Sirpiglenastat

科技日报北京10月9日电 （记者张佳欣）美国纽约大学朗格尼健康中心的新研究发现，通过阻止癌细胞获得燃料，一种新的药物组合安全地限制了小鼠胰腺癌的生长。相关论文9日在线发表于《自然·癌症》杂志。该发现揭示了胰腺癌细胞如何寻找替代燃料来源，以避免饥饿并保持生长。当由血液供应的氧气、血糖和其他资源变得稀缺，快速生长的胰腺肿瘤密度越来越高，会切断自身的血液供应。在这种环境下，转换“燃料”的能力导致了胰腺癌的致命性。胰腺导管腺癌（PDAC）细胞使用谷氨酰胺酶将氨基酸谷氨酸转化为谷氨酰胺，这种形式可作为燃料以维持肿瘤的快速生长。新药物组合旨在防止PDAC细胞发生这种转换。DRP-104是一种肿瘤靶向前体药物，它通过模仿谷氨酰胺来让癌细胞饥饿，谷氨酰胺广泛抑制所有使用谷氨酰胺的代谢途径。在当前研究中，单独使用DRP-104治疗可降低胰腺癌小鼠模型中PDAC的生长速度。重要的是，研究团队还发现，DRP-104导致PDAC细胞陷入代谢危机，然而，PDAC细胞通过一种称为细胞外信号调节激酶（ERK）的蛋白质增加信号传导，可弥补谷氨酰胺代谢的损失。当该团队将DRP-104与一种阻断ERK信号通路的现有药物曲美替尼结合使用时，与单独使用DRP-104治疗相比，进一步提高了胰腺癌小鼠模型的生存率。研究人员表示，这些药物已进行了临床试验，如果被证明有效，最终可能改善患者的治疗结果。未来，研究团队将了解谷氨酰胺的拮抗作用如何影响胰腺癌中其他适应性营养物的清除机制，以及这些机制是否也可以成为治疗靶标。

[09-October-2023] NEW YORK, Oct. 9, 2023 /PRNewswire/ -- A new combination of treatments safely decreased growth of pancreatic cancer in mice by preventing cancer cells from scavenging for fuel, a new study finds. Led by researchers at NYU Grossman School of Medicine, its Department of Radiation Oncology, and the Perlmutter Cancer Center, the work builds on prior discoveries at NYU Langone that revealed how pancreatic cancer cells, to avert starvation and keep growing, find alternate fuel sources. Normally supplied by the bloodstream, oxygen, blood sugar, and other resources become scarce as the increasing density of fast-growing pancreatic tumors cuts off their own blood supply. In this environment, the ability to switch fuels contributes to the deadliness of pancreatic cancers. Published online October 9 in Nature Cancer, the new study involves a drug designed to prevent pancreatic ductal adenocarcinoma (PDAC) cells from one such switch. PDAC cells use the enzyme glutaminase to convert the amino acid glutamate into glutamine, a form that can be burned for fuel to sustain rapid tumor growth. Drugs designed to block glutaminase, however, have been shown to cause cancer cells to switch to still other scavenging pathways. For this reason, the field next looked at experimental treatments like DRP-104, designed by Dracen Pharmaceuticals, a new "prodrug" form of the compound 6-Diazo-5-oxo-L-norleucine (DON) that is preferentially activated within tumors to overcome toxicity issues seen with DON. DON was designed to starve cancer cells by mimicking glutamine, which unlike glutaminase blockers, broadly inhibits all metabolic pathways that use glutamine. Currently in clinical trials against non-small cell lung cancer, DRP-104 cannot be burned as fuel, but clings to the same enzymes as glutamine. In the current study, DRP-104 treatment alone decreased PDAC growth in mouse models of pancreatic cancer. Importantly, the current team also found that PDAC cells pushed into metabolic crisis by DRP-104 increase signaling through a protein called extracellular signal-regulated kinase or ERK, to make up for their loss of glutamine metabolism. When the team combined DRP-104 with an existing drug that blocks the ERK signaling pathway, trametinib, it further improved survival in pancreatic cancer mouse models compared to DRP-104 treatment alone. "Despite a decade of advances in understanding how cancer cells switch fuel sources, we have not yet effectively translated this into clinically relevant therapies," says corresponding study author Alec Kimmelman, MD, PhD, the Anita Steckler and Joseph Steckler Chair of Radiation Oncology at NYU Langone Health. "Broad antagonism of metabolic pathways with glutamine analogs may provide another mode of attack against these highly resistant tumor cells. The fact that such drugs are already being tested in the clinic makes us hopeful that we may finally see patient outcomes improve, if this approach proves to be effective in clinical trials." Moving forward, the research team will seek to understand how glutamine antagonism impacts other adaptive nutrient scavenging mechanisms in pancreatic cancers and whether these could be targeted as well. The success of such approaches will depend on careful balancing of improved therapeutic efficacy and toxicity from the potential effects on normal tissues, Kimmelman adds. Along with Kimmelman, authors from Perlmutter Cancer Center and the Department of Radiation Oncology at NYU Langone were Joel Encarnación-Rosado, Albert Sohn, Douglas Biancur, Elaine Lin, Victoria Osorio-Vasquez, and Diana González-Baerga. Also Perlmutter authors were Ende Zhao and Diane Simeone. Also authors of the study were Tori Rodrick and Drew Jones from the Division of Advanced Research Technologies at NYU Grossman School of Medicine; Seth Parker from the Department of Biochemistry & Molecular Biology at University of British Columbia in Vancouver, and Yumi Yokoyama and Robert Wild from Dracen Pharmaceuticals, Inc., of San Diego. Funding for the study came from Perlmutter Cancer Center support grant P30CA016087 and National Cancer Institute grants P01A1080192, P01CA117969, R35CA232124, P30CA016087-38, 1R01CA251726-01A1; as well as from the Lustgarten Foundation, Stand Up to Cancer, and the Howard Hughes Medical Gilliam Fellowships. Kimmelman has financial interests in Vescor Therapeutics, is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals and OncoRev, and has been a consultant for Deciphera and Abbvie. These relationships are being managed according with the policies of NYU Langone Health. Yokoyama and Wild are employees of, and have ownership in, Dracen Pharmaceuticals, maker of DRP-104. Contact: Gregory Williams gregory.williams@nyulangone.org