Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism

重新审视抗血管生成疗法以靶向激素敏感的前列腺癌代谢

• 批准号: 10671250
• 负责人: Daniel Edward Frigo
• 金额: $ 56.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-12 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671250
• 关键词: Androgen Receptor; Androgens; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antineoplastic Agents; Bioenergetics; Biological Markers; Blood Vessels; Ca(2+)-Calmodulin Dependent Protein Kinase; Cancer Patient; Carbon; Castrate sensitive prostate cancer; Castration; Cells; Citric Acid Cycle; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dependence; Disease Progression; Drug Combinations; Genomics; Glucose; Glutaminase; Goals; Growth; Histopathology; Immunohistochemistry; Life; Link; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Metabolic; Metabolism; Metastatic Prostate Cancer; Modeling; Nutrient; Oncogenic; Outcome; Pathway interactions; Patient Selection; Patients; Phase II Clinical Trials; Phase III Clinical Trials; Phosphotransferases; Pre-Clinical Model; Process; Progression-Free Survivals; Prostate Cancer therapy; Randomized; Relapse; Research; Resistance; Selection Criteria; Signal Pathway; Signal Transduction; Specimen; Starvation; Stress; Testing; Therapeutic Effect; Tissues; Toxic effect; Tumor Angiogenesis; Tumor Promotion; Vegf inhibition; Visit; Xenograft procedure; advanced prostate cancer; angiogenesis; antitumor effect; bevacizumab; cancer cell; candidate marker; cytotoxic; deprivation; drug discovery; genetic signature; high risk; improved; in silico; inhibitor; innovation; lymph nodes; mass spectrometric imaging; men; novel strategies; novel therapeutic intervention; novel therapeutics; patient subsets; phase II trial; phase III trial; potential biomarker; predicting response; prostate cancer progression; protein biomarkers; rapid growth; rational design; resistance mechanism; response; standard of care; synergism; therapeutic target; time use; tumor; tumor metabolism

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.

项目摘要 在晚期前列腺癌患者中，血管生成抑制剂与标准治疗的III期临床试验 治疗显示出明显的抗肿瘤活性，但未能改善总存活率。为什么有些人受益 而其他疗法的效果尚不清楚。我们的初步数据显示， 回补信号通路，补充从三羧酸（TCA）循环中虹吸的代谢物 对于快速生长，通过抑制CAMKK 2或转氨酶，虽然最初有效，但总是让位于CAMKK 2 或转氨酶抑制剂抗性。值得注意的是，我们发现这些复发性肿瘤的一个共同特征是 增加血管生成。事实上，对患者来源的肿瘤标本的分析表明， 血管生成和回补信号通路之间的补偿性联系，表明当一个人 一个过程是低的，另一个需要高，以维持肿瘤的代谢需求，与最强的逆 相关性发生在对前列腺癌敏感的前列腺癌中。该提案的目的是评估是否共同- 靶向癌细胞回补代谢和肿瘤血管生成可以协同作用， 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 从而指导患者选择。我们的核心假设是， 血管生成迫使细胞进入半饥饿状态， 增强肿瘤对抑制中心碳代谢的敏感性。我们进一步假设， 回补信号可以预测对抗血管生成治疗的反应。我们将测试我们的假设与 以下目的：目的1将评估血管生成作为对CAMKK 2抑制的抗性机制， 回补应激我们将研究在激素依赖模型中CAMKK 2和VEGF抑制之间的协同作用。 敏感性前列腺癌，无论是否进行手术阉割，并描述对回补的影响 体积和成像质谱，以及它们对肿瘤特征的影响，通过MRI，组织病理学， 免疫组化目的2将确定一种临床级的回补应激诱导剂是否会使前列腺敏感 癌症对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 确定一个抑制剂的转氨酶，这也阻止回补的影响。目标3将评估是否 回补信号预测患者对抗血管生成治疗的敏感性。为此，我们将审问 两项已完成的、组织丰富的II期试验，测试了抗血管生成药物阿西替尼的术前疗效 舒尼替尼治疗高危、极高危和早期转移性前列腺癌。本研究 是非常重要的和创新的，因为它将：1）为一种新形式的药物组合提供理论基础， 代谢调节剂和抗血管生成剂，用于治疗前列腺癌敏感性; 2）开发 新的候选生物标志物，用于指导患者在治疗中选择临床活性血管生成抑制剂 用于前列腺癌的方案;和3）促进靶向CAMKK 2的新药发现工作。