Effective combination therapy for MTAP-deficient bladder carcinoma by targeting metabolic vulnerability and modulating tumor immune microenvironment

通过针对代谢脆弱性和调节肿瘤免疫微环境，有效治疗 MTAP 缺陷型膀胱癌

• 批准号: 10665614
• 负责人: Jianjun Gao
• 金额: $ 52.51万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665614
• 关键词: 9p21; Address; Adenine; Adenosine; Biological Markers; Bladder Neoplasm; CDKN2A gene; Cancer Model; Cancer cell line; Cell physiology; Cells; Characteristics; Chromosomes; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Enzymes; Folic Acid Antagonists; Fostering; Freezing; Genes; Genomics; Genotype; Goals; Human; Immunologics; Immunotherapy; Impairment; Institutional Review Boards; Interferons; Knock-out; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metabolic; Molecular; Mus; Pathway interactions; Patients; Pemetrexed; Phase II Clinical Trials; Phosphorylases; Pyrimidine; Reporting; Research; Resistance; Sampling; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor Tissue; Tumor-infiltrating immune cells; biological heterogeneity; bladder Carcinoma; bladder transitional cell carcinoma; cancer cell; cell killing; checkpoint therapy; chromosome loss; cytotoxic; cytotoxicity; effective therapy; genetic signature; immune cell infiltrate; improved; in vivo; inhibitor; knock-down; knockout gene; neoplastic cell; novel; patient subsets; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; receptor; resistance mechanism; response; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT The long-term goals of this project are to define the mechanisms of resistance to immunotherapy and to develop effective therapies for patients with metastatic bladder cancer (BC). The overall objective of this proposal is to establish successful combination therapies for patients with a specific genomic subset of metastatic BC harboring homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene from the chromosome 9p21 region. Although novel immune checkpoint therapy (ICT), including anti-PD1/PD-L1, provides substantial benefits to patients with metastatic BC, response rates are usually modest at 15% to 25%. This is partly because this biologically heterogeneous cancer is still treated clinically as a uniform disease. Therefore, identification of specific genomic subtypes of BC that confer insensitivity to ICT may provide novel opportunities to improve clinical responses. We have confirmed that ~1/4 of BC contain homozygous deletion of MTAP (MTAPdef) from the 9p21region. The MTAP gene encodes for an essential enzyme to catalyze methylthioadenosine (MTA) in the salvage pathway for adenine synthesis. Tumor MTAPdef leads to both immunologic and metabolic consequences. Immunologically, tumor MTAPdef results in accumulation of its substrate MTA, which acts through the adenosine 2B receptor (A2BR) to inhibit IFN signaling and T cell function. Therefore, MTAPdef BC may foster a “cold” tumor immune microenvironment (TIME) unfavorable to ICT. Metabolically, tumor MTAPdef results in a lack of salvage pathway adenine synthesis; thus, MTAPdef BC should be very sensitive to the cytotoxic effects of anti-folate agents (e.g., pemetrexed), which effectively inhibit de novo adenine synthesis. This concept is confirmed by pre-clinical and clinical data to be presented. Importantly, our data also indicate that pemetrexed increases tumor immune cell infiltration and PD-L1 expression and thus may sensitize BC to ICT. Based on these data, we hypothesize that, by targeting the metabolic vulnerability of MTAPdef BC and directly modulating its tumor immune microenvironment, effective combination therapies can be established for MTAPdef BC. To test this hypothesis, we proposed two Specific Aims: (1) Define the immunological consequences of MTAPdef in BC; (2) Identify successful combination therapies specifically targeting MTAPdef BC. Patient-derived BC tissues, gene knockout and “rescue” mouse BC models, and samples from an IRB-approved clinical trial will be used to address these goals. At completion, we expect to establish the contribution of MTAPdef and/or loss of adjacent genes such as CDKN2A in the 9p21 region to the BC TIME. In addition, we will determine the extent of TIME modulation by pemetrexed +/- avelumab (anti-PD-L1) in relation to their therapeutic efficacy in patients with metastatic BC. Furthermore, we will define the preclinical therapeutic benefits of triple combination treatment with pemetrexed, anti-PD-L1, and A2RB inhibitor on mouse MTAPdef BC. These findings are important for the establishment of novel, biomarker-guided, highly effective combination therapies that can be tested in clinical trials. These data could be extrapolated to 14% of all cancers containing MTAPdef in the 9p21 region.

项目摘要/摘要 该项目的长期目标是定义抵抗免疫疗法的机制并发展 转移性膀胱癌（BC）患者的有效疗法。该提议的总体目的是 为具有特定基因组子集BC的特定基因组子集的患者建立成功的联合疗法 来自染色体的甲基丁基腺苷磷酸化酶（MTAP）基因的纯合缺失 9p21区域。尽管新型免疫检查点疗法（ICT）（包括抗PD1/PD-L1）提供了大量 对BC转移性的患者的好处，反应率通常为15％至25％。这部分是因为 这种在生物学上异质性癌症在临床上仍被视为一种均匀的疾病。因此，识别 BC的特定基因组亚型，对ICT不敏感的会议可能会提供新的机会来改善 临床反应。我们已经确认，BC的〜1/4包含MTAP（MTAPDEF）的纯合缺失（MTAPDEF） 9P21Region。 MTAP基因编码为催化甲基噻吩并腺苷（MTA）的必需酶 腺嘌呤合成的打捞途径。肿瘤MTAPDEF导致免疫学和代谢 结果。在免疫学上，肿瘤MTAPDEF导致其底物MTA的积累，从而通过 腺苷2B受体（A2BR）抑制IFN信号传导和T细胞功能。因此，MTAPDEF BC可能会培养 “冷”肿瘤免疫环境（时间）不利于ICT。代谢，肿瘤MTAPDEF导致A 缺乏打捞途径腺嘌呤合成；因此，MTAPDEF BC应该对 抗叶酸剂（例如，Pemetrexed），可有效抑制从头腺嘌呤的合成。这个概念是 通过临床前和临床数据确认。重要的是，我们的数据还表明pemeterexed 增加肿瘤免疫球浸润和PD-L1表达，从而可能将BC感知到ICT。基于 这些数据，我们假设通过针对MTAPDEF BC的代谢脆弱性并直接调节 可以为MTAPDEF BC建立其肿瘤免疫环境，有效的组合疗法。测试 这个假设，我们提出了两个具体的目的：（1）定义MTAPDEF在BC中的免疫学后果； （2）确定专门针对MTAPDEF BC的成功组合疗法。患者衍生的BC组织，基因 敲除和“救援”鼠标BC模型以及来自IRB批准的临床试验的样本将用于 解决这些目标。完成后，我们希望建立MTAPDEF和/或相邻损失的贡献 9p21区域中CDKN2A等基因到BC时间。此外，我们将确定时间的程度 Pemetrexed +/- avelumab（抗PD-L1）的调节与患者的治疗效率有关 BC转移性此外，我们将定义三重组合治疗的临床前治疗益处 在小鼠MTAPDEF BC上使用Pemetrexed，抗PD-L1和A2RB抑制剂。这些发现对 建立可以在临床中测试的新型生物标志物引导，高效的组合疗法 试验。这些数据可以推断到9P21区域中包含MTAPDEF的所有癌症的14％。