Preclinical evaluation of the efficacy and mechanism of action for an alkylated polyamine analogue diethylnorspermine in treating pheochromocytoma/paraganglioma

烷基化多胺类似物二乙基去甲精胺治疗嗜铬细胞瘤/副神经节瘤的疗效和作用机制的临床前评估

• 批准号: 10188669
• 负责人: Hans K. Ghayee
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188669
• 关键词: Address; Agreement; Anabolism; Animals; Basic Science; Biochemical; Biochemistry; Biological Markers; Biological Models; Biological Process; Breast Cancer Treatment; Cancer Model; Cancer Patient; Catecholamines; Cell Line; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cyclophosphamide; DL-alpha-Difluoromethylornithine; DNA Repair; Dacarbazine; Data; Disease; Disease Resistance; Dose; Event; Extra-Adrenal Pheochromocytoma; FDA approved; Florida; Foundations; Future; Genetic; Genomics; Growth; Hormone secretion; Human; In Vitro; Knowledge; Legal patent; Light; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolism; Metastatic Pheochromocytoma; Mus; Mutation; Neoplasm Metastasis; ODC1 gene; PC12 Cells; Paraganglioma; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phase II Clinical Trials; Pheochromocytoma; Polyamines; Probability; Prognosis; Sampling; Solid; Succinate Dehydrogenase; Succinates; Therapeutic; Time; Translating; Tumor Tissue; Universities; Up-Regulation; Vincristine; Work; Xenograft Model; Xenograft procedure; analog; base; burden of illness; cancer therapy; cell growth; effective therapy; efficacy evaluation; experimental study; follow-up; improved; in vivo; inhibitor/antagonist; innovation; metabolome; metabolomics; mouse model; mutant; neoplastic cell; neuroendocrine cancer; new therapeutic target; novel; optimal treatments; phase II trial; preclinical evaluation; response; standard of care; tissue culture; treatment duration; treatment effect; treatment response; tumor; tumor metabolism

Abstract: Adrenal pheochromocytomas (PCC) and extra-adrenal pheochromocytomas (paragangliomas, (PGL)) are rare neuroendocrine malignancies that carry high disease burden due to excessive hormone secretion by tumor cells and high probability of metastasis [1]. Metastatic disease is especially prevalent in carriers of deleterious mutations in the subunits of succinate dehydrogenase complex (SDHx), which makes this patient group the highest treatment priority [2, 3]. The absence of effective treatment for this lethal disease remains a major clinical challenge. Our preliminary analysis of the PCC/PGL metabolome in cell lines and patient tumor samples demonstrated up-regulation of the polyamine pathway upon SDHx deficiency. N- alkylated polyamine analogue N1, N11diethylnorspermine (DENSPM) offers an exciting and innovative pharmacological approach to targeting over-reactive polyamine pathway. DENSPM has been FDA approved for clinical trial use (Phase I [4, 5]), and was evaluated for treatment of breast cancer malignancies in Phase II trial [6]. In agreement with the metabolomic analysis, our preliminary data demonstrate that DENSPM polyamine analogue is highly effective at targeting PCC-derived cells, both in vitro and in the mouse xenograft model. Importantly, DENSPM appears to be remarkably potent against PCC/PGL tumor cells with a loss of the SDHx function that present the highest clinical concern. Based on our preliminary data and the follow-up work outlined in this application, an opportunity would open for a Phase II clinical trial at the University of Florida (UF) to treat patients with metastatic PCC/PGL using DENSPM as UF has an active patent on this drug. To proceed to the clinical trial it is necessary to directly compare DENSPM to the current standard of care treatment and to evaluate the relevant biomarkers, as is proposed here. We propose that augmented polyamine metabolism that we now uncovered in SDHx-deficient tumors (tissue and cells) could be a vulnerability point unique to these (and not other) tumors that could be successfully targeted pharmacologically with DENSPM. This study will put forward the first safe and effective pharmacological treatment against metastatic tumors with a loss of the SDHx function and transform the lives of many patients urgently needing treatment.

翻译后摘要：肾上腺嗜铬细胞瘤（PCC）和肾上腺外嗜铬细胞瘤（副神经节瘤， （PGL））是罕见的神经内分泌恶性肿瘤，由于激素过多， 肿瘤细胞的分泌和高转移概率[1]。转移性疾病尤其普遍， 琥珀酸脱氢酶复合物（SDHx）亚基中有害突变的携带者， 该患者组的治疗优先级最高[2，3]。对这种致命疾病缺乏有效治疗 仍然是一个重大的临床挑战。我们对细胞系中PCC/PGL代谢组的初步分析， 患者肿瘤样品显示SDHx缺乏时多胺途径的上调。不，不 烷基化多胺类似物N1，N11二乙基去甲精胺（DENSPM）提供了一种令人兴奋的创新 药理学方法靶向过度反应性多胺途径。DENSPM已获得FDA批准 用于临床试验（I期[4，5]），并在II期评价了乳腺癌恶性肿瘤的治疗 审判[6]。与代谢组学分析一致，我们的初步数据表明，DENSPM 多胺类似物在体外和小鼠异种移植物中均可高效靶向PCC衍生细胞 模型重要的是，DENSPM似乎对PCC/PGL肿瘤细胞非常有效， SDHx功能是临床上最关注的问题。根据我们的初步数据和后续工作， 在本申请中概述，佛罗里达大学将有机会进行II期临床试验 (UF)使用DENSPM作为UF治疗患有转移性PCC/PGL的患者具有该药物的有效专利。到 进行临床试验时，有必要直接将DENSPM与当前的护理标准进行比较 治疗和评估相关的生物标志物，如这里所提出的。我们建议， 我们现在在SDHx缺陷肿瘤（组织和细胞）中发现的多胺代谢可能是一种新的代谢途径。 这些（而不是其他）肿瘤特有的脆弱点可以成功地靶向 关于DENSPM本研究将提出首个安全有效的药物治疗方案， 转移性肿瘤的SDHx功能丧失，改变了许多患者的生活，迫切需要 治疗

项目成果

Metabolomics in paraganglioma: applications and perspectives from genetics to therapy.

• DOI: 10.1530/erc-22-0376
• 发表时间: 2023-06-01
• 期刊: ENDOCRINE-RELATED CANCER
• 影响因子: 3.9
• 作者: Richter, Susan;Garrett, Timothy J.;Bechmann, Nicole;Clifton-Bligh, Roderick J.;Ghayee, Hans K.
• 通讯作者: Ghayee, Hans K.