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: 10262790
• 负责人: JANE B TREPEL
• 金额: $ 109.75万
• 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/10262790
• 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; Immune response; Immunity; Immunophenotyping; Institutes; Institution; 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; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Oncologist; Paclitaxel; Pancreatic Adenocarcinoma; Paraffin Embedding; Patients; Pediatric Oncology; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Plexiform Neurofibroma; Population; Preparation; Process; Publications; Publishing; Research; S Phase; Sampling; Serous; Severities; Signal Pathway; Signal Transduction; Specialist; T-Lymphocyte; Technology; Therapy trial; Tissue Embedding; Transitional Cell Carcinoma; Translational Research; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States; United States National Institutes of Health; Universities; Vaccine Therapy; 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; design; digital; drug development; drug discovery; drug mechanism; early phase clinical trial; effector T cell; epigenetic therapy; hormone receptor-positive; immune checkpoint blockade; in vivo; inhibitor/antagonist; insight; invention; lung small cell carcinoma; malignant breast neoplasm; molecular subtypes; monocyte; neuro-oncology; neurofibroma; new technology; new therapeutic target; novel; novel therapeutics; pediatric patients; peripheral blood; phase 2 study; 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 FY2020 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 FY2020. 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 FY2020. 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 examine 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 in FY2020. 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.) in 2017, 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. and in FY2020, we have performed immune subset analysis on multiple HDAC inhibitor clinical trials, including combination therapy trials with checkpoint inhibitors. 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 and chaperone inhibitors. 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 9 published clinical trials, two currently submitted manuscripts and one manuscript in preparation. In 2017 we published the first immune profiling of the systemic immune response to an HDAC inhibitor in clinical trial. In FY2020 we published the induction of hyperacetylation in pediatric patients in response to combination epigenetic therapy in collaboration with Dr. Patrick Brown, Johns Hopkins University (Clin. Cancer Res.). We have a manuscript submitted on the first pediatric trial of the HDAC inhibitor entinostat in collaboration with the Pediatric Early Phase Clinical Trials Network, which includes specialists in pediatric oncology from some of the premier research institutions in the United States. We also have a manuscript in preparation on a clinical trial of entinostat plus pembrolizumab in metastatic non-small cell lung cancer. 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 has recently finished accrual and we completed our PD assessment. We are helping to bring entinostat to Japan for the treatment of women with breast cancer. Working closely with Kyowa Kirin, we completed the Phase I clinical trial of entinostat as monotherapy or in combination with exemestane and this study has been submitted for publication. In FY2020 working with Kyowa Kirin we completed a Phase 2 study of the same design. Overall, we are 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, Broad Institute), 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 patent issued in FY2018. 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 2020, 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 FY2020 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, with several manuscripts currently under review. We have a new collaboration with Dr. Nitin Roper on SCLC with a manuscript under review. We have continued our collaborations with Dr. Jay Berzofsky and his team on circulating tumor cells and immune subsets in breast cancer and prostate cancer patients treated with vaccine therapy, with a manuscript currently in preparation. We have continued our collaborations with Drs. Madan, Karzai, Gulley and Dahut on prostate cancer pharmacodynamics, and have several manuscripts in preparation or under review. 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's 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). We 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 (Clin. Cancer Res. 2020).

我们在 2020 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 (PD) 测定，并在我们于 2020 财年开放的临床试验中实施这些 PD 测定。我们的具体目标是（1）确定治疗是否达到了患者的目标； (2) 在全身水平以及肿瘤和肿瘤微环境中探讨治疗对宿主的影响； (3) 与临床研究人员合作，将新技术引入他们的项目，包括在校内、校外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机制。 2020 财年，我们开展了 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）稀有细胞非免疫PD（即循环肿瘤细胞和循环内皮细胞），以及（3）基因表达的数字分析，可以对新鲜、冷冻或福尔马林固定、石蜡包埋的组织进行基因表达的数字分析，极大地方便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中免疫基因表达的系统性影响。对于我们合作的大多数临床试验，我们都包括通过多参数流式细胞术评估的免疫帕金森病。我们在 2020 财年的多项临床试验中发现了与生存率的相关性。这些探索性数据深入了解了治疗对外周免疫的影响，正如 2017 年发表在 Nature（Wherry 等人）和 PNAS（Ramalingam 等人）上的那样，这些数据可以提供反映效应 T 细胞和肿瘤相互作用的有价值的信息，并作为检查点封锁反应的潜在血液指标，正如我们在 2019 年与包括 Drs. 等人在内的临床团队合作发表的那样。 Karzai、Madan、Gulley 和 Dahut 对接受抗 PD-L1 抗体 durvalumab 和 PARP 抑制剂 olaparib 治疗的去势抵抗性前列腺癌患者进行免疫分析，证明了 CD8+ T 细胞重新焕发活力的证据。我们还关注单核细胞、肿瘤相关巨噬细胞和骨髓源性抑制细胞的多个群体和亚群，包括与 T 细胞一样的功能标记物的表达。 2020财年，我们对多个HDAC抑制剂临床试验进行了免疫子集分析，包括检查点抑制剂的联合治疗试验。这些数据共同让我们了解了患者在基线时和对治疗的反应中先天免疫和适应性免疫的功能相互作用，这反过来又为未来的临床研究提供了联合疗法，以增强抗肿瘤活性。在药物类别中，我们重点关注 HDAC 抑制剂和分子伴侣抑制剂。此前，我们开发了一种 PD 测定法，用于评估体内 HDAC 抑制剂活性。 NCI 为我们的工作申请了专利，该专利于 2016 年颁发。我们已在多项临床试验中实施了这项技术，其中包括 9 项已发表的临床试验、2 项目前已提交的手稿和 1 项正在准备的手稿。 2017 年，我们发表了第一份临床试验中对 HDAC 抑制剂的全身免疫反应的免疫分析。在 2020 财年，我们与约翰·霍普金斯大学（临床癌症研究）的 Patrick Brown 博士合作，发表了联合表观遗传疗法诱导儿科患者过度乙酰化的研究。我们提交了一份关于 HDAC 抑制剂恩替司他与儿科早期临床试验网络合作的首次儿科试验的手稿，该网络包括来自美国一些主要研究机构的儿科肿瘤学专家。我们还有一份关于恩替司他联合派姆单抗治疗转移性非小细胞肺癌的临床试验的手稿正在准备中。我们是 ECOG-ACRIN 癌症研究小组 FDA 恩替司他治疗激素受体阳性晚期乳腺癌 3 期注册试验的国家实验室中心，我们的 PD 是该试验唯一的综合生物标志物。该试验最近完成了应计，我们完成了 PD 评估。我们正在帮助将恩替司他带到日本，用于治疗患有乳腺癌的女性。我们与 Kyowa Kirin 密切合作，完成了恩替司他作为单一疗法或与依西美坦联合治疗的 I 期临床试验，该研究已提交发表。在 2020 财年，我们与 Kyowa Kirin 合作完成了相同设计的第二阶段研究。总体而言，我们正在与 NIH 的 15 个分支机构、三个生物技术公司进行临床试验，与阿斯利康进行两项药物试验，以及与学术界（约翰·霍普金斯、克利夫兰诊所、达纳法伯、博德研究所）进行的四项试验，共同涵盖国内和国际的 1 期、2 期和 3 期试验。通过研究伴侣抑制剂，我们之前将 Hsp40 确定为新的抗癌靶点。美国国立卫生研究院 (NIH) 就该发明申请了专利，并于 2018 财年颁发了专利。与博士。美国国家癌症研究所的 Len Neckers 和加州大学旧金山分校的 Jason Gestwicki 正在努力争取两项国防部奖项，其中包括进一步开发旨在实现我们在实验室确定的目标的药物。我们一直在与Brigitte Widemann博士和她的团队合作进行NF1相关肿瘤的免疫浸润分析，包括2020年，NF1相关丛状神经纤维瘤、非典型神经纤维瘤、生物潜力不确定的非典型神经纤维瘤、恶性周围神经鞘瘤的外周血和肿瘤的免疫分析 肿瘤。 2020 财年，我们继续与 Anish Thomas 博士合作，对其小细胞肺癌 (SCLC) 临床试验进行免疫分析和循环肿瘤细胞分析，目前有几份手稿正在审查中。我们与 Nitin Roper 博士就 SCLC 进行了新的合作，手稿正在审查中。我们继续与 Jay Berzofsky 博士和他的团队合作，研究接受疫苗治疗的乳腺癌和前列腺癌患者的循环肿瘤细胞和免疫亚群，目前正在准备一份手稿。我们继续与博士合作。 Madan、Karzai、Gulley 和 Dahut 研究了前列腺癌药效学，并有几篇手稿正在准备或正在审查中。我们在 Jung-min Lee 博士的 CHK1 抑制剂 prexasertib 治疗 BRCA 野生型三阴性乳腺癌（Oncogue，2020）和 BRCA 野生型高级别浆液性卵巢癌（J.Immunother.Cancer，2020）的临床试验中进行了 PD 分析，并对 BRCA 野生型和突变型患者早期病程中的先天性和适应性免疫细胞进行了比较分析 卵巢癌（Oncol. Lett. 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 Rep. 2020)，并在 Mioara Larion 博士的 IDH1mut 神经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 (Neuro-oncology 2020)。我们开发了一种针对冷冻和 FFPE 患者样本中 MGMT 基因表达的检测方法，并为吴静博士对 MGMT 作为胶质母细胞瘤临床生物标志物地位的概述做出了贡献（Trends Cancer 2020）。我们在 Andrea Apolo 博士的卡博替尼治疗转移性尿路上皮癌 2 期试验中确定了卡博替尼对先天性和适应性免疫细胞的影响 (Lancet Oncol. 2020)。在 Christine Alewine 博士对晚期胰腺腺癌患者进行的 LMB-100 加白蛋白结合型紫杉醇试验中，我们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增加之间存在关联 (Clin. Cancer Res. 2020)。