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

基本信息

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
项目类别：
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

项目摘要

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 期临床试验治疗方法明确显示出抗肿瘤活性，但未能提高总体生存率。我们的初步数据表明，这些疗法的封锁。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。事实上，对患者来源的肿瘤样本的分析表明存在一种增加的血管生成。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，其中最强的逆该提案的目的是评估激素诱导的前列腺癌是否存在关联。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型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。我们的中心假设是阻断。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。回补信号可以预测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 抑制的抵抗机制我们将研究激素模型中 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对回补的影响体积和成像质谱分析，以及它们通过 MRI、组织病理学和成像技术对肿瘤特征的影响目标 2 将确定临床级回补应激诱导剂是否使前列腺敏感。为了进一步评估我们的中心假设，目标 2 将研究癌症与抗血管生成疗法的抗肿瘤作用。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，我们将进行询问。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和舒尼替尼治疗患有高风险、极高风险和早期转移性前列腺癌的男性。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 2) 开发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药物；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模式；3) 促进针对 CAMKK2 的新药发现工作。