Abstract A30: Activation of GCN2 by HC-7366 results in significant anti-tumor efficacy as monotherapy and in combination with Venetoclax in AML models

IF 11.5 Q1 HEMATOLOGY
Feven Tameire, P. Wojnarowicz, S. Fujisawa, Sharon Huang, O. Reilly, C. Dudgeon, Nick Collette, J. Drees, Kathryn T. Bieging-Rolett, Takashi O. Kangas, Weiyu Zhang, M. Fumagalli, Iman Dewji, Yunfang Li, Anissa S. H. Chan, Xiaohong X. Qiu, B. Harrison, Ashley LaCayo, K. Staschke, A. C. Rigby, S. Ramurthy, E. Lightcap, D. Surguladze, N. Bose
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引用次数: 0

Abstract

The integrated stress response (ISR) is an adaptive signaling pathway that cells utilize to respond to a wide range of extrinsic and intrinsic stresses, many of which are important for tumorigenesis. Activation of ISR plays a dual role in cell fate decisions; while the ISR promotes survival, prolonged activation of ISR induces apoptosis. Activation of General Control Nonderepressible 2 (GCN2), an ISR kinase that senses and responds to nutrient stress conditions results in anti-tumor activity. We are developing HC-7366, a first-in-class, first-in-human GCN2 activator, and are currently evaluating it in a phase 1 clinical trial in solid tumors (NCT05121948). Here we present a series of studies characterizing the antitumor effects of HC-7366 in acute myeloid leukemia (AML). Higher expression of GCN2 and ISR markers such as ATF4 has been observed in primitive or minimally differentiated AML cells, suggesting that AML may be particularly sensitive to HC-7366. Encouragingly, in vivo efficacy studies in MOLM-16 and KG-1 tumor models showed 100% complete response and 100% tumor growth inhibition, respectively. Analysis of tumors from treated mice by IHC demonstrated activation of ISR as evidenced by increased expression of the ATF4 targets, ASNS and PSAT1, confirming that HC-7366 is functioning as a GCN2 activator in vivo. In the MV4-11 model, a differentiated subtype of AML that shows limited response to venetoclax, the combination of HC-7366 and venetoclax produced strong benefit resulting in 26% tumor regression. Enhanced activation of ISR pathway was again observed when HC-7366 was combined with venetoclax. HC-7366 treatment also impacted possible venetoclax resistance mechanisms by increasing the levels of PUMA while reducing levels of S100A8/A9 proteins. To investigate the effects of the compound on primary AML, we performed an ex vivo screen using cells from AML patients and treatment with HC-7366 showed a remarkable decrease in cell proliferation. Furthermore, in a xenotransplantable model of patient-derived AML, we found that HC-7366 significantly reduced mature myeloid (CD33+) AML cells in the bone marrow as compared to standard of care (SOC) agents, including venetoclax. We confirmed that activation of ISR, reduction in cell viability, and inhibition of protein synthesis following treatment with HC-7366 was dependent on GCN2 using CRISPR knockout cells. In addition, HC-7366 reduced mitochondrial respiration in MOLM-16 cells, suggesting effects on cellular bioenergetics. Metabolomics analyses of AML xenograft tumors showed that HC-7366 significantly altered metabolites associated with amino acid metabolism, urea cycle, and oxidative stress. Together, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity in AML as a single agent and in combination with venetoclax, supporting its investigation in clinical trials in patients with AML. Citation Format: Feven Tameire, Paulina M. Wojnarowicz, Sho Fujisawa, Sharon Huang, Owen Reilly, Crissy Dudgeon, Nicholas Collette, Jeremy Drees, Kathryn Bieging-Rolett, Takashi O Kangas, Weiyu Zhang, Maria Fumagalli, Iman Dewji, Yunfang Li, Anissa SH Chan, Xiaohong Qiu, Ben Harrison, Ashley LaCayo, Kirk A. Staschke, Alan C. Rigby, Savithri Ramurthy, Eric S. Lightcap, David Surguladze, Nandita Bose. Activation of GCN2 by HC-7366 results in significant anti-tumor efficacy as monotherapy and in combination with Venetoclax in AML models [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A30.
摘要:HC-7366激活GCN2在AML模型中作为单一治疗和与Venetoclax联合治疗均具有显著的抗肿瘤疗效
综合应激反应(integrated stress response, ISR)是一种适应性信号通路,细胞利用它来响应广泛的外在和内在应激,其中许多应激对肿瘤的发生很重要。ISR的激活在细胞命运决定中起双重作用;虽然ISR促进存活,但ISR的长时间激活会诱导细胞凋亡。GCN2是一种ISR激酶,可感知并响应营养胁迫条件,其激活可导致抗肿瘤活性。我们正在开发HC-7366,这是一种同类首创、首次用于人体的GCN2激活剂,目前正在实体肿瘤的1期临床试验中进行评估(NCT05121948)。在这里,我们提出了一系列研究表征HC-7366在急性髓性白血病(AML)中的抗肿瘤作用。在原始或最低分化的AML细胞中观察到GCN2和ISR标记物如ATF4的高表达,表明AML可能对HC-7366特别敏感。令人鼓舞的是,MOLM-16和KG-1肿瘤模型的体内疗效研究分别显示100%完全缓解和100%肿瘤生长抑制。经免疫组化处理的小鼠肿瘤分析显示,ATF4靶点、ASNS和PSAT1的表达增加,证明了ISR的激活,证实HC-7366在体内发挥GCN2激活剂的作用。在MV4-11模型(一种对venetoclax反应有限的分化亚型AML)中,HC-7366与venetoclax联合使用产生了强大的益处,肿瘤消退率为26%。当HC-7366与venetoclax联合使用时,ISR通路的激活再次增强。HC-7366处理还通过增加PUMA水平同时降低S100A8/A9蛋白水平影响了可能的venetoclax耐药机制。为了研究该化合物对原发性AML的作用,我们使用AML患者的细胞进行了离体筛选,用HC-7366治疗显示细胞增殖显著减少。此外,在患者源性AML的异种移植模型中,我们发现与标准护理(SOC)药物(包括venetoclax)相比,HC-7366显著减少骨髓中成熟髓系(CD33+) AML细胞。我们证实,使用CRISPR敲除细胞,HC-7366处理后,ISR的激活、细胞活力的降低和蛋白质合成的抑制依赖于GCN2。此外,HC-7366降低了MOLM-16细胞的线粒体呼吸,提示对细胞生物能量学有影响。AML异种移植肿瘤的代谢组学分析显示,HC-7366显著改变了与氨基酸代谢、尿素循环和氧化应激相关的代谢物。总之,我们的体外和体内实验结果表明,HC-7366是一种有效的GCN2激活剂,在AML中具有很强的抗肿瘤活性,无论是单独使用还是与venetoclax联合使用,都支持其在AML患者的临床试验中的研究。引用格式:7 . Tameire, Paulina M. Wojnarowicz, Sho Fujisawa, Sharon Huang, Owen Reilly, Crissy Dudgeon, Nicholas Collette, Jeremy Drees, Kathryn Bieging-Rolett, Takashi O Kangas,张卫宇,Maria Fumagalli, Iman Dewji,李云芳,Anissa SH Chan,邱晓红,Ben Harrison, Ashley LaCayo, Kirk A. Staschke, Alan C. Rigby, savthri Ramurthy, Eric S. Lightcap, David Surguladze, Nandita Bose。HC-7366激活GCN2,在AML模型中无论是单独治疗还是与Venetoclax联合治疗,均具有显著的抗肿瘤疗效[摘要]。摘自:AACR特别会议论文集:急性髓性白血病和骨髓增生异常综合征;2023年1月23-25日;费城(PA): AACR;血癌发现[j]; 2009;4(3 -增刊):摘要/ Abstract
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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