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.

项目摘要在患有晚期前列腺癌的患者中，具有标准护理的血管生成抑制剂的III期临床试验疗法表现出明显的抗肿瘤活性，但未能改善总体生存率。为什么有些男人受益从这些疗法中，而其他疗法尚不清楚。我们的初步数据表明封锁复制从三核酸（TCA）循环的代谢产物复制代谢物的变性信号通路为了快速生长，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性。值得注意的是，我们发现这些中继肿瘤的共同特征是血管生成增加。实际上，对患者衍生肿瘤标本的分析表明存在血管生成与厌氧信号通路之间的补偿性关联，表明当一个过程很低，另一个需要很高才能维持肿瘤的代谢需求，而强劲的倒数发生在马敏感的前列腺癌中的关联。该提案的目的是评估是否共同靶向癌细胞的厌食代谢和肿瘤血管生成可以协同处理骑马敏感的前列腺癌。我们还试图确定旋律信号的生物标志物是否可以预测反应进行抗血管生成疗法，因此指导患者选择。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，该状态会损害杂乱无章并急剧增强肿瘤对抑制中央碳代谢的敏感性。我们进一步假设食管信号传导可以预测对抗血管生成疗法的反应。我们将通过以下目的：AIM 1将评估血管生成作为对CAMKK2抑制和变性应激。我们将研究CAMKK2和VEGF抑制之间的协同作用。有或没有手术cast割的敏感前列腺癌，并表征对使用的影响批量和成像质谱法及其对肿瘤特征的影响通过MRI，组织病理学和免疫组织化学。 AIM 2将确定静脉抗应力敏感性前列腺的临床级诱导剂是否癌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，AIM 2将确定谷氨酰胺酶的抑制剂的作用，谷氨酰胺酶也可以阻止静脉粥样硬化。 AIM 3将评估是否对患者抗血管生成疗法的敏感性的变性信号传导预测。为此，我们将讯问两项完成的，富含组织的II期试验，测试了抗血管生成剂的术前效率和舒尼替尼在男性中，出现高风险，高风险和早期转移性前列腺癌。这项研究具有高度意义和创新性，因为它将：1）设定一种新形式的药物组合形式的理由代谢调节剂和抗血管生成，用于治疗骑马敏感的前列腺癌； 2）发展新的候选生物标志物指导患者选择治疗中临床活性血管生成抑制剂前列腺癌的模式； 3）促进针对CAMKK2的新药物发现工作。