Signal Transduction Events and the Regulation of Cell Growth

信号转导事件和细胞生长的调节

• 批准号: 10487280
• 负责人: JANE B TREPEL
• 金额: $ 119.99万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487280
• 关键词: Academia; American College of Radiology Imaging Network; Antibodies; Apoptotic; Area; Award; Biological; Biological Assay; Biological Markers; Biotechnology; Blood; CD8-Positive T-Lymphocytes; CHEK1 gene; Cancer Patient; Capillary Leak Syndrome; Cells; Characteristics; Childhood; Clinic; Clinical; Clinical Drug Development; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Network; Collaborations; Combined Modality Therapy; Data; Drug Design; Drug Targeting; Eastern Cooperative Oncology Group; Endothelial Cells; Event; Exemestane; Extramural Activities; Flow Cytometry; Formalin; Freezing; Future; Gene Expression; Gene Expression Profiling; Glioblastoma; Glioma; Goals; Histone Deacetylase Inhibitor; Immune; Immune checkpoint inhibitor; Immunity; Immunophenotyping; International; Japan; Laboratories; Legal patent; MGMT gene; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Manuscripts; Metabolic; Metabolism; Molecular; Molecular Chaperones; Molecular Target; Mutate; Myeloid-derived suppressor cells; NF1 gene; Natural Immunity; Nature; Neoplasm Circulating Cells; Neoplasms; Neurofibrosarcoma; Nivolumab; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Oncologist; Paclitaxel; Pancreatic Adenocarcinoma; Paraffin Embedding; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plexiform Neurofibroma; Population; Prednisone; Preparation; Process; Publications; Publishing; Research; S phase; Sampling; Serous; Severities; Signal Pathway; Signal Transduction; T-Lymphocyte; Technology; Tissue Embedding; Transitional Cell Carcinoma; Translational Research; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States National Institutes of Health; Woman; Work; adaptive immunity; advanced breast cancer; anti-cancer; anticancer research; base; cancer clinical trial; castration resistant prostate cancer; cell growth regulation; clinical biomarkers; clinical development; digital; docetaxel; drug development; drug discovery; drug mechanism; early phase clinical trial; effector T cell; hormone receptor-positive; immune checkpoint blockade; in vivo; inhibitor/antagonist; insight; invention; ipilimumab; lung small cell carcinoma; malignant breast neoplasm; molecular subtypes; monocyte; neuro-oncology; neurofibroma; new technology; new therapeutic target; novel; novel therapeutics; pembrolizumab; peripheral blood; phase II trial; phase III trial; programs; response; targeted treatment; therapeutic development; translational scientist; treatment response; trend; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

Our major activities in FY2021 were to work with clinical investigators to develop new pharmacodynamic (PD) assays tailored to their clinical trials and to implement these PD assays in the clinical trials we have open in FY2021. Our specific objectives are (1) to determine if a therapy hit its target in the patient; (2) interrogate the impact of the therapy on the host, both at the systemic level, and in the tumor and tumor microenvironment; (3) work with clinical investigators to introduce new technology into their programs, including transfer of our technology intramurally, extramurally and internationally; and (4) work in collaboration with clinical and basic translational investigators to identify new drug targets and new drug mechanisms. We worked on more than 60 clinical trials in FY2021. We have focused on three main areas of biomarker analysis; (1) immune PD, (2) rare cell non-immune PD (i.e. circulating tumor cells and circulating endothelial cells), and (3) digital analyses of gene expression that can be performed on fresh, frozen, or formalin-fixed, paraffin-embedded tissue, to greatly facilitate the assessment of gene expression in tumor samples. In addition, we examined systemic effects of immune- and non-immune targeted therapy on immune gene expression in peripheral blood. For the majority of the clinical trials on which we collaborate we are including immune PD as assessed by multiparameter flow cytometry. We have found correlations with survival in multiple clinical trials. These exploratory data have provided insight into the impact of therapy on peripheral immunity, which, as published in Nature (Wherry et al.) and PNAS (Ramalingam et al.), can provide valuable information reflective of the interaction of effector T cells and tumor and serve as a potential blood-based indicator of response to checkpoint blockade, as we published in 2019 in a collaboration with a clinical team including Drs. Karzai, Madan, Gulley and Dahut on immune profiling of castration-resistant prostate cancer patients treated with the anti-PD-L1 antibody durvalumab plus the PARP inhibitor olaparib demonstrating evidence of CD8+ T cell reinvigoration. We have also focused on multiple populations and subpopulations of monocytes, tumor-associated macrophages and myeloid-derived suppressor cells, including, as with T-cells, expression of functional markers. In FY2021, we have performed immune subset analysis on multiple HDAC inhibitor clinical trials. Together these data have afforded us a view of the functional interplay of innate and adaptive immunity in patients at baseline and in response to treatment, which in turn, suggests combination therapies for future clinical studies to enhance antitumor activity. Among drug classes we have focused on HDAC inhibitors, chaperone inhibitors, and the multikinase inhibitor cabozantinib. Previously we developed a PD assay for assessment of HDAC inhibitor activity in vivo. The NCI applied for a patent on our work, which issued in 2016. We have implemented this technology in multiple clinical trials, including 13 published clinical trials. In 2021 we published the first pediatric trial of the HDAC inhibitor entinostat in collaboration with the Pediatric Early Phase Clinical Trials Network (PMID: 33438318). We also published a manuscript on the impact of entinostat plus pembrolizumab on peripheral immunity in metastatic non-small cell lung cancer (PMID: 33203644). We are the National Laboratory Center of a Phase 3 ECOG-ACRIN Cancer Research Group FDA registration trial for entinostat in hormone receptor-positive advanced breast cancer, for which our PD is the only integrated biomarker. The trial was recently published and our PD assessment confirmed target inhibition in entinostat-treated patients (PMID: 34357781). We are helping to bring entinostat to Japan for the treatment of women with breast cancer. Working closely with Kyowa Kirin, we completed clinical trials of entinostat as monotherapy or in combination with exemestane and these studies have been submitted for publication. Overall, we have been working on clinical trials with 15 Branches of the NIH, three biotech companies and on two pharma trials with AstraZeneca, as well as four trials with academia (Johns Hopkins, Cleveland Clinic, Dana Farber, MIT), together encompassing Phase 1, Phase 2, and Phase 3 trials, both nationally and internationally. Working on chaperone inhibitors we previously identified Hsp40 as a new anticancer target. NIH filed for patent on this invention and the initial patent issued in FY2018 and a second patent issued in 2020. With Drs. Len Neckers of NCI and Jason Gestwicki of UCSF we are working on two DOD awards that include further development of drugs designed to hit the target we identified in my lab. We have been collaborating with Dr. Brigitte Widemann and her team on analysis of the immune infiltrate in NF1-associated tumors, including in 2021, immune analysis of peripheral blood and tumor of NF1-associated plexiform neurofibromas, atypical neurofibromas, atypical neurofibromatous neoplasms of uncertain biologic potential, and malignant peripheral nerve sheath tumors. In FY2021 we have continued our collaborations with Dr. Anish Thomas on immune profiling and circulating tumor cell analyses of his small cell lung cancer (SCLC) clinical trials, and published several manuscripts with with Dr. Thomas and Dr. Nitin Roper on SCLC (PMID: 34162872; PMID: 33848478). In FY21 we have continued our collaborations with Drs. Madan, Karzai, Gulley and Dahut on prostate cancer pharmacodynamics, and have several manuscripts in preparation, and a manuscript published in 2021 on cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer (PMID: 32969563). We performed PD analysis in Dr. Jung-min Lee's clinical trials of the CHK1 inhibitor prexasertib in BRCA wild-type triple-negative breast cancer (Oncologist, 2020), and BRCA wild-type high-grade serous ovarian cancer (J. Immunother. Cancer, 2020), and an analysis comparing innate and adaptive immune cells in the early course of patients with BRCA wild-type and mutated ovarian cancer (Oncol. Lett. 2019). We have performed immunophenotyping analysis in Dr. Neckers' study demonstrating the first in vivo activity of an LDH inhibitor (Cell Rep. 2020), and gene expression analysis of metabolism in Dr. Mioara Larion's analysis of metabolic reprogramming in molecular subtypes of IDH1mut gliomas (Neuro-oncology 2020). We developed an assay for MGMT gene expression from frozen and FFPE patient samples and contributed to Dr. Jing Wu's overview of MGMT status as a clinical biomarker in glioblastoma (Trends Cancer 2020). We identified the impact of cabozantinib on innate and adaptive immune cells in Dr. Andrea Apolo's Phase 2 trial of cabozantinib in metastatic urothelial carcinoma (Lancet Oncol. 2020). In FY2021 in collaboration with Dr. Apolo we have continued to define the the impact of cabozantinib on systemic immunity in combination with the checkpoint inhibitors nivolumab and ipilimumab (PMID: 32915679), and further analyses have been submitted and are in preparation. We have continued our work on circulating endothelial cells and identified an association of the severity of capillary leak syndrome with increases in apoptotic circulating endothelial cells in Dr. Christine Alewine's LMB-100 plus Nab-Paclitaxel trial of patients with advanced pancreatic adenocarcinoma (PMID: 31792036).

我们在2021财年的主要活动是与临床研究人员合作开发适合其临床试验的新药效学（PD）分析，并在我们在2021财年开放的临床试验中实施这些PD分析。我们的具体目标是：(1)确定一种疗法是否达到了患者的目标；(2)在系统水平、肿瘤和肿瘤微环境中探究治疗对宿主的影响；(3)与临床研究人员合作，将新技术引入他们的项目，包括在内部、外部和国际上转让我们的技术；(4)与临床和基础转化研究人员合作，确定新的药物靶点和新的药物作用机制。我们在2021财年进行了60多项临床试验。我们专注于生物标志物分析的三个主要领域；(1)免疫PD，(2)罕见细胞非免疫PD（即循环肿瘤细胞和循环内皮细胞），(3)基因表达的数字化分析，可在新鲜、冷冻或福尔马林固定石蜡包埋的组织上进行，极大地促进了肿瘤样本中基因表达的评估。此外，我们还研究了免疫和非免疫靶向治疗对外周血免疫基因表达的全身影响。在我们合作的大多数临床试验中，我们通过多参数流式细胞术评估了免疫PD。我们在多个临床试验中发现了与生存的相关性。这些探索性数据为治疗对外周免疫的影响提供了见解，正如发表在Nature （Wherry等人）和PNAS （Ramalingam等人）上的那样，可以提供反映效应T细胞与肿瘤相互作用的有价值信息，并作为对检查点封锁反应的潜在血液指标，正如我们在2019年与包括博士在内的临床团队合作发表的那样。Karzai, Madan， Gulley和Dahut研究了抗pd - l1抗体durvalumab加PARP抑制剂olaparib治疗的去势抵抗性前列腺癌患者的免疫谱，证明了CD8+ T细胞再生的证据。我们还关注单核细胞、肿瘤相关巨噬细胞和髓源性抑制细胞的多个群体和亚群，包括功能标记物的表达，如t细胞。在2021财年，我们对多个HDAC抑制剂临床试验进行了免疫亚群分析。综上所述，这些数据为我们提供了先天免疫和适应性免疫在患者基线和治疗反应中的功能相互作用的观点，这反过来又为未来临床研究提供了联合治疗以增强抗肿瘤活性的建议。在药物类别中，我们专注于HDAC抑制剂，伴侣抑制剂和多激酶抑制剂cabozantinib。之前，我们开发了一种PD测定法来评估体内HDAC抑制剂的活性。NCI为我们的工作申请了专利，并于2016年发布。我们已经在多个临床试验中实施了这项技术，其中包括13个已发表的临床试验。2021年，我们与儿科早期临床试验网络（PMID: 33438318）合作，发表了HDAC抑制剂恩替诺他的首个儿科试验。我们还发表了一篇关于恩替诺他联合派姆单抗对转移性非小细胞肺癌外周免疫影响的论文（PMID: 33203644）。我们是ECOG-ACRIN癌症研究小组（ECOG-ACRIN Cancer Research Group）在FDA注册的依替诺他治疗激素受体阳性晚期乳腺癌的3期临床试验的国家实验室中心，我们的PD是唯一的综合生物标志物。该试验最近发表，我们的PD评估证实了恩替诺他治疗患者的靶抑制作用（PMID: 34357781）。我们正在帮助将安替司他带到日本，用于治疗女性乳腺癌。我们与Kyowa Kirin密切合作，完成了恩替诺他单药或与依西美坦联合的临床试验，这些研究已提交发表。总的来说，我们一直在与美国国立卫生研究院的15个分支机构、三家生物技术公司、阿斯利康的两项制药试验以及与学术界（约翰霍普金斯大学、克利夫兰诊所、达纳法伯、麻省理工学院）的四项试验进行临床试验，包括国内和国际的1期、2期和3期试验。在研究伴侣蛋白抑制剂时，我们之前发现Hsp40是一个新的抗癌靶点。NIH申请了该发明的专利，并于2018财年颁发了初始专利，并于2020年颁发了第二项专利。Drs。国家癌症研究所的Len Neckers和加州大学旧金山分校的Jason Gestwicki我们正在争取两项国防部奖励，包括进一步开发药物，以达到我们在实验室确定的目标。我们一直与Brigitte Widemann博士及其团队合作分析nf1相关肿瘤的免疫浸润，包括2021年nf1相关丛状神经纤维瘤、非典型神经纤维瘤、生物潜能不确定的非典型神经纤维瘤和恶性周围神经鞘肿瘤的外周血和肿瘤免疫分析。在2021财年，我们继续与Anish Thomas博士就其小细胞肺癌（SCLC）临床试验的免疫分析和循环肿瘤细胞分析进行合作，并与Thomas博士和Nitin Roper博士发表了几篇关于SCLC的手稿（PMID: 34162872; PMID: 33848478）。在21财年，我们继续与博士合作。Madan, Karzai， Gulley和Dahut在前列腺癌药理学方面的研究，并有多篇论文正在准备中，并于2021年发表了一篇关于卡博赞替尼联合多西他赛和泼尼松治疗转移性去势抵抗性前列腺癌的论文（PMID: 32969563）。我们对Jung-min Lee博士的CHK1抑制剂prexasertib在BRCA野生型三阴性乳腺癌（Oncologist, 2020）和BRCA野生型高级别浆液性卵巢癌（J. Immunother）的临床试验进行了PD分析。Cancer, 2020)，以及一项比较BRCA野生型和突变卵巢癌患者早期先天免疫细胞和适应性免疫细胞的分析(Oncol。博士论文,2019)。我们在Neckers博士的研究中进行了免疫表型分析，证明了LDH抑制剂的首次体内活性（Cell代表2020），并在Mioara Larion博士的IDH1mut胶质瘤分子亚型代谢重编程分析中进行了代谢基因表达分析（神经肿瘤学2020）。我们开发了一种从冷冻和FFPE患者样本中检测MGMT基因表达的方法，并为Jing Wu博士提供了MGMT作为胶质母细胞瘤临床生物标志物的概述（Trends Cancer 2020）。我们在Andrea Apolo博士的cabozantinib治疗转移性尿路上皮癌的2期试验中确定了cabozantinib对先天和适应性免疫细胞的影响（Lancet Oncol. 2020）。在2021财年，我们与Apolo博士合作，继续确定cabozantinib与检查点抑制剂nivolumab和ipilimumab （PMID: 32915679）联合使用对全身免疫的影响，并已提交进一步的分析并正在准备中。我们继续研究循环内皮细胞，并在Christine Alewine博士的晚期胰腺腺癌患者LMB-100加nab -紫杉醇试验中发现毛细血管渗漏综合征的严重程度与循环内皮细胞凋亡的增加之间存在关联（PMID: 31792036）。