Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer.
Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer.
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DOI：
10.34067/kid.0000282019
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发表时间：
2020-05-28
期刊：
影响因子：
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通讯作者：
Weiss RH
中科院分区：
文献类型：
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作者：
Trott JF;Aboud OA;McLaughlin B;Anderson KL;Modiano JF;Kim K;Jen KY;Senapedis W;Chang H;Landesman Y;Baloglu E;Pili R;Weiss RH
肾癌(或肾细胞癌，RCC)是美国第六大最常见的恶性肿瘤，而且发病率正在上升。尽管有新的治疗方法，包括靶向治疗和免疫治疗，但大多数RCC对治疗具有抵抗力。因此，几个实验室一直在评估新的治疗方法，既有使用单一药物的，也有使用组合的。尽管我们之前已经证明了双重PAK4/烟酰胺磷酸核糖基转移酶(NAMPT)抑制剂KPT-9274和免疫检查点抑制剂(CPI)在临床上的有效性，但无论是在临床上还是在肾癌免疫活性动物模型中，都没有对这种组合进行评估。在本研究中，我们使用自发性小鼠肾癌的肾细胞腺癌(RECA)模型。雄性BALB/CJ小鼠皮下注射Renca细胞，在可触及肿瘤后，给予KPT-9274和/或抗程序性细胞死亡1(PDCD1；PD1)抗体治疗21d。对肿瘤进行测量，然后在动物安乐死时将其切除，以供后续研究。我们发现，联合应用KPT-9274和抗PD1抗体可显著降低同种异体移植物的生长，而动物的体重没有明显减轻。这与(小鼠)naprt表达降低有关，表明这些肿瘤对NAMPT的依赖性与我们在人类肾细胞癌中观察到的情况相似。无论治疗条件如何，肿瘤的组织学表现为实质性的坏死，抗体染色的肿瘤细胞的流式细胞术分析表明，KPT-9274和抗PD1抗体的增强治疗作用不是由T细胞向肿瘤的渗透所驱动的。这项研究强调了Renca模型在评估对KPT-9274和检查点抑制剂(CPI)的免疫学反应方面的潜力，并建议联合使用这种疗法可以提高肾癌的疗效，而不是单独使用CPI。
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer. In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti–programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies. We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors. This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.