Sunday, November 24, 2024
11/24/2024
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 (-MLT) and autophagy/macropinocytosis (HCQ) will have a synergistic/additive effect in growth inhibition PDAC.
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