Preclinical drug development in pancreatic cancer

胰腺癌的临床前药物开发

• 批准号: 10702516
• 负责人: Udo Rudloff
• 金额: $ 206.93万
• 依托单位: DIVISION OF BASIC 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/10702516
• 关键词: Achievement; Address; Aftercare; Antitumor Response; Back; Biological; Biological Availability; Biological Markers; Biological Products; Blindness; Blood - brain barrier anatomy; CCR; CTLA4 gene; Cancer Model; Cancer Patient; Canis familiaris; Cell Nucleolus; Cells; Chemicals; Chromosomes; Clinical; Communicable Diseases; DNA Polymerase I; DNA Sequence Alteration; Data; Development; Diabetic Retinopathy; Disease; Disseminated Malignant Neoplasm; Docking; Dose; Dose-Limiting; Drug Combinations; Drug Kinetics; Electrocardiogram; Environment; Eye diseases; FDA approved; Fibrosis; Future; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Genome; Hemorrhage; Host Defense; Human; Immune; Immune Targeting; Immunologics; Immunooncology; Inflammation; Inflammatory; Interferon Type I; Intramural Research Program; Investigational New Drug Application; Investigational Therapies; Ion Channel; Laboratories; Legal patent; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measurement; Mediating; Medical; Modeling; Molecular Target; Monitor; NF-kappa B; Neoplasm Metastasis; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Nucleoplasm; Oncology; Oral; Organ; PD-1/PD-L1; Pancreas; Patients; Peptides; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Physiological; Plasma; Polymerase; Population; Pre-Clinical Model; Preclinical Drug Development; Prevalence; Process; Production; Pyrazines; Pyrimidine; Rattus; Regimen; Reporting; Research; Resources; Retina; Retinal Detachment; Risk; Role; Safety; Schedule; Scheme; Serious Adverse Event; Serum; Signal Transduction; Solid; Solid Neoplasm; T-Cell Activation; Tablets; Technology; Testing; Therapeutic; Toxic effect; Toxicokinetics; Transcript; Translational Research; Tumor-associated macrophages; Untranslated RNA; Work; base; cancer cell; cancer immunotherapy; checkpoint inhibition; checkpoint therapy; clinical translation; cohort; design; drug candidate; drug development; drug discovery; effective therapy; efficacy study; first-in-human; immune checkpoint; improved; in silico; innate immune checkpoint; innovation; macrophage; mannose receptor; neovascular; novel; novel anticancer drug; online course; pancreatic cancer patients; pharmacophore; phase 1 study; phase I trial; pre-clinical; preclinical development; preclinical efficacy; preclinical safety; predicting response; predictive marker; programs; proliferative diabetic retinopathy; pyrimidine analog; receptor; research clinical testing; resistance mechanism; response; safety study; sarcoma; scaffold; scale up; screening; side effect; small molecule; small molecule inhibitor; small molecule libraries; therapy development; tumor

My laboratory aims to address the unmet medical need for more effective treatments for pancreas cancer patients by developing new cancer drugs. Scientific achievements with regard to the pursued drug development projects in the last year include: 1. Identification of a clinically safe dose level of metarrestin, a first-in-class small molecule targeting genome organization in metastatic cancer cells. Metarrestin is a novel, first-in-class small molecule inhibitor with selective activity against the metastatic phenotype of cancer cells. It has impressive activity in preclinical pancreatic and other cancer metastasis models. FDA approved the IND application in November 2019 (IND#146042). Metarrestin is currently administered to patients with advanced malignancies in escalating doses to determine safety and tolerability of the drug. PK data from the first two cohorts of patients treated with metarrestin identified a regimen of a loading dose followed by a maintenance dose as safe which achieves human-equivalent therapeutic levels of prior preclinical efficacy studies in plasma and does not carry risk(s) of drug accumulation upon multiple dose administration. No dose-limiting toxicities have occurred so far in patients treated with metarrestin. However, two patients had prolongations of their QTc intervals during EKG monitoring which was reported as metarrestin-related suspected unexpected serious adverse reaction (SUSAR) and is currently actively followed. Preclinical work has shown that metarrestin inhibits polymerase I transcription and reduces expression levels of the pyrimidine-rich non-coding transcript (PNCTR) long non-coding RNA (lnRNA) which is an essential scaffold of the PNC and which is transcribed by polymerase I. Loss of PNCTR transcripts leads to disassembly of the PNC, translocation of PNC components into the nucleoplasm, and separation of ultrastructural components of the nucleolus due to loss of physiologic phase-phase separation. PNCTR transcript levels, genomic alterations of the PNCTR locus on chromosomes 13, 14, 15, 21 and 22, PNC prevalence as well as pol I transcript ratios are currently evaluated as biomarkers to predict response to metarrestin. Medicinal chemistry work has commenced to develop a back-up candidate of metarrestin with decreased ability to cross the blood brain barrier and lower the risk of neurological side effects. Recognizing the educational value of the successful clinical translation of metarrestin for essential processes of drug development from the initial high-content screen testing chemical compounds to disassemble the PNC, the medicinal chemistry campaign, preclinical work, IND enabling studies, to now clinical testing, an online course summarizing key milestones in translational processes of metarrestin's development has been designed and is now in its second year. 2. Preclinical development of small molecule-based innate checkpoint modulators targeting CD206 on TAMs. Prior work of ours has shown that the mannose receptor CD206 on M2-like TAMs functions as an immune checkpoint. CD206 activation via either peptide- or small molecule leads is able to reprogram TAMs from a pro-tumor, immune suppressive to an anti-tumor, inflammatory phenotype able to reinvigorate innate anti-tumor responses via direct cancer cell phagocytosis. CD206 is an attractive target for novel cancer immunotherapy in immunologically 'cold' cancers which currently do not respond to T cell activation via immune checkpoint inhibition. Our group previously described a first-in-class, synthetic host defense peptide RP-182 which activates CD206 and reprograms TAM in solid organ tumors. In silico screening of large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor interface has identified the phenyl-imidoazo[2,3] pyrazine-based drug candidate NCGC00413972. NCGC00413972 has limited off-target activity in large panels of kinases, GPCRs, or ion channels, showed a large therapeutic window in rat toxicity studies. After successful competition for resources from CCR's Drug Development Consortium (DDC) for further preclinical development and clinical translation a dedicated phase I/II study evaluating safety, tolerability, and efficacy in sarcoma-bearing dogs has commenced prior to applying for support of IND enabling studies. A scale-up synthesis scheme of NCGC00413972 for the production of clinical grade drug substance has been devised. Additional preclinical work has shown that NCGC00413972 has dual function; via activation of canonical NF-kB signaling and an early inflammatory gene response NCGC00413972 induces M2 macrophage killing. Internalized CD206 receptors after treatment with NCGC00413972 on the other hand induce an interferon type I response which reprograms M2 to M1-like macrophages, induces cancer cell phagocytosis, and anti-tumor activity. Current mechanism of action studies to increase efficacy of CD206 innate immune checkpoint therapy via NCGC00413972 explore (1) combinations of immuno oncology agents with synergistic mechanisms as NCGC00413972, and (2) selection of tumors with CD206 positive immune profiles most likely to respond to NCGC00413972. Spurned by recent reports that CD206 positive macrophages mediate disease-causing processes in non-malignant conditions like eye disease, infectious diseases, or type II diabetes, we have evaluated NCGC00413972 in a preclinical model of proliferative diabetic retinopathy. NCGC00413972 substantially reduced sub-retinal fibrosis, the cause of retinal detachment, vitriol hemorrhages, and blindness in diabetic retinopathy. As a first indication for CD206 checkpoint modulators outside oncology we protected a possible role of NCI's proprietary CD206 small molecule technology NCGC00413972 in the treatment of diabetic retinopathy via filing of Prov Patent Appl E-167-2021 (MBHB 21-0949-PRO) METHODS AND COMPOSITIONS FOR THE TREATMENT FOR INFLAMMATION AND FIBROSIS IN RETINAL NEOVASCULAR DISEASES.

我的实验室旨在通过开发新的癌症药物来满足胰腺癌患者对更有效治疗的未满足的医疗需求。去年所开展的药物开发项目的科学成就包括： 1.确定了metarrestin的临床安全剂量水平，metarrestin是一种针对转移性癌细胞基因组组织的一流小分子。 Metarrestin 是一种新型、一流的小分子抑制剂，具有针对癌细胞转移表型的选择性活性。它在临床前胰腺和其他癌症转移模型中具有令人印象深刻的活性。 FDA 于 2019 年 11 月批准了 IND 申请（IND#146042）。 Metarrestin 目前用于晚期恶性肿瘤患者，剂量逐渐增加，以确定该药物的安全性和耐受性。前两组接受metarrestin治疗的患者的PK数据确定了负荷剂量随后维持剂量的方案是安全的，该方案达到了先前临床前血浆疗效研究的人体等效治疗水平，并且在多剂量给药时不存在药物蓄积的风险。迄今为止，接受metarrestin治疗的患者尚未发生剂量限制性毒性。然而，两名患者在心电图监测期间出现 QTc 间期延长，据报告为与metarrestin 相关的疑似意外严重不良反应（SUSAR），目前正在积极随访。临床前工作表明，metarrestin 抑制聚合酶 I 转录，并降低富含嘧啶的非编码转录物 (PNCTR) 长非编码 RNA (lnRNA) 的表达水平，lnRNA 是 PNC 的重要支架，由聚合酶 I 转录。PNCTR 转录物的丢失导致 PNC 解体，PNC 成分易位到 核质，以及由于生理相间分离丧失而导致核仁超微结构成分的分离。目前，PNCTR 转录物水平、13、14、15、21 和 22 号染色体上 PNCTR 基因座的基因组改变、PNC 患病率以及 pol I 转录物比率被评估为预测对metarrestin 反应的生物标志物。药物化学工作已开始开发metarrestin的备用候选药物，该候选药物可降低穿过血脑屏障的能力并降低神经副作用的风险。认识到metarrestin成功临床转化对药物开发基本过程的教育价值，从最初的高内涵筛选测试化合物到拆卸PNC、药物化学活动、临床前工作、IND支持研究，再到现在的临床测试，设计了一个总结metarrestin开发转化过程中关键里程碑的在线课程，目前已进入第二年。 2.针对TAM上的CD206的基于小分子的先天检查点调节剂的临床前开发。我们之前的工作表明，M2 样 TAM 上的甘露糖受体 CD206 可充当免疫检查点。通过肽或小分子引线激活 CD206 能够将 TAM 从促肿瘤、免疫抑制性重新编程为抗肿瘤、炎症表型，能够通过直接癌细胞吞噬作用重振先天抗肿瘤反应。 CD206 是免疫“冷”癌症中新型癌症免疫疗法的一个有吸引力的靶标，这些癌症目前无法通过免疫检查点抑制对 T 细胞激活做出反应。我们的团队之前描述了一种一流的合成宿主防御肽 RP-182，它可以激活实体器官肿瘤中的 CD206 并重新编程 TAM。使用源自与 CD206 受体界面对接的 RP-182 的药效团模型对大型化学文库进行计算机筛选，鉴定出基于苯基-亚氨基偶氮[2,3]吡嗪的候选药物 NCGC00413972。 NCGC00413972 在大量激酶、GPCR 或离子通道中具有有限的脱靶活性，在大鼠毒性研究中显示出较大的治疗窗口。在成功竞争 CCR 药物开发联盟 (DDC) 的资源以进行进一步的临床前开发和临床转化后，一项专门的 I/II 期研究已开始，该研究评估了患有肉瘤的狗的安全性、耐受性和有效性，然后再申请 IND 支持研究的支持。设计了用于生产临床级原料药的NCGC00413972的放大合成方案。其他临床前工作表明 NCGC00413972 具有双重功能； 通过激活经典 NF-kB 信号传导和早期炎症基因反应，NCGC00413972 诱导 M2 巨噬细胞死亡。另一方面，用 NCGC00413972 治疗后内化的 CD206 受体会诱导 I 型干扰素反应，将 M2 重编程为 M1 样巨噬细胞，诱导癌细胞吞噬作用和抗肿瘤活性。目前通过 NCGC00413972 提高 CD206 先天免疫检查点疗法疗效的作用机制研究探索 (1) 免疫肿瘤药物与 NCGC00413972 等协同机制的组合，以及 (2) 选择最有可能对 NCGC00413972 产生反应的 CD206 阳性免疫特征的肿瘤。最近有报道称 CD206 阳性巨噬细胞介导眼病、传染病或 II 型糖尿病等非恶性疾病的致病过程，但我们对此不以为然，在增殖性糖尿病视网膜病变的临床前模型中评估了 NCGC00413972。 NCGC00413972 显着减少视网膜下纤维化，这是糖尿病视网膜病变中视网膜脱离、硫酸出血和失明的原因。作为肿瘤学之外 CD206 检查点调节剂的第一个适应症，我们通过提交临时专利申请 E-167-2021 (MBHB 21-0949-PRO) 来保护 NCI 专有的 CD206 小分子技术 NCGC00413972 在治疗糖尿病视网膜病变中的可能作用。视网膜新生血管 疾病。