Preclinical drug development in pancreatic cancer

胰腺癌的临床前药物开发

• 批准号: 10014588
• 负责人: Udo Rudloff
• 金额: $ 135.68万
• 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/10014588
• 关键词: Achievement; Address; Adult; Aftercare; Animal Cancer Model; Antibodies; Antitumor Response; Back; Biodistribution; Biogenesis; Biological; Biological Availability; Biological Markers; Biological Products; Biophysics; Blood - brain barrier anatomy; Blood Circulation; CCR; CTLA4 gene; Cancer Model; Cancer Patient; Cancer Therapy Evaluation Program; Cations; Cell Line; Cells; Chemicals; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Complement; Complex; Computer Simulation; Coupled; Coupling; Cyclization; Development; Diels Alder reaction; Docking; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Elongation Factor; Employee; Enrollment; Environment; Evaluation; Event; Fibroblasts; Formulation; Genome; Goals; Host Defense; Hour; Immune; Immunologic Surveillance; Immunologics; Immunooncology; Immunotherapeutic agent; Immunotherapy; Inflammatory; Intramural Research Program; Investigational Therapies; KRAS2 gene; Knockout Mice; Laboratories; Laboratory Finding; Lead; Legal patent; Licensing; Link; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Mediating; Medical; Methods; Modeling; Molecular; Molecular Target; Mus; Mutation; Myeloid Cells; Neoplasm Metastasis; Neurologic; Oral; Organ; PD-1/PD-L1; PDCD1LG1 gene; Pancreas; Pancreatic Adenocarcinoma; Patients; Pattern; Peptides; Perfusion; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenocopy; Phenotype; Pilot Projects; Post-Translational Protein Processing; Preclinical Drug Development; Preclinical Testing; Preparation; Property; Protein Isoforms; Reaction; Reporting; Review Committee; Ribosomal RNA; Ribosomes; Risk; Rodent; Safety; Seizures; Serum; Solid; Specimen; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Transforming Growth Factor beta; Transgenic Animals; Translational Research; Translations; Tumor-associated macrophages; Uncertainty; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Up-Regulation; Variant; Work; Xenograft procedure; advanced disease; anti-PD-L1; arm; base; biophysical properties; biophysical techniques; cancer cell; cancer stem cell; cancer therapy; capsule; checkpoint inhibition; chemotherapy; clinical development; clinical phenotype; clinical translation; cycloaddition; drug candidate; drug development; drug discovery; effective therapy; epileptic encephalopathies; first-in-human; gemcitabine; genome editing; immune checkpoint; immunoregulation; improved; inhibitor/antagonist; innovation; invention; lead series; macrophage; mouse model; neurotoxicity; novel; novel anticancer drug; novel therapeutic intervention; novel therapeutics; off-patent; palmitoylation; pancreatic cancer model; pancreatic cancer patients; pharmacokinetics and pharmacodynamics; pharmacophore; pharmacovigilance; pre-clinical; preclinical development; preclinical safety; preclinical study; predictive marker; programs; pyrimidine analog; research clinical testing; resistance mechanism; safety study; scaffold; screening; side effect; small molecule; small molecule inhibitor; small molecule libraries; stem-like cell; therapy development; tumor; tumor growth; tumor progression

My laboratory aims to address the unmet medical need of 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. Preclinical and clinical development of metarrestin (U.S. Patent filing E-114-2018-0-US-01 (738874 BIO.0353-18) 'Metarrestin for the Treatment of Pancreas Cancer'). Metarrestin is a novel 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 an IND package including GLP toxicokinetic studies in rodent and non-rodent species as well as manufacturing of clinical grade metarrestin capsules has been completed. PK studies in five species showed metarrestin to be a low clearance compound (under review) with high bioavailability and biodistribution with drug-induced neurological events including seizures as the lead clinical toxicity of the compound. A safe first-in-human starting dose level of 1mg every 48 hours administered orally has been calculated which is in, or close to, the therapeutic range of metarrestin predicated from preclinical studies. A phase I protocol has been approved by NCI CCRs Scientific Review Committee and IND filing is anticipated in Q3 2019. Preclinical work identified the translation elongation factor eEF1A2 upregulated in cancer as the molecular target of metarrestin and interference with ribosomal biogenesis as a novel mechanism of action induced by the drug. The mechanism of action of metarrestin has been linked to post-translational modifications of eEF1A2 and disruption of the PES1-BOP1 complex involved in rRNA processing and ribosome formation. Genome-edited mice including eEF1A2 knockout mice which phenocopy the clinical phenotype the neurotoxicity of metarrestin have been generated. These mouse models are planned to be used to (1) establish informative PK/TK signatures upon treatment with metarrestin which are predictive of the neurological phenotypes, such as seizures and epileptic encephalopathies, emerging as possible side effects of metarrestin treatment; (2) to validate tissue and circulation biomarkers, as well as neurological and neuropathological pattern, derived from phenotypical assessment after treatment with metarrestin; and (3) to interrogate serum from cancer patients enrolled into phase I clinical testing for PK/PD correlations and serum biomarker changes predictive of imminent neurotoxicity observed in mice to improve pharmacovigilance and 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. 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 which restores immune surveillance leading to anti-tumor response in a variety of animal models of cancer (License number: L-051-2017/0; issued U.S. patent; 'Peptide-Based Methods for Treating Pancreatic Cancer'). A bioanalytical method to measure such synthetic short HDPs in complex biological specimens for PK and toxicokinetic studies has been developed (under review). 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. Formulation and PK studies are under way to evaluate RP-182 as a preclinical first-in-class innate checkpoint drug candidate. Based on prior work with RP-182, CD206 small molecule innate checkpoint modulators have been identified after screening large chemical libraries with a pharmacophore model derived from RP-182 docked onto CD206. The lead series is significantly more potent than RP-182, and has undergone SAR-guided optimization and PK evaluation which showed excellent biodistribution and a preliminary safe toxicity profile. An Employee Invention Report (NIH Ref.: E-105-2019; 'Small Molecules with Selective Activity Against the M2 Phenotype of Macrophages') has been filed and following delineation of the chemical space of the lead series on its target CD206 a filing for Composition of Matter is planned. New drug designs with RP-182 are manufactured which include the coupling of RP-182 to PD-1/PD-L1 antibodies generated via [3+2] cycloaddition (click- de-click-like reaction) followed by a retro- Diels-Alder reaction or to a scaffold in preparation of creating tripod immuno-oncology agents (coupled immunocytokines, checkpoint regulators, and RP-182 to one scaffold). 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 myelofibrotic CAFs) in these tumors which rapidly returns to pre-treatment values creating uncertainty about during, and possibly rationale, for prolonged administration of stromal modulation therapy. The conducted preclinical work also 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' is testing the concept in patients. 4. KRAS-mutational isotype directed molecular therapy. A CTEP-sponsored phase II pilot study treating patients whose tumors harbor G12R KRAS isoform somatic variants (NCT03040986; Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations) has not proceeded to the 2nd stage due to lack of efficacy of the selected MEK inhibitor. This clinical study was a direct translation of our laboratory findings of increased sensitivity of KRAS G12R mutational isoform-harboring cell lines and patient-derived xenotransplantation models. 5. Target deconvolution of a multikinase inhibitor with anti-metastatic properties identifies TAOK3 as a key contributor to a cancer stem cell-like phenotype. While this work adds to the understanding how to target cancer stem-like cells, due to due concerns about the toxicity of the multikinase inhibitor NCGC00188382 (inhibitor #1), the molecule was not selected for further preclinical studies or clinical translation.

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未满足的更有效治疗的医疗需求。近一年来开展的药物开发项目取得的科研成果包括：1。metarrestin的临床前和临床开发（美国专利申请E-114-2018-0-US-01 （738874 BIO.0353-18）“metarrestin用于治疗胰腺癌”）。甲氧雷斯汀是一种新型的小分子抑制剂，对癌细胞的转移表型具有选择性活性。它在胰腺和其他癌症转移模型中具有令人印象深刻的活性。在NCATS弥合介入发展差距（bridges）项目的支持下，包括GLP在啮齿动物和非啮齿动物物种中的毒性动力学研究以及临床级甲脲素胶囊的生产在内的IND包已经完成。在5个物种中进行的PK研究表明，甲氨脲素是一种低清除率的化合物（正在审查中），具有高生物利用度和生物分布，药物引起的神经事件包括癫痫是该化合物的主要临床毒性。已计算出每48小时口服1mg的安全首次人体起始剂量水平，该剂量处于或接近临床前研究预测的甲氨restin治疗范围。I期方案已获得NCI ccr科学审查委员会的批准，预计将于2019年第三季度提交IND申请。临床前研究发现，肿瘤中上调的翻译延伸因子eEF1A2是甲氨restin的分子靶点，干扰核糖体生物发生是该药诱导的一种新的作用机制。甲骨restin的作用机制与eEF1A2的翻译后修饰和参与rRNA加工和核糖体形成的PES1-BOP1复合物的破坏有关。包括eEF1A2基因敲除小鼠在内的基因组编辑小鼠已经产生，这些小鼠表现出甲脲素神经毒性的临床表型。这些小鼠模型计划用于(1)建立甲他雷斯汀治疗后的信息PK/TK特征，这些特征可预测神经表型，如癫痫发作和癫痫性脑病，这些可能是甲他雷斯汀治疗的副作用；(2)验证组织和循环生物标志物，以及神经和神经病理模式，由甲氨restin治疗后的表型评估得出；(3)询问参加I期临床试验的癌症患者的血清，以检测小鼠中观察到的PK/PD相关性和预测即将发生的神经毒性的血清生物标志物变化，以提高甲氨restin抗癌治疗的药物警惕性和安全性。这些临床前安全性研究的补充是药物化学方面的努力，以开发一种改良的甲脲素衍生物作为后备候选物，具有改进的物理化学性质，以降低穿过血脑屏障的能力，降低神经系统副作用的风险。2. 靶向CD206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，从而在多种癌症动物模型中恢复免疫监视，从而导致抗肿瘤反应（许可号：L-051-2017/0；已颁发的美国专利；“肽类方法治疗胰腺癌”）。已经开发了一种生物分析方法来测量复杂生物标本中这种合成的短HDPs，用于PK和毒性动力学研究（正在审查中）。RP-182被证明是免疫治疗（抗pd - l1）或化疗联合治疗免疫“冷”癌症的一种有吸引力的药物，目前这些癌症对T细胞激活通过免疫检查点抑制没有反应。RP-182作为临床前一流先天检查点候选药物的配方和PK研究正在进行中。基于先前对RP-182的研究，利用与CD206对接的RP-182衍生的药效团模型筛选大型化学文库后，发现了CD206小分子先天检查点调节剂。该先导系列比RP-182更有效，并经过sar引导优化和PK评估，显示出良好的生物分布和初步的安全毒性。一份员工发明报告（NIH Ref.: E-105-2019；“对巨噬细胞M2表型具有选择性活性的小分子”）已经提交，并且在其靶标CD206的先导系列化学空间描述之后，计划提交物质组成的申请。利用RP-182设计的新药包括将RP-182与PD-1/PD-L1抗体偶联，这些抗体通过[3+2]环加成（click- de-click-样反应）产生，然后进行retro- Diels-Alder反应或与支架偶联，以制备三脚架免疫肿瘤药物（将免疫细胞因子、检查点调节剂和RP-182偶联到一个支架上）。3. 胰腺癌间质调节与抗癌联合治疗。在胰腺癌转基因动物的临床前研究表明，TGFbeta抑制和吉西他滨共同抑制肿瘤生长，延长小鼠生存期。tgf - β抑制介导的基质调节通过改变这些肿瘤中癌症相关成纤维细胞（CAF）表型（增加炎症性与骨髓纤维化CAF的比例）增加灌注，这些肿瘤迅速恢复到治疗前的值，从而在基质调节治疗期间和可能的理由上产生不确定性。所进行的临床前工作还确定了免疫检查点PD-L1的上调是该方法的耐药机制之一。临床方案“M7824 （MSB0011359C）联合吉西他滨治疗既往治疗过的晚期胰腺腺癌成人的IB/II期单臂研究”正在患者中测试这一概念。4. kras突变同型定向分子治疗。由于所选MEK抑制剂缺乏疗效，cep赞助的一项治疗肿瘤中含有G12R KRAS异体变异体患者的II期试点研究（NCT03040986；硫酸塞鲁美替尼治疗KRAS G12R突变的局部晚期或转移性胰腺癌患者）尚未进入第二阶段。这项临床研究直接转化了我们的实验室发现，即KRAS G12R突变异种异种移植细胞系和患者来源的异种移植模型的敏感性增加。5. 具有抗转移特性的多激酶抑制剂的靶反褶积鉴定出TAOK3是癌症干细胞样表型的关键贡献者。虽然这项工作增加了对如何靶向癌症干细胞样细胞的理解，但由于对多激酶抑制剂NCGC00188382（抑制剂#1）的毒性的担忧，该分子未被选择用于进一步的临床前研究或临床翻译。