interventions with standard control diets; we will analyze changes in tumor expression of genes involved in choline metabolism and associated changes in MRI/MRS visible choline spectra. Mindful of reports that, in some models of androgen independent prostate cancer, soy based dietary supplements can enhance tumor aggressiveness, we will include both the androgen responsive and androgen independent forms of LNCaP-SCID prostate cancer in our studies. It is important to note that this effort is closely interfaced with strong BIDMC research programs in clinical MRI/MRS prostate cancer imaging, in diet based complementary cancer therapies and in prostate cancer biomarker development. We are thus well positioned to utilize the findings of this R21 project in the design of an expanded follow-on research effort, including, if appropriate, human clinical trials. Many prostate cancer patients would like to incorporate diet-based therapies into their treatment plan, and soy enriched diets and soy dietary supplements are widely advocated as potentially beneficial compliments to standard prostate cancer management. However, because of the biological heterogeneity of prostate cancer, we do not have a reliable strategy for designing and monitoring soy based dietary interventions that will benefit (or at least not harm) individual patients. This project represents an important pre-clinical stage in the development of a protocol to utilize Magnetic Resonance Imaging and MR spectroscopy (MRI/MRS); a powerful non-invasive imaging technology already available in many medical centers, to monitor the response of prostate cancer to soy based dietary interventions.