Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism

项目概要 在晚期前列腺癌患者中，采用标准护理的血管生成抑制剂的 III 期临床试验 治疗显示出明显的抗肿瘤活性，但未能提高总体生存率。为什么有些男性受益 这些疗法是否有效，而其他疗法是否有效，仍不清楚。我们的初步数据表明，封锁 回补信号通路，补充从三羧酸 (TCA) 循环中吸出的代谢物 通过抑制 CAMKK2 或谷氨酰胺酶来实现快速生长，虽然最初有效，但总是让位于 CAMKK2 或谷氨酰胺酶抑制剂耐药性。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，对患者来源的肿瘤标本的分析表明，存在 血管生成和回补信号通路之间的代偿性关联，表明当一个 一个过程低，另一个需要高才能维持肿瘤的代谢需求，其中最强的逆 关联发生在激素敏感的前列腺癌中。该提案的目标是评估是否共同 靶向癌细胞回补代谢和肿瘤血管生成可以协同治疗激素敏感 前列腺癌。我们还试图确定回补信号的生物标志物是否可以预测反应 抗血管生成治疗，从而指导患者选择。我们的中心假设是阻塞 血管生成迫使细胞进入半饥饿状态，从而损害回补并显着 增强肿瘤对中心碳代谢抑制的敏感性。我们进一步假设生物标志物 回补信号可以预测对抗血管生成治疗的反应。我们将用以下方法检验我们的假设 目标如下：目标 1 将评估血管生成作为 CAMKK2 抑制的抵抗机制； 回补应激。我们将在激素模型中研究 CAMKK2 和 VEGF 抑制之间的协同作用 有或没有手术去势的敏感前列腺癌，并使用以下方法描述其对回补的影响 体积和成像质谱分析，以及通过 MRI、组织病理学和成像技术对肿瘤特征的影响 免疫组织化学。目标 2 将确定临床级回补应激诱导剂是否会使前列腺敏感 癌症与抗血管生成疗法的抗肿瘤作用。为了进一步评估我们的中心假设，目标 2 将 确定谷氨酰胺酶抑制剂的作用，该抑制剂也可以阻止回补。目标 3 将评估是否 回补信号可预测患者对抗血管生成治疗的敏感性。为此，我们将询问 两项已完成的、富含组织的 II 期试验，测试了抗血管生成药物阿西替尼的术前疗效 舒尼替尼用于患有高风险、极高风险和早期转移性前列腺癌的男性。这项研究 非常重要且具有创新性，因为它将：1）为整合药物的新形式的药物组合奠定基础 用于治疗激素敏感性前列腺癌的代谢调节剂和抗血管生成剂； 2）开发 新的候选生物标志物可指导患者选择治疗中具有临床活性的血管生成抑制剂 前列腺癌的图式； 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.