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PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA

PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA
p16 缺乏的黑色素瘤的个性化治疗
批准号:
9933633
负责人:
Romi Gupta
金额:
$7.43万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-01 至 2020-07-31

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项目成果

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中文摘要
翻译
项目摘要 仅在美国,每年就有超过10,000人死于黑色素瘤,目前的治疗方法 晚期黑色素瘤不能提供持久的临床益处。因此,改进的分子 对黑色素瘤的了解对于开发有效的治疗方法至关重要。根据癌症基因组 阿特拉斯(TCGA)黑色素瘤数据超过45%的黑色素瘤缺乏肿瘤抑制基因p16。不过,目前还没有具体的 个性化治疗选项可用于p16缺陷黑色素瘤。因此,我们进行了一次创新的 大规模可药物基因组RNAi筛选及细胞分裂周期7(CDC7)激酶候选 这对于p16缺陷黑色素瘤的生存是必要的。ShRNA诱导的CDC7基因敲除被抑制 体内p16基因缺陷的黑色素瘤和转移。我们的中心假设是p16缺陷 黑色素瘤依靠CDC7生存,抑制CDC7对治疗有治疗价值 P16缺陷性黑色素瘤。总体目标是确定遗传和药理学的影响 CDC7对黑色素瘤生长和转移的抑制作用 P16缺陷性黑色素瘤。具体地说,在目标1中,我们将确定遗传和药理学的影响 CDC7对黑色素瘤生长和转移的抑制作用为此,将确定CDC7在 P16缺失背景下的肿瘤生长和转移。此外,使用小分子XL413 CDC7抑制剂,单独或与BRAFV600E抑制剂维莫拉非尼联合使用(用于黑色素瘤联合 BRAFV600E突变和p16缺失),我们将确定CDC7单独的药理抑制 或与BRAFV600E抑制剂联合使用可有效治疗p16缺陷的黑色素瘤 活着。这种实验方法将利用黑色素瘤肿瘤生长和转移的小鼠模型,并将 利用耶鲁大学孢子来源的已建立的和黑色素瘤患者来源的短期黑色素瘤培养 皮肤癌。在目标2中,我们将确定为什么CDC7对于p16缺陷黑色素瘤的生存是必要的。 使用转录组范围的基因表达谱和串联亲和纯化和质谱学- 基于蛋白质组学的方法,我们发现p16缺陷的黑色素瘤细胞表现出未折叠的激活。 蛋白反应(UPR)途径,CDC7可能通过 转录因子HOXA1促进黑色素瘤生长和转移。因此,我们将确定 CDC7如何通过HOXA1在p16缺陷黑色素瘤细胞中调节UPR通路。此外,我们还将测试 CDC7缺失是否能抑制p16缺陷黑色素瘤细胞的生长和转移 通过恢复HOXA1的表达和UPR途径的活性而被拯救。总体而言,我们希望发现一个 可靶向有效个体化的CDC7驱动的新型可药物遗传易损性途径 P16缺陷黑色素瘤的治疗,包括高度侵袭性转移性黑色素瘤的治疗。
英文摘要
Project Summary Melanoma account for over 10,000 deaths annually in the United States alone and current therapies for advanced-stage melanoma do not provide durable clinical benefit. Therefore, improved molecular understanding of melanoma is essential for developing effective therapies. According to The Cancer Genome Atlas (TCGA) melanoma data over 45% melanoma lack tumor suppressor p16. However, there is no specific personalized treatment option available for p16-deficient melanoma. Therefore, we performed an innovative large-scale druggable genome RNAi screen and identified Cell division cycle 7 (CDC7) kinase as a candidate that is necessary for the survival of p16-deficient melanoma. shRNA-induced knockdown of CDC7 inhibited p16-deficient melanoma tumors and metastases in vivo. Our central hypothesis is that p16-deficient melanoma depends upon CDC7 for their survival and CDC7 inhibition will be of therapeutic value for treating p16-deficient melanoma. The overall objective is to determine the effect of genetic and pharmacological inhibition of CDC7 on melanoma tumor growth and metastasis and understand why CDC7 is necessary for p16-deficient melanoma. Specifically, in Aim 1, we will determine the effect of genetic and pharmacological inhibition of CDC7 on melanoma tumor growth and metastasis. To this end, will determine the role of CDC7 in tumor growth and metastasis in the context of p16-deficiency. Additionally, using XL413, a small molecule inhibitor of CDC7, alone or in combination with BRAFV600E inhibitor vemurafenib (for melanoma co-harboring both BRAFV600E mutation and p16-deficiency), we will determine if pharmacological inhibition of CDC7 alone or in combination with BRAFV600E inhibitors can be employed to effectively treat p16-deficient melanoma in vivo. The experimental approach will utilize mouse models of melanoma tumor growth and metastasis and will utilize established and melanoma patient-derived short-term melanoma cultures available from Yale SPORE in Skin Cancer. In Aim 2, we will determine why CDC7 is necessary for the survival of p16-deficient melanoma. Using transcriptome-wide gene expression profiling and Tandem Affinity Purification and mass spectrometry- based proteomics approaches, we find that the p16-deficient melanoma cells show activation of Unfolded Protein Response (UPR) pathway and that CDC7 maintains the activity of UPR pathway potentially via transcription factor HOXA1 to promote melanoma tumor growth and metastasis. Therefore, we will determine how CDC7 regulates UPR pathway via HOXA1 in p16-deficient melanoma cells. Additionally, we will test whether CDC7-loss induced tumor growth and metastasis inhibition of p16-deficient melanoma cells can be rescued by restoring HOXA1 expression and the UPR pathway activity. Collectively, we expect to uncover a novel CDC7-driven druggable genetic vulnerability pathway that can be targeted for effective personalized therapy of p16-deficient melanoma, including for highly aggressive metastatic melanoma.
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国内基金
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  • 批准年份:
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