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Preclinical drug development in pancreatic cancer

胰腺癌的临床前药物开发

基本信息

批准号：
10262275
负责人：
Udo Rudloff
金额：
$ 153.92万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10262275
关键词：
Achievement Address Adult Alanine Animal Cancer Model Antitumor Response Back Binding Biodistribution Biogenesis Biological Availability Biological Markers Biological Products Biophysics Blood - brain barrier anatomy Blood Circulation CTLA4 gene Cancer Model Cancer Patient Canis familiaris Cations Cell Nucleus Cell physiology Cells Chemical Structure Chemicals Clinical Clinical Protocols Complement Complex Cyclization Cyclohexanol Development Docking Dose Drug Delivery Systems Drug Kinetics Effector Cell Elongation Factor Enrollment Environment Evaluation FDA approved Fibroblasts Formulation G-Protein-Coupled Receptors Genome Host Defense Hour Hydrogen Bonding Immune Immunologic Surveillance Immunologics Immunotherapeutic agent Immunotherapy In Vitro Inflammatory Intramural Research Program Investigational New Drug Application Investigational Therapies Ion Channel Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Mediating Medical Memory Modeling Molecular Target Mus Myeloid Cells Neoplasm Metastasis Neurologic Oral Organ PD-1/PD-L1 Pancreas Pancreatic Adenocarcinoma Patients Peptides Perfusion Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phase I Clinical Trials Phenocopy Phenotype Phosphotransferases Positioning Attribute Post-Translational Protein Processing Preclinical Drug Development Preclinical Testing Production Property Protein Biosynthesis Pyrazines RNA Splicing Rattus Regulatory T-Lymphocyte Research Ribosomes Risk Safety Seizures Serine Serum Solid Structure-Activity Relationship T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Toxic effect Toxicokinetics Transforming Growth Factor beta Transgenic Animals Translational Research Translations Tumor-associated macrophages Up-Regulation Work anti-PD-L1 anti-cancer arm base biophysical properties biophysical techniques cancer cell cancer therapy capsule checkpoint inhibition chemotherapy clinical translation drug candidate drug development drug discovery effective therapy epileptic encephalopathies first-in-human gemcitabine genome editing immune checkpoint immune-related adverse events immunogenic immunoregulation improved in silico in vivo innate immune checkpoint innovation lead series macrophage mouse model neurotoxicity novel novel anticancer drug novel therapeutic intervention palmitoylation pancreatic cancer model pancreatic cancer patients pharmacophore pharmacovigilance pre-clinical preclinical development preclinical efficacy preclinical safety predictive marker programmed cell death ligand 1 programs pyrimidine analog rRNA Precursor receptor research clinical testing resistance mechanism safety study screening side effect small molecule small molecule inhibitor small molecule libraries therapy development tumor tumor growth tumor progression

项目摘要

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. Clinical translation of metarrestin. 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 pancreatic and other cancer metastasis models. Supported by NCATS' Bridging Interventional Development Gaps (BrIDGs) program IND enabling studies and manufacturing of clinical grade metarrestin capsules were completed. FDA approved the IND application in November 2019 (IND#146042). Using a safe first-in-human starting dose level of 1mg every 48 hours administered orally the phase I clinical protocol NCI 20-C-0023 is currently accruing patients with advanced solid organ cancers to determine safety and tolerability of the drug. Preclinical work has identified the translation elongation factor eEF1A2 upregulated in solid organ cancers as the molecular target of metarrestin. The factor eEF1A2 stabilizes the nucleolar PeBoW complex comprised of the components BOP1, PES1, and WDR12. Inhibition of eEF1A2 leads to rapid disassembly of the PeBoW complex, translocation of the PeBoW components into the nucleus, loss of splicing function of the large 47S ribosomal RNA precursors, loss of ribosomal pre-assembly, stalling of ribosomal biogenesis, and loss of protein synthesis function of the cell. Metarrestin binds to eEF1A2 via formation of hydrogen bonds between serine 331 and the cyclo-hexanol group of the compound. Genome-edited mice which have replaced the murine alanine on position 331 of eEF1A2 with serine and which phenocopy the neurotoxicity of metarrestin have been generated. These mouse models are used to (1) study the binding of metarrestin to its molecular target in vivo, (2) establish informative PK signatures upon treatment with metarrestin which are predictive of the neurological phenotype, such as seizures and epileptic encephalopathies, and (3) to validate tissue and circulation biomarkers predictive of neurotoxicity from cancer patients enrolled onto the phase I clinical trial to improve pharmacovigilance and the safety profile of anticancer therapy with metarrestin. These preclinical safety studies are complemented with medicinal chemistry efforts to develop a modified metarrestin derivative as a back-up candidate with improved physiochemical properties to decrease the ability to cross the blood brain barrier and lower the risk of neurological side effects. Additional in vitro studies have identified unique binding partners of eEF1A2 as well as post-translational modifications of eEF1A2 associated with metarrestin activity which will be interrogated as possible novel anti-cancer targets or biomarkers. 2. Preclinical development of peptide- and small molecule-based innate checkpoint modulators targeting CD206. A novel method of biophysical homology screening identified RP-182, a first-in-class immunomodulatory host defense peptide which is able to reprogram pro-tumor M2-like tumor associated macrophages into M1-like macrophages and which restores immune surveillance leading to anti-tumor response in a variety of animal models of cancer. RP-182 was shown to be an attractive agent for immunotherapy (anti-PD-L1) or chemotherapy treatment combinations in immunologically 'cold' cancers which currently don't respond to T cell activation via immune checkpoint inhibition. CD206 small molecule-based innate checkpoint modulators have been identified after screening large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor. The lead series is significantly more potent than RP-182, and after SAR-guided optimization and PK evaluation has identified the phenyl-imidoazo[2,3] pyrazine-based drug candidate NCGC00413972 which is currently evaluated in pre-IND studies. The drug candidate has limited off-target activity in large panels of kinases, GPCRs, or ion channels, showed a large therapeutic window in rat toxicity studies, and is planned to undergo safety and tolerability testing in dogs prior to applying at NCATS BrIDGs program for support of IND enabling studies and production of clinical grade compound. 3. Combined stromal modulation and anti-cancer therapy in pancreatic cancer. Preclinical work in transgenic animals with pancreas cancer has shown that TGFbeta inhibition and gemcitabine cooperate to suppress tumor growth and extend survival in mice. TGFbeta inhibition-mediated stromal modulation increases perfusion via alteration of the cancer-associated fibroblast (CAF) phenotype (increases the ratio of inflammatory vs myelofibroblastic CAFs) in these tumors which rapidly returned to pre-treatment values due to intrinsic resistance mechanisms in the myelofibroblastic CAF fraction. Anti-tumor activity of TGFbeta inhibition in combination with gemcitabine is generated via immunogenic cooperativity of the two agents including the reprogramming of T regulatory cells from an effector-memory towards a naive cell phenotype. Additional preclinical work identified upregulation of the immune checkpoint PD-L1 as one of the resistance mechanisms of this approach. The clinical protocol 'A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination with Gemcitabine in Adults with Previously Treated Advanced Adenocarcinoma of the Pancreas' was testing the concept in patients. The study is currently on hold after the occurrence of a grade 5 immune-related adverse event.

我的实验室旨在通过开发新的癌症药物来解决胰腺癌患者更有效治疗的未满足的医疗需求。过去一年所进行的药物开发项目的科学成果包括：1. metarrestin的临床翻译。Metarrestin是一种新型的，一流的小分子抑制剂，对癌细胞的转移表型具有选择性活性。它在胰腺癌和其他癌症转移模型中具有令人印象深刻的活性。在NCATS的弥合干预性开发差距（BrIDGs）计划的支持下，完成了IND使能研究和临床级metarrestin胶囊的生产。FDA于2019年11月批准了IND申请（IND#146042）。I期临床方案NCI 20-C-0023使用每48小时口服1 mg的安全首次人体起始剂量水平，目前正在招募晚期实体器官癌患者，以确定药物的安全性和耐受性。临床前工作已经确定了在实体器官癌中上调的翻译延伸因子eEF 1A 2作为metarrestin的分子靶点。因子eEF 1A 2稳定由组分BOP 1、PES 1和WDR 12组成的核仁PeBoW复合物。eEF 1A 2的抑制导致PeBoW复合物的快速分解，PeBoW组分易位到细胞核中，大的47 S核糖体RNA前体的剪接功能丧失，核糖体预组装丧失，核糖体生物发生停滞，以及细胞蛋白质合成功能丧失。Metarrestin通过丝氨酸331和化合物的环己醇基团之间形成氢键与eEF 1A 2结合。已经产生了基因组编辑的小鼠，其已经用丝氨酸替换了eEF 1A 2的位置331上的鼠丙氨酸，并且其表型复制了美他瑞司汀的神经毒性。这些小鼠模型用于（1）研究体内metarrestin与其分子靶标的结合，（2）在用metarrestin治疗后建立信息性PK特征，其可预测神经学表型，例如癫痫发作和癫痫性脑病，以及（3）验证组织和循环生物标志物，预测入组I期临床试验的癌症患者的神经毒性，以提高药物警戒和使用美他瑞司汀的抗癌疗法的安全性特征。这些临床前安全性研究与药物化学工作相辅相成，以开发一种修饰的metarrestin衍生物作为具有改善的理化性质的备用候选物，以降低穿过血脑屏障的能力并降低神经系统副作用的风险。另外的体外研究已经鉴定了eEF 1A 2的独特结合配偶体以及与metarrestin活性相关的eEF 1A 2的翻译后修饰，其将作为可能的新型抗癌靶标或生物标志物进行研究。2.靶向CD 206的基于肽和小分子的先天检查点调节剂的临床前开发。一种新的生物物理同源性筛选方法鉴定了RP-182，这是一种一流的免疫调节宿主防御肽，能够将促肿瘤M2样肿瘤相关巨噬细胞重编程为M1样巨噬细胞，并恢复免疫监视，从而在多种癌症动物模型中产生抗肿瘤反应。RP-182被证明是一种有吸引力的药物，用于免疫治疗（抗PD-L1）或免疫“冷”癌症的化疗治疗组合，目前这些癌症通过免疫检查点抑制对T细胞活化没有反应。在用源自对接到CD 206受体上的RP-182的药效团模型筛选大型化学文库后，已经鉴定了基于CD 206小分子的先天检查点调节剂。先导系列的效力显著高于RP-182，在SAR指导的优化和PK评价后，已确定了基于苯基-咪唑偶氮[2，3]吡嗪的候选药物NCGC 00413972，目前正在IND前研究中进行评价。该候选药物在大量激酶、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，并计划在NCATS BrIDGs项目中申请之前在犬中进行安全性和耐受性试验，以支持IND使能研究和临床级化合物的生产。3.胰腺癌中基质调节和抗癌治疗的联合应用。胰腺癌转基因动物的临床前研究表明，TGF β抑制和吉西他滨协同抑制肿瘤生长并延长小鼠的生存期。在这些肿瘤中，TGF β抑制介导的基质调节通过改变癌症相关成纤维细胞（CAF）表型（增加炎性与骨髓成纤维细胞CAF的比例）增加灌注，由于骨髓成纤维细胞CAF部分的内在抗性机制，这些肿瘤迅速恢复到治疗前值。TGF β抑制与吉西他滨组合的抗肿瘤活性通过两种药剂的免疫原性协同作用产生，包括调节性T细胞从效应记忆向幼稚细胞表型的重编程。额外的临床前工作将免疫检查点PD-L1的上调确定为该方法的耐药机制之一。临床方案"M7824（MSB 0011359 C）联合吉西他滨治疗既往接受过治疗的晚期胰腺腺癌成人的IB/II期单组研究“正在患者中测试这一概念。该研究目前在发生5级免疫相关不良事件后暂停。