YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model.
YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model.
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DOI：
10.3390/cancers14010143
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发表时间：
2021-12-29
期刊：
影响因子：
5.2
通讯作者：
Lang D
中科院分区：
文献类型：
--
作者：
Huang L;Zhai Y;Fajardo CD;Lang D
黑色素瘤的治疗选择是有限的。在之前的一项研究中，我们发现小分子化合物YK-4-279在黑色素瘤小鼠模型中阻断了肿瘤进展。肿瘤诱导和药物给药在以前的工作中同时发生。我们目前研究的目的是测试YK-4-279在已经开始但未进展的黑色素瘤病变小鼠中的疗效。我们已经发现，YK-4-279仍然能够显著减弱黑色素瘤进展，尽管没有达到先前试验的程度。使用与人类疾病相关的临床前体内小鼠模型，我们的研究结果支持YK-4-279有希望作为黑色素瘤治疗的选择。需要更多的选择来有效治疗黑色素瘤。在先前的研究中，我们发现小分子药物YK-4-279几乎完全抑制了BrafCA; Tyr-CreERT 2;Ptenflox/flox转基因小鼠模型中的肿瘤进展。YK-4-279对肿瘤起始没有影响，但阻断了侵袭性黑色素瘤的进展。我们目前的研究被设计为治疗模型，其中在色素性病变形成期间施用YK-4-279。研究设计包括使用三个组：（1）仅接受DMSO而没有药物的对照组（MOCK），（2）在我们先前的研究中在肿瘤诱导时施用YK-4-279的小鼠（YK-4-279），和（3）在肿瘤起始期间治疗的小鼠（YK-4-279延迟）。虽然MOCK小鼠具有肿瘤进展，但YK-4-279和YK-4-279延迟组均具有显著的进展阻断或延迟。YK-4-279组中的大多数小鼠具有进展阻断，而YK-4-279延迟组具有部分阻断（雄性小鼠中60%或雌性小鼠中29%）或雌性疾病进展延迟（对照组中28天至YK-4-279延迟组中50天）。在这里，我们证明了YK-4-279在黑色素瘤的临床前治疗模型中对阻断或延迟肿瘤进展具有显著影响。
Therapeutic options for melanoma are limited. In a prior study, we discovered the small molecule compound, YK-4-279, blocked tumor progression in a mouse model of melanoma. Tumor induction and drug administration occurred concurrently in this previous work. The aim of our current study was to test the efficacy of YK-4-279 in mice with already initiated but not progressed melanoma lesions. We have found that YK-4-279 was still able to attenuate melanoma progression significantly, although not to the degree as the prior trial. Using a preclinical in vivo mouse model that has relevancy to human disease, our findings support that there is promise for YK-4-279 as an option for melanoma therapy. More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the BrafCA;Tyr-CreERT2;Ptenflox/flox transgenic mouse model. YK-4-279 had no effect on tumor initiation but blocked progression of invasive melanoma. Our current study was designed as a treatment model, where YK-4-279 was administered during pigmented lesion formation. The study design included the use of three groups: (1) a control group that received only DMSO without a drug (MOCK), (2) mice following our prior studies with YK-4-279 administered at the time of tumor induction (YK-4-279), and (3) mice treated during tumor initiation (YK-4-279 delay). While the MOCK mice had progression of tumors, both YK-4-279 and YK-4-279 delay groups had a significant block or delay of progression. The majority of mice in the YK-4-279 groups had a block of progression, while the YK-4-279 delay group had either a partial block (60% in male mice or 29% in females) or a delay in disease progression in females (28 days in controls to 50 days in YK-4-279 delay group). Here, we demonstrate that YK-4-279 has a significant impact on blocking or delaying tumor progression in a pre-clinical treatment model of melanoma.
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