Preclinical drug development in pancreatic cancer

胰腺癌的临床前药物开发

• 批准号: 10926173
• 负责人: Udo Rudloff
• 金额: $ 252.82万
• 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/10926173
• 关键词: Achievement; Address; Antitumor Response; Biological; Biological Availability; Biological Markers; Blindness; CTLA4 gene; Cancer Model; Canis familiaris; Cell Nucleolus; Cells; Chemicals; Chromatin; Chromosomes; Clinical; DNA Sequence Alteration; Data; Dedications; Development; Developmental Therapeutics Program; Diabetic Retinopathy; Disease; Disseminated Malignant Neoplasm; Dose; Dose Limiting; Drug Combinations; Drug Design; Drug Kinetics; Education; Electrocardiogram; Enhancers; Environment; Epigenetic Process; Eye diseases; Fibrosis; Future; Genetic Transcription; Genome; Hemorrhage; Human; Immune; Immune Targeting; Immunologics; Immunooncology; Inflammatory; Interferon Type I; Intramural Research Program; Investigational Therapies; Laboratories; Ligation; Liquid substance; Liver Fibrosis; Macrophage; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measurement; Mediating; Medical; Molecular Target; Monitor; Mus; Mutation; Myeloid Cells; National Center for Advancing Translational Sciences; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Nucleolar Proteins; Nucleoplasm; Oral; Organ; PD-1/PD-L1; Pancreas; Patient Selection; Patients; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Physical condensation; Plasma; Polymerase; Population; Pre-Clinical Model; Preclinical Drug Development; Prevalence; Process; Pyrazines; Pyrimidine; Regimen; Regulation; Reporting; Repression; Research; Ribosomal RNA; Risk; Safety; Schedule; Serious Adverse Event; Serum; Signal Transduction; Solid; Solid Neoplasm; T-Cell Activation; Tablets; Technology; Testing; Therapeutic; Therapeutic Equivalency; Toxic effect; Toxicokinetics; Transcript; Translation Process; Translational Research; Tumor-associated macrophages; United States National Institutes of Health; Untranslated RNA; Work; analog; cancer cell; cancer classification; cancer immunotherapy; cell killing; checkpoint inhibition; clinical candidate; clinical center; clinical translation; cohort; design; drug candidate; drug development; drug discovery; effective therapy; efficacy study; first-in-human; human study; immune checkpoint; improved; in silico; innate immune checkpoint; mannose receptor; manufacture; molecular marker; non-alcoholic fatty liver disease; novel; novel anticancer drug; phase 1 study; phase 1 testing; phase I trial; pre-clinical; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; predicting response; predictive marker; programs; proliferative diabetic retinopathy; promoter; recruit; research clinical testing; resistance mechanism; response; safety study; sarcoma; scaffold; screening; small molecule; small molecule inhibitor; small molecule libraries; therapeutic development; therapy development; tumor

My laboratory aims to address the unmet medical need for more effective treatments for patients afflicted by pancreas and other solid organ cancers 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. 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 six 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 exceeding efficacious levels of prior preclinical efficacy studies in plasma and do not carry risk(s) of drug accumulation. No clinical dose-limiting toxicities have occurred so far in patients treated with metarrestin. However, two patients had prolongations of their QTc intervals observed during EKG monitoring which are currently followed as possible metarrestin-related suspected unexpected serious adverse reaction (SUSAR). Recent preclinical work has shown that metarrestin inhibits polymerase I transcription via disruption of liquid phase-phase separation (LPPS) in the nucleolus. LPPS is regulated by biomolecular condensates (BMCs) which direct the unique ultrastructure of the nucleolus necessary for rRNA synthesis, rRNA processing, and the assembly of the SSU processome. Reduced 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, leads to disassembly of the PNC and translocation of PNC components into the nucleoplasm. PNCTR transcript levels, genomic alterations of the PNCTR locus on chromosomes 21, PNC prevalence as well as mutations in intrinsically disordered regions (IDRs) of nucleolar proteins which are involved in the regulation of LPPS are currently evaluated as biomarkers to predict response to metarrestin. 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 clinical testing, a NIH FAES course summarizing key milestones in translational processes of metarrestin's development has been designed and is now in its third year. 2. Preclinical development and clinical translation of small molecule-based innate checkpoint modulators targeting CD206 on tumor associated macrophages (TAMs). Prior work of ours has shown that the mannose receptor CD206 on M2-like TAMs functions as an immune checkpoint. CD206 activation reprograms TAMs from a pro-tumor, immune suppressive to an anti-tumor, inflammatory phenotype and CD206 ligation is able to reinvigorate innate anti-tumor responses via direct cancer cell phagocytosis. Due to its restricted expression, 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 has via in silico screening of large chemical libraries identified a phenyl-imidoazo[2,3] pyrazine-based small molecule drug candidate, NCGC72, which has recently been selected for IND enabling studies and clinical translation by the Therapeutic Development Branch (TDB), NCATS. NCGC72 induces tumor regressions in murine and human preclinical cancer models. NCGC72 has limited off-target activity and showed a large therapeutic window in preclinical safety and toxicity studies. NCGC72 is currently evaluated in a dedicated phase I/II study for safety, tolerability, and efficacy in sarcoma-bearing dogs. After acceptance of NCGC72 as a clinical candidate by the TDB, NCATS, manufacturing of GMP drug substance for both GLP safety and toxicokinetic studies and clinical grade product for human phase I testing has commenced with IND filing estimated in 2025 and start of clinical testing in 2026. Additional preclinical work has focused on NCGC72's dual mechanism of action of (1) M2-like macrophage killing and (2) the reprogramming of alternatively activated, M2-like TAMs into a proinflammatory phenotype via the induction of an interferon type I response. Current mechanism of action studies have shown that blockade of NCGC72-mediated M2-like cell killing recruits TAMs for enhanced reprogramming, cancer cell phagocytosis, and tumor control, and that the interferon type I response triggered by NCGC72, which is essential for M2-to-M1-like switching, induces a select number of epigenetic changes releasing repression of closed chromatin of promotors and enhancers in alternatively activated, M2-like TAMs. Current work expanding on these findings is studying (1) rationale designed drug combinations of immuno oncology agents with NCGC72, and (2) molecular markers to select tumors most likely to respond to NCGC72. Spurned by recent reports that CD206 positive macrophages mediate disease-causing processes in non-malignant conditions like eye disease or type II diabetes, we previously evaluated NCGC72 in a preclinical model of proliferative diabetic retinopathy. NCGC72 substantially reduced sub-retinal fibrosis and vitriol hemorrhages, causes of blindness in diabetic retinopathy. To extend possible indications of NCI's proprietary CD206 small molecule technology NCGC72 for the treatment of non-malignant diseases further, we are currently evaluating NCGC72 in a preclinical model of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis.

我的实验室旨在通过开发新的癌症药物来满足胰腺癌和其他实体器官癌症患者的未满足的更有效治疗的医疗需求。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。 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。前六组接受metarrestin治疗的患者的PK数据表明，先用负荷剂量再用维持剂量的方案是安全的，该方案达到的人体等效治疗水平超过了先前临床前血浆疗效研究的有效水平，并且不存在药物蓄积的风险。迄今为止，接受metarrestin治疗的患者尚未出现临床剂量限制性毒性。然而，两名患者在心电图监测期间观察到 QTc 间期延长，目前正在追踪可能与metarrestin 相关的疑似意外严重不良反应（SUSAR）。最近的临床前研究表明，metarrestin 通过破坏核仁中的液相分离 (LPPS) 来抑制聚合酶 I 转录。 LPPS 受生物分子凝聚体 (BMC) 调节，生物分子凝聚体指导 rRNA 合成、rRNA 加工和 SSU 加工组组装所需的独特核仁超微结构。富含嘧啶的非编码转录物 (PNCTR) 长非编码 RNA (lnRNA) 的表达水平降低，该长链非编码 RNA (lnRNA) 是 PNC 的重要支架，由聚合酶 I 转录，导致 PNC 解体和 PNC 成分易位到核质中。 PNCTR 转录水平、21 号染色体上 PNCTR 基因座的基因组改变、PNC 患病率以及参与 LPPS 调节的核仁蛋白本质无序区域 (IDR) 的突变目前被评估为预测对 Metarrestin 反应的生物标志物。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、再到临床测试，NIH FAES课程总结了metarrestin开发转化过程的关键里程碑，现已设计，现已进入第三个年头。 2.针对肿瘤相关巨噬细胞（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和临床转化。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。 CD206 激活将 TAM 从促肿瘤、免疫抑制性重新编程为抗肿瘤、炎症表型，并且 CD206 连接能够通过直接癌细胞吞噬作用重振先天抗肿瘤反应。由于其表达受限，CD206 成为免疫“冷”癌症中新型癌症免疫治疗的一个有吸引力的靶标，这些癌症目前不通过免疫检查点抑制对 T 细胞激活做出反应。我们的团队通过对大型化学库进行计算机筛选，确定了一种基于苯基亚氨基偶氮[2,3]吡嗪的小分子候选药物 NCGC72，该药物最近已被 NCATS 治疗开发部门 (TDB) 选择用于 IND 启动研究和临床转化。 NCGC72 在小鼠和人类临床前癌症模型中诱导肿瘤消退。 NCGC72 的脱靶活性有限，并且在临床前安全性和毒性研究中显示出较大的治疗窗口。目前正在一项专门的 I/II 期研究中评估 NCGC72 在患有肉瘤的狗中的安全性、耐受性和有效性。在 TDB、NCATS 接受 NCGC72 作为临床候选药物后，用于 GLP 安全性和毒代动力学研究的 GMP 原料药以及用于人体 I 期测试的临床级产品的生产已开始，预计将于 2025 年提交 IND 申请，并于 2026 年开始临床测试。其他临床前工作重点关注 NCGC72 的双重作用机制（1）M2 样巨噬细胞 (2) 通过诱导 I 型干扰素反应，将选择性激活的 M2 样 TAM 重新编程为促炎表型。目前的作用机制研究表明，阻断 NCGC72 介导的 M2 样细胞杀伤可招募 TAM 来增强重编程、癌细胞吞噬作用和肿瘤控制，并且 NCGC72 触发的 I 型干扰素反应（对于 M2 到 M1 样转换至关重要）会诱导一定数量的表观遗传变化，释放启动子和增强子封闭染色质的抑制 在替代激活的、类似 M2 的 TAM 中。目前对这些发现进行扩展的工作正在研究 (1) 免疫肿瘤药物与 NCGC72 的药物组合的基本原理设计，以及 (2) 用于选择最有可能对 NCGC72 产生反应的肿瘤的分子标记。最近有报道称 CD206 阳性巨噬细胞介导眼病或 II 型糖尿病等非恶性疾病的致病过程，但我们之前在增殖性糖尿病视网膜病变的临床前模型中评估了 NCGC72。 NCGC72 显着减少了视网膜下纤维化和硫酸出血，这是导致糖尿病视网膜病变失明的原因。为了进一步扩展NCI专有的CD206小分子技术NCGC72治疗非恶性疾病的可能适应症，我们目前正在非酒精性脂肪性肝病（NAFLD）和肝纤维化的临床前模型中评估NCGC72。

项目成果

Loss of PDPK1 abrogates resistance to gemcitabine in label-retaining pancreatic cancer cells.

PDPK1的损失消除了对标签胰腺癌细胞中吉西他滨的抵抗力。

• DOI: 10.1186/s12885-018-4690-1
• 发表时间: 2018-07-31
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Li D;Mullinax JE;Aiken T;Xin H;Wiegand G;Anderson A;Thorgeirsson S;Avital I;Rudloff U
• 通讯作者: Rudloff U

A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers.

一项试点研究评估非CD133大肠癌干细胞作为生物标志物的潜在作用。

• DOI: 10.7150/jca.4542
• 发表时间: 2012
• 期刊: Journal of Cancer
• 影响因子: 3.9
• 作者: Langan RC;Mullinax JE;Ray S;Raiji MT;Schaub N;Xin HW;Koizumi T;Steinberg SM;Anderson A;Wiegand G;Butcher D;Anver M;Bilchik AJ;Stojadinovic A;Rudloff U;Avital I
• 通讯作者: Avital I

Label-retaining liver cancer cells are relatively resistant to sorafenib.

• DOI: 10.1136/gutjnl-2012-303261
• 发表时间: 2013-12
• 期刊: Gut
• 影响因子: 24.5
• 作者: Xin HW;Ambe CM;Hari DM;Wiegand GW;Miller TC;Chen JQ;Anderson AJ;Ray S;Mullinax JE;Koizumi T;Langan RC;Burka D;Herrmann MA;Goldsmith PK;Stojadinovic A;Rudloff U;Thorgeirsson SS;Avital I
• 通讯作者: Avital I

TYRO3-mediated regulation of MITF: a novel target in melanoma?

TYRO3 介导的 MITF 调节：黑色素瘤的新靶点？

• DOI: 10.1111/j.1755-148x.2009.00649.x
• 发表时间: 2010
• 期刊: Pigment cell & melanoma research
• 影响因子: 4.3
• 作者: Rudloff,Udo;Samuels,Yardena
• 通讯作者: Samuels,Yardena

Surgery for Li Fraumeni syndrome: pushing the limits of surgical oncology.

李弗劳梅尼综合征的手术：突破肿瘤外科的极限。

• DOI: 10.1097/coc.0b013e3182880bc5
• 发表时间: 2015
• 期刊: American journal of clinical oncology
• 作者: Langan,RussellC;Lagisetty,KiranH;Atay,Scott;Pandalai,Prakash;Stojadinovic,Alexander;Rudloff,Udo;Avital,Itzhak
• 通讯作者: Avital,Itzhak