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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：
10486801
负责人：
Udo Rudloff
金额：
$ 196.26万
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/10486801
关键词：
Achievement Address Adult Agonist Alanine Back Binding Biogenesis Biological Biological Availability Biological Markers Biological Products Blood - brain barrier anatomy CTLA4 gene Cancer Model Canis familiaris Cell Nucleus Cell physiology Cells Clinical Clinical Protocols Clinical Research Complex Cyclohexanol Data Development Disseminated Malignant Neoplasm Docking Dose Drug Delivery Systems Drug Kinetics Effector Cell Elongation Factor Environment FDA approved Fibroblasts Funding Future G-Protein-Coupled Receptors Genes Genome Host Defense Hour Hydrogen Bonding Immune Immune Targeting Immune checkpoint inhibitor Immunologics Immunooncology Immunotherapeutic agent In Vitro Inflammatory Interferon Type I Interleukin-12 Intramural Research Program Investigational New Drug Application Investigational Therapies Ion Channel Laboratories Lead Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Measurement Mediating Medical Memory Modeling Molecular Target Mus Myeloid Cells NF-kappa B Neoplasm Metastasis Neurologic Normal Cell Oral Organ PD-1/PD-L1 Pancreas Patients Peptides Perfusion Phagocytosis Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenocopy Phenotype Phosphotransferases Plasma Positioning Attribute Post-Translational Protein Processing Preclinical Drug Development Production Property Protein Biosynthesis Pyrazines RNA Splicing Radiation therapy Rattus Regulatory T-Lymphocyte Research Resistance Ribosomal RNA Ribosomes Risk Safety Schedule Seizures Serine Serum Signal Transduction Solid Solid Neoplasm T-Cell Activation Testing Therapeutic Toxic effect Toxicokinetics Transforming Growth Factor beta Transgenic Animals Translational Research Translations Tumor-associated macrophages Up-Regulation Work advanced pancreatic cancer base cancer cell cancer therapy capsule checkpoint inhibition clinical translation design drug candidate drug development drug discovery effective therapy efficacy study efficacy testing epileptic encephalopathies first-in-human gemcitabine genome editing high throughput screening immune checkpoint immunogenic improved in silico in vivo innate immune checkpoint innovation lead optimization macrophage mannose receptor neurotoxicity novel novel anticancer drug novel therapeutic intervention pancreatic cancer patients pharmacophore pharmacovigilance phase 1 study phase I trial pre-clinical preclinical development preclinical efficacy predictive marker programmed cell death ligand 1 programs pyrimidine analog rRNA Precursor receptor research clinical testing resistance mechanism response safety study sarcoma screening side effect small molecule small molecule inhibitor small molecule libraries therapy development tumor tumor growth

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; NCT04222413 is currently accruing patients with advanced solid organ cancers to determine safety and tolerability of the drug. Preliminary PK data from the first patients treated with metarrestin appear to indicate that after multiple dosing metarrestin reaches therapeutic levels in plasma. It is expected that the current dosing schedule will be modified to twice a week or once weekly dosing to reduce drug accumulation of metarrestin and optimize exposure. 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, previously not identified as a cancer target, which is 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 of the large 47S ribosomal RNA precursors, loss of rRNA processing function, 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 and binding of metarrestin to eEF1A2 is guided by post-translational modification which differ in metastatic cancer cells vs normal cells. 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 and are used to (1) study the binding of metarrestin to its molecular target in vivo and (2) establish informative PK signatures which are predictive of the neurological phenotype, such as seizures and epileptic encephalopathies to improve pharmacovigilance and the safety profile of anticancer therapy with metarrestin. Medicinal chemistry work has been started to develop a back-up candidate with decrease 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 future biomarkers or leads for rationale-designed combination studies. 2. Preclinical development of small molecule-based innate checkpoint modulators targeting CD206 on TAMs. The first-in-class synthetic host defense peptide RP-182 targets the mannose receptor CD206 on M2-like TAMs and was shown by our group to be an attractive agent for immunotherapy in immunologically 'cold' cancers which currently don't respond to T cell activation via immune checkpoint inhibition. In silico screening of large chemical libraries with a pharmacophore model derived from RP-182 docked onto the CD206 receptor has identified the phenyl-imidazo[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, and is planned to undergo safety, tolerability, and efficacy testing in sarcoma-bearing dogs prior to applying for support of IND enabling studies and production of clinical grade compound. Recent work showed that NCGC00413972 has dual function; via activation of canonical NF-kB signaling and an early inflammatory gene response the candidate induces M2 macrophage killing. Internalized NCGC00413972 induces an interferon type I response which reprograms M2 to M1-like macrophages, induces cancer cell phagocytosis, and anti-tumor activity. Additional mechanism of action studies will inform rationale-designed combinations to enhance the activity of NCGC00413972. 3. 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 'Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer' (NCI 20-C-0074; NCT04327986) is testing the concept of overcoming resistance to TGFbeta inhibition via the addition of pro-immunogenic agents including IL-12 agonists, PD-L1 checkpoint inhibitors, and stereotactic radiation therapy.

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）。根据I期临床方案NCI 20-C-0023; NCT 04222413，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。来自第一批接受metarrestin治疗的患者的初步PK数据似乎表明，多次给药后，metarrestin在血浆中达到治疗水平。预计当前给药方案将修改为每周两次或每周一次给药，以减少美他瑞司汀的药物蓄积并优化暴露。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稳定核仁PeBoW复合物，以前未被鉴定为癌症靶标，其由组分BOP 1，PES 1和WDR 12组成。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前体的剪接丧失，rRNA加工功能丧失，核糖体预组装丧失，核糖体生物合成停滞，以及细胞蛋白质合成功能丧失。metarrestin通过在丝氨酸331和化合物的环己醇基团之间形成氢键与eEF 1A 2结合，并且metarrestin与eEF 1A 2的结合由转移性癌细胞与正常细胞不同的翻译后修饰指导。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，并且用于（1）研究美他瑞司汀与其体内分子靶标的结合和（2）建立预测神经学表型的信息PK特征，如癫痫发作和癫痫性脑病，以改善药物警戒和使用美他瑞司汀的抗癌治疗的安全性。药物化学工作已经开始，以开发一种通过血脑屏障能力降低和降低神经副作用风险的备用候选药物。其他体外研究已经确定了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，将其作为合理设计的组合研究的可能未来生物标志物或先导物进行研究。2.靶向TAM上CD 206的基于小分子的先天检查点调节剂的临床前开发。一流的合成宿主防御肽RP-182靶向M2样TAM上的甘露糖受体CD 206，并且我们的研究小组表明，它是一种有吸引力的免疫治疗剂，用于免疫学上的“冷”癌症，目前通过免疫检查点抑制对T细胞活化没有反应。采用源自RP-182对接至CD 206受体的药效团模型对大型化学文库进行计算机模拟筛选，已鉴定出基于苯基咪唑并[2，3]吡嗪的候选药物NCGC 00413972。NCGC 00413972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，并计划在申请支持IND使能研究和生产临床级化合物之前在荷肉瘤犬中进行安全性、耐受性和有效性试验。最近的研究表明，NCGC 00413972具有双重功能;通过激活经典NF-κ B信号传导和早期炎症基因反应，候选物诱导M2巨噬细胞杀伤。内化的NCGC 00413972诱导I型干扰素应答，其将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。其他作用机制研究将为合理设计的联合用药提供信息，以增强NCGC 00413972的活性。3.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“免疫检查点抑制剂M7824和免疫细胞因子M9241联合立体定向体部放疗（SBRT）治疗成人晚期胰腺癌”（NCI 20-C-0074; NCT 04327986）正在测试通过添加促免疫原性剂（包括IL-12激动剂、PD-L1检查点抑制剂、和立体定向放射治疗。