Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism

项目总结 在晚期前列腺癌患者中，血管生成抑制剂的III期临床试验和标准护理 治疗显示出明显的抗肿瘤活性，但未能提高总体存活率。为什么有些男性受益 来自这些疗法的药物，而其他疗法则不清楚。我们的初步数据显示，封锁 无性信号通路，补充三羧酸(TCA)循环中虹吸的代谢物 对于快速生长，通过抑制CAMKK2或谷氨酰胺酶，虽然最初有效，但总是让位于CAMKK2 或谷氨酰胺酶抑制剂耐药。值得注意的是，我们发现这些复发肿瘤的一个共同特征是 血管生成增加。事实上，对患者来源的肿瘤样本的分析表明，存在一种 血管生成和停滞信号通路之间的代偿性关联，表明当一个人 过程是低的，另一个需要高的，以维持肿瘤的代谢需求，与最强的反向 发生在激素敏感型前列腺癌中。这项提案的目标是评估是否共同- 靶向肿瘤细胞逆行代谢和肿瘤血管生成可协同治疗激素敏感性 前列腺癌。我们还试图确定逆性信号的生物标志物是否可以预测反应。 抗血管生成治疗，因此，指导患者的选择。我们的中心假设是阻止 血管生成迫使细胞进入半饥饿状态，从而损害复苏并戏剧性地 增强肿瘤对中枢碳代谢抑制的敏感性。我们进一步假设生物标记物 逆行信号可以预测抗血管生成治疗的反应。我们将使用 以下目标：Aim 1将评估血管生成作为抵抗CAMKK2抑制和 性欲减退。我们将在激素抑制模型中研究CAMKK2和血管内皮生长因子抑制的协同作用。 有或没有手术去势的敏感前列腺癌和特征的影响。 散体和成像质谱学，以及它们对肿瘤特征的影响通过核磁共振、组织病理学和 免疫组织化学。目标2将确定一种临床级应激诱导剂是否会使前列腺增敏 肿瘤抗血管生成治疗的抗肿瘤作用。为了进一步评估我们的中心假设，目标2将 确定一种谷氨酰胺酶抑制剂的效果，它也可以阻止逆转。目标3将评估 信号失活预测患者对抗血管生成治疗的敏感性。为此，我们将审问 两个完整的、组织丰富的II期试验，测试了抗血管生成剂阿西替尼的术前疗效 和舒尼替尼对患有高危、非常高危和早期转移性前列腺癌的男性。这项研究 具有重要意义和创新性，因为它将：1)为一种新形式的药物组合建立理论基础 代谢调节剂和抗血管生成药物治疗激素敏感型前列腺癌；2)开发 指导患者选择治疗中临床活性血管生成抑制剂的新候选生物标志物 前列腺癌的方案；以及3)促进针对CAMKK2的新药发现工作。

PROJECT SUMMARY In patients with advanced prostate cancer, phase III clinical trials of angiogenesis inhibitors with standard of care therapies demonstrated clear antitumor activity but failed to improve overall survival. Why some men benefited from those therapies while others did not remains unclear. Our preliminary data indicate that blockade of anaplerotic signaling pathways, which replenish metabolites syphoned from the tricarboxylic acid (TCA) cycle for rapid growth, by inhibition of CAMKK2 or glutaminase, while initially effective, invariably gives way to CAMKK2 or glutaminase inhibitor resistance. Notably, we found that a common feature of these relapsed tumors is increased angiogenesis. Indeed, analysis of patient-derived tumor specimens indicate that there exists a compensatory association between angiogenesis and anaplerotic signaling pathways, suggesting that when one process is low, the other needs to be high to sustain the tumor’s metabolic demands, with the strongest inverse association occurring in hormone-sensitive prostate cancer. The goal of this proposal is to evaluate whether co- targeting cancer cell anaplerotic metabolism and tumor angiogenesis can synergize to treat hormone-sensitive prostate cancer. We also seek to determine whether biomarkers of anaplerotic signaling can predict response to antiangiogenic therapy and therefore, guide patient selection. It is our central hypothesis that blocking angiogenesis forces cells into a state of semi-starvation that compromises anaplerosis and dramatically enhances tumor sensitivity to inhibition of central carbon metabolism. We further hypothesize that biomarkers of anaplerotic signaling can predict response to antiangiogenic therapy. We will test our hypotheses with the following aims: Aim 1 will evaluate angiogenesis as a mechanism of resistance to CAMKK2 inhibition and anaplerotic stress. We will investigate synergy between CAMKK2 and VEGF inhibition in models of hormone- sensitive prostate cancer with or without surgical castration and characterize the effects on anaplerosis using bulk and imaging mass spectrometry, as well as their impact on tumor features via MRI, histopathology, and immunohistochemistry. Aim 2 will determine if a clinical-grade inducer of anaplerotic stress sensitizes prostate cancers to the antitumor effects of antiangiogenic therapy. To further evaluate our central hypothesis, Aim 2 will determine the effects of an inhibitor of glutaminase, which also blocks anaplerosis. Aim 3 will assess whether anaplerotic signaling predicts for sensitivity to antiangiogenic therapy in patients. To do this, we will interrogate two completed, tissue-rich phase II trials that tested the presurgical efficacy of the antiangiogenic agents axitinib and sunitinib in men presenting with high-risk, very high-risk, and early metastatic prostate cancer. This research is highly significant and innovative because it will: 1) set rationale for a new form of drug combinations integrating metabolic modulators and antiangiogenics for the treatment of hormone-sensitive prostate cancer; 2) develop new candidate biomarkers to guide patient selection for clinically active angiogenesis inhibitors in treatment schemas for prostate cancer; and 3) facilitate new drug discovery efforts targeting CAMKK2.