Choline Metabolism in Prostate Cancers: Response to Dietary Soy Phytochemicals

描述（由申请人提供）：许多前列腺癌患者希望将饮食疗法纳入他们的治疗计划，大豆富含饮食和大豆膳食补充剂被广泛提倡作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学异质性，我们没有一个可靠的策略来设计和监测基于大豆的饮食干预措施，这将有利于（或至少不会伤害）个别患者。最近，在前列腺癌小鼠模型中，我们发现了基因表达的变化，表明大豆膳食补充剂抑制肿瘤生长也会改变肿瘤胆碱代谢。这一发现对于我们对这种疾病的基本了解以及它可能转化为一种非侵入性策略来监测基于大豆的人类前列腺癌饮食疗法具有潜在的重要意义。该项目代表了利用MRI/MRS（一种强大的非侵入性成像技术，已在许多医疗中心使用）来监测前列腺癌对大豆饮食干预的反应的方案开发的重要临床前阶段。前列腺癌MR谱的代谢变化特征包括胆碱升高和柠檬酸盐共振峰降低，这些MRS变化的幅度与肿瘤的分级（侵袭性）成正比。我们自己对人类前列腺组织的分析表明，胆碱激酶的过度表达模式（胆碱激酶：在含膜脂的胆碱从头合成途径中的第一个和可能的调节酶）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，在建立的前列腺癌动物模型（LNCaP-SCID模型）中，我们发现大豆植物化学（SPC）膳食补充剂在可靠地抑制前列腺癌生长和转移的同时，也降低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检验一个假设，即大豆膳食补充剂对前列腺癌生长的影响可以通过肿瘤胆碱代谢的变化来监测。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的表达变化以及MRI/MRS可见胆碱谱的相关变化。考虑到有报道称，在一些雄激素非依赖性前列腺癌模型中，大豆膳食补充剂可以增强肿瘤的侵袭性，我们将在我们的研究中包括LNCaP-SCID前列腺癌的雄激素反应型和雄激素非依赖性形式。值得注意的是，这项工作与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志物开发方面的强大研究项目密切相关。因此，我们可以很好地利用这个R21项目的发现来设计一个扩大的后续研究工作，包括，如果合适的话，人体临床试验。许多前列腺癌患者希望将饮食疗法纳入他们的治疗计划，大豆营养饮食和大豆膳食补充剂被广泛提倡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学异质性，我们没有一个可靠的策略来设计和监测基于大豆的饮食干预措施，这将有利于（或至少不会伤害）个别患者。该项目代表了利用磁共振成像和磁共振波谱（MRI/MRS）开发方案的重要临床前阶段；一种强大的非侵入性成像技术已经在许多医疗中心可用，以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.