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SLC6A14 as a unique drug target to treat pancreatic cancer

SLC6A14作为治疗胰腺癌的独特药物靶点

基本信息

批准号：
10652149
负责人：
Yangzom Doma Bhutia
金额：
$ 35.51万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-12 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652149
关键词：
Amino Acid Transporter Amino Acids Area Aspartate Attenuated Autophagocytosis Biochemical Biological Carbon Cell Line Cells Combined Modality Therapy Compensation DNA Development Drug Combinations Drug Targeting Essential Amino Acids Genetic Genetic Models Glutamates Glutathione Goals Growth Human Hydroxychloroquine In Vitro KPC model KRASG12D Laboratories Lesion Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Modeling Molecular Monitor Non-Essential Amino Acid Nutrient Oxidative Stress Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Process Proteomics Publishing Sampling Signal Pathway Signal Transduction Starvation Stress Testing Tissue Sample Treatment Efficacy Tryptophan Tumor Tissue Up-Regulation Xenograft procedure anti-cancer attenuation cancer cell deprivation efficacy testing experimental study histone methylation implantation improved in vivo Model inhibition of autophagy innovation interest knock-down metabolomics molecular marker mouse model neoplastic novel nutrition pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pharmacologic response targeted treatment therapy outcome treatment strategy

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is lethal. Our laboratory has identified SLC6A14 to be highly upregulated in PDAC. SLC6A14 is a broad selective amino acid transporter with the ability to transport both essential and non-essential amino acids, which includes amino acids for mTORC1 activation, one-carbon moiety for DNA/histone methylation, and provide precursors for glutathione synthesis to counteract oxidative stress. We have already published using cell lines and xenograft mouse models that genetic deletion or pharmacological blockade of SLC6A14 attenuates PDAC growth by causing amino acid starvation and inhibition of mTORC1 signaling pathway. Using LSL-KrasG12D/+; LSL-p53R172H/+; Pdx-1 Cre (KPC) spontaneous mouse model of PDAC, we have recently shown that deletion of Slc6a14 improves the overall survival in the KPC mice. More interestingly, we have found that SLC6A14 inactivation induces autophagy and macropinocytosis, a nutrient scavenging mechanism that can partly compensate for the amino acid deficit caused by SLC6A14 loss. In this proposal, our goal is to evaluate SLC6A14 as a potential drug target for PDAC, characterize autophagy and macropinocytosis induced in response to SLC6A14 loss, and investigate the efficacy of a combination therapy targeting SLC6A14 and autophagy/macropinocytosis for a better therapeutic outcome in PDAC as opposed to targeting SLC6A14 alone. To achieve these goals, we propose three specific aims. In Aim 1, we will demonstrate whether SLC6A14 inactivation attenuates PDAC growth in KPC mice. For this, we will generate KPC mice in Slc6a14+/+ and Slc6a14-/- background to test whether genetic deletion of Slc6a14 will delay the development and advancement of PanIN lesions leading to a reduction in the total neoplastic area in KPC mice. Next, we will treat the KPC mice with and without a-MLT, to test whether pharmacological blockade of Slc6a14 attenuates PDAC growth in KPC mice. In Aim 2, we will characterize autophagy and macropinocytosis induced in response to SLC6A14 inactivation, as an alternate mechanism of amino acid acquisition in PDAC. For this, we will use SLC6A14 inactivated (genetic knockdown and a-MLT blockade) human PDAC cell lines and pancreatic tissue samples from KPC mice and study the induction of autophagy and macropinocytosis in these samples. In Aim 3, we will determine whether concurrent inhibition of SLC6A14 and autophagy/macropinocytosis will lead to a better therapeutic outcome in PDAC. For this, we will use human PDAC cell line as well as orthotopic implantation mouse models, and test whether a two-drug combination (a-MLT/HCQ) that simultaneously targets SLC6A14 (𝛼-MLT) and autophagy/macropinocytosis (HCQ) will have a synergistic/additive effect in growth inhibition PDAC.

胰腺导管腺癌（PDAC）是致命的。我们的实验室已经鉴定出SLC 6A 14是高度在PDAC中上调。SLC 6A 14是一种广泛的选择性氨基酸转运蛋白，具有转运必需和非必需氨基酸，包括用于mTORC 1激活的氨基酸，一碳 DNA/组蛋白甲基化的部分，并提供谷胱甘肽合成的前体，以抵消氧化应力我们已经发表了使用细胞系和异种移植小鼠模型， SLC 6A 14的药理学阻断通过引起氨基酸饥饿而减弱PDAC生长，抑制mTORC 1信号通路。使用LSL-KrasG 12 D/+; LSL-p53 R172 H/+; Pdx-1 Cre（KPC）自发在PDAC小鼠模型中，我们最近发现Slc 6a 14的缺失改善了PDAC小鼠的总体存活率。 KPC小鼠。更有趣的是，我们发现SLC 6A 14失活诱导自噬，巨胞饮作用，一种可以部分补偿氨基酸缺乏的营养清除机制 SLC 6A 14丢失。在这项提案中，我们的目标是评估SLC 6A 14作为一个潜在的药物靶点， PDAC，表征响应于SLC 6A 14损失诱导的自噬和巨胞饮，并研究靶向SLC 6A 14和自噬/巨胞饮作用的联合疗法对于更好地治疗肿瘤的功效与单独靶向SLC 6A 14相反，PDAC的治疗结果。为了实现这些目标，我们建议三个具体目标。在目标1中，我们将证明SLC 6A 14失活是否会减弱PDAC的生长。 KPC小鼠。为此，我们将在Slc 6a 14 +/+和Slc 6a 14-/-背景下产生KPC小鼠，以测试是否遗传 Slc 6a 14的缺失将延迟PanIN病变的发展和进展，从而减少 KPC小鼠的总肿瘤面积。接下来，我们将用和不用α-MLT处理KPC小鼠，以测试是否 Slc 6a 14的药理学阻断减弱了KPC小鼠中的PDAC生长。在目标2中，我们将描述自噬和巨胞饮诱导响应SLC 6A 14失活，作为一种替代机制， PDAC中的氨基酸获取。为此，我们将使用失活的SLC 6A 14（遗传敲低和a-MLT 阻断）人PDAC细胞系和来自KPC小鼠的胰腺组织样品，并研究自噬和巨胞饮作用。在目标3中，我们将确定是否同时抑制 SLC 6A 14和自噬/巨胞饮作用将导致PDAC的更好的治疗结果。为此，我们使用人PDAC细胞系以及原位植入小鼠模型，并测试两种药物是否同时靶向SLC 6A 14（α-MLT）和自噬/巨胞饮的组合（α-MLT/HCQ） (HCQ)将在生长抑制PDAC中具有协同/累加效应。