StarD5, a protein that translocates cholesterol to the plasma membrane, is a novel target for Colon Cancer

结直肠癌（CRC）是美国癌症死亡的第三大原因。CRC难治 因为大多数现有疗法不能显著地消除称为“癌干”的癌症种子 细胞（CRCSC）。细胞胆固醇代谢是CRCSC的一个最重要的靶点。然而，在这方面， 靶向该途径的现有疗法，例如他汀类药物，不能显著抑制细胞中的胆固醇水平 这是由于控制癌细胞中胆固醇水平的冗余机制。然而，胆固醇的利用率 由选择的一组特定胆固醇转运蛋白调节，如果靶向， CRC细胞的质膜（PM）生物物理性质。我们发现了一种胆固醇转运蛋白 称为StarD 5，这是唯一已知的调节胆固醇转运到细胞的哺乳动物蛋白质 膜的StarD 5在人结肠癌组织中显著过表达，特别是在结肠癌组织中。 CRCSC。抑制StarD 5导致体外和体内结肠CSC的显著抑制，以及 PM中的胆固醇含量导致PM流动性增加和胰岛素样生长因子-1的强烈抑制 受体（IGF 1 R）和表皮生长因子受体（EGFR）信号传导。我们建议详细审查， StarD 5过表达对结肠癌发生、进展和患者预后的意义 以及StarD 5调节对人CRCSC中CRCSC表型的影响（目的1）。我们 我也想了解StarD 5抑制如何调节CSC的机制。为此，我们建议 确定StarD 5抑制对PM流动性、铂剂流入和生长因子信号传导的影响 PM（目标2）。此外，我们计划检查StarD 5的小分子抑制剂的功效。 使用原代人结肠球状体对CRCSC表型的影响以及确定它们在CRCSC表型中的功效。 与FDA批准的化疗和靶向治疗（帕尼单抗）联合治疗晚期 CSCs的动物模型（目的3）。这些研究将提供新的见解， 膜胆固醇调节癌症生长，并为癌症治疗提供了一类新的靶点 这可能导致长期缓解和/或通过靶向耐药CRCSC治愈。

Colorectal cancer (CRC) is the third leading cause of cancer death in the US. It is difficult to cure CRC because majority of the existing therapies fail to significantly obliterate seeds of cancer called `cancer stem cells (CRCSCs). Cellular cholesterol metabolism is a single most important target for CRCSCs. However, existing therapies that target this pathway, e.g. statins fail to significantly inhibit cholesterol levels in the cells due to redundant mechanisms that govern cholesterol levels in cancer cells. However, cholesterol utilization is regulated by select group of specific cholesterol transport proteins, which if targeted, can have critical effect on plasma membrane (PM) biophysical properties of CRC cells. We have identified a cholesterol transport protein called StarD5, which is the only known mammalian protein that regulates cholesterol transport to cell membrane. StarD5 is significantly overexpressed in human colon cancer tissues and particularly in colon CRCSCs. Inhibition of StarD5 resulted in significant inhibition of colon CSCs in vitro and in vivo, as well as cholesterol contents in PM resulting in increased PM fluidity and robust inhibition of Insulin-like growth factor-1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) signaling. We propose to examine, in detail, the significance of StarD5 overexpression on colon cancer initiation, progression, and patient outcomes as well as impact of StarD5 modulation on CRCSC phenotype in human CRCSCs (Aim 1). We would also like to understand mechanisms of how StarD5 inhibition regulates CSCs. To that end, we propose to determine the effect of StarD5 inhibition on PM fluidity, influx of platinum agents, and growth factor signaling initiated in PM (Aim 2). Moreover, we plan to examine the efficacy of small molecular inhibitors of StarD5 (SD5i) on CRCSC phenotype using primary human colon spheroids as well as determine their efficacy of in combination with FDA-approved chemotherapy and targeted therapy (panitumumab) against advanced animal models of CSCs (Aim 3). The studies will provide novel insight into how alternation in membrane cholesterol regulates cancer growth, and provide a novel class of target for cancer therapies that may lead to long-term remission and/or cure by targeting therapy resistant CRCSCs.