Preclinical drug development in pancreatic cancer

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对更有效治疗的未满足的医疗需求。近一年来开展的药物开发项目取得的科研成果包括：1。甲氨restin临床安全剂量水平的鉴定，甲氨restin是一种靶向转移性癌细胞基因组组织的一流小分子。甲氧雷斯汀是一种新型的、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）。甲氨restin目前用于晚期恶性肿瘤患者，剂量不断增加，以确定药物的安全性和耐受性。来自前两组接受甲氨restin治疗的患者的PK数据表明，负荷剂量后维持剂量的方案是安全的，达到了先前临床前血浆疗效研究中与人类相当的治疗水平，并且在多次给药时不存在药物积累的风险。到目前为止，用甲脲素治疗的患者未发生剂量限制性毒性。然而，2例患者在心电图监测期间出现QTc间隔延长，报告为甲他素相关的疑似意外严重不良反应（SUSAR），目前正在积极随访。临床前研究表明甲骨restin抑制聚合酶I的转录并降低富含嘧啶的非编码转录物（PNCTR）长链非编码RNA （lnRNA）的表达水平，而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的分解，PNC成分易位到核质中。而核仁超微结构成分的分离由于失去了生理相相分离。目前，PNCTR转录水平、13、14、15、21和22号染色体上PNCTR位点的基因组改变、PNC患病率以及pol I转录比率被评估为预测甲脲素应答的生物标志物。药物化学工作已经开始开发一种备选的甲脲素，它通过血脑屏障的能力降低，神经系统副作用的风险降低。认识到甲氧雷斯汀成功临床转化对药物开发基本过程的教育价值，从最初的高含量筛选测试化合物到分解PNC，药物化学运动，临床前工作，IND使能研究，到现在的临床测试，一个总结甲氧雷斯汀开发转化过程中关键里程碑的在线课程已经设计出来，现在是它的第二年。2. 靶向TAMs上CD206的小分子先天检查点调节剂的临床前开发。我们之前的工作已经表明，甘露糖受体CD206在m2样tam上起免疫检查点的作用。CD206通过肽或小分子引线激活，能够将tam从促肿瘤、免疫抑制型重编程为抗肿瘤、炎症型，能够通过直接的癌细胞吞噬来重振先天的抗肿瘤反应。CD206是一种有吸引力的新型癌症免疫治疗靶点，用于目前通过免疫检查点抑制对T细胞激活没有反应的免疫“冷”癌症。我们的团队先前描述了一种一流的合成宿主防御肽RP-182，它激活CD206并重新编程实体器官肿瘤中的TAM。利用连接CD206受体界面的RP-182衍生的药效团模型对大型化学文库进行了硅筛选，确定了基于苯基咪唑[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很大的治疗窗口。在成功竞争CCR药物开发联盟（DDC）的资源以进一步进行临床前开发和临床转化之后，在申请支持IND研究之前，已经开始了专门的I/II期研究，评估患有肉瘤的狗的安全性、耐受性和有效性。设计了NCGC00413972用于临床级原料药生产的放大合成方案。额外的临床前工作表明NCGC00413972具有双重功能；NCGC00413972通过激活NF-kB信号和早期炎症基因反应诱导M2巨噬细胞杀伤。另一方面，NCGC00413972治疗后，内化CD206受体诱导干扰素I型反应，将M2重编程为m1样巨噬细胞，诱导癌细胞吞噬，提高抗肿瘤活性。目前通过NCGC00413972提高CD206先天免疫检查点治疗疗效的作用机制研究探索了(1)像NCGC00413972这样具有协同作用机制的免疫肿瘤药物的组合，以及(2)选择CD206阳性免疫特征最有可能对NCGC00413972产生反应的肿瘤。最近有报道称CD206阳性巨噬细胞介导非恶性疾病（如眼病、传染病或II型糖尿病）的致病过程，但我们在增殖性糖尿病视网膜病变的临床前模型中评估了NCGC00413972。NCGC00413972显著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。作为肿瘤外CD206检查点调节剂的首个适应症，我们通过申请专利apple E-167-2021 (MBHB 21-0949-PRO)，保护了NCI专有的CD206小分子技术NCGC00413972在糖尿病视网膜病变治疗中的可能作用。

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.