Nanotechnology enabled targeting of p53 deficiency in human cancer

纳米技术能够靶向人类癌症中的 p53 缺陷

基本信息

批准号：
9193391
负责人：
Xiaoming He
金额：
$ 37.15万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-08 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193391
关键词：
Alginates Alleles Amanita Amanitins Amino Acids Antibodies Antineoplastic Agents Biodistribution Breast CD44 gene Cancer Patient Catalytic Domain Cell Adhesion Molecules Cells Clinic Clinical Colorectal Colorectal Cancer Complex Cyclic Peptides Data Dose Drug resistance Encapsulated Ensure Epithelial Cells Essential Genes Fluorouracil Gene Dosage Genes Genomics Human Hydrogels In Vitro Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Medicine Microcapsules drug delivery system Morbidity - disease rate Mutation Nanotechnology Nature Normal Cell Operative Surgical Procedures POLR2A gene Protein p53 Proteins Public Health Publishing RNA Polymerase II Regimen Research Resistance Signal Transduction Stem cells TP53 gene Technology Testing Translating Tumor Suppressor Proteins Variant Water abstracting base cancer cell cancer therapy enzyme pathway experience fight against improved in vivo malignant breast neoplasm miniaturize mortality mouse model mutant nanoparticle neoplastic cell novel novel strategies overexpression oxaliplatin resistance mechanism stem systemic toxicity targeted delivery targeted treatment three dimensional cell culture tumor tumorigenic

项目摘要

Project Summary/Abstract There has been little change in mortality rate of human colorectal cancer (CRC) in the past decades and the treatment options available for CRC are still very limited today. In CRC and most other human cancers, the tumor suppressor TP53 gene is frequently inactivated by mutation or deletion. Consequently, tremendous effort has been made to restore the p53 activity for cancer therapy. However, no p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 signaling. Therefore, instead of restoring the p53 activity, identifying vulnerabilities conferred by TP53 deletion or mutation is a novel strategy for fighting against the p53 deficiency in human cancer. In a recent study published in Nature, we confirmed that genomic deletion of TP53 is frequently accompanied by the partial loss of neighboring essential genes and cancer cells with hemizygous TP53 deletion are remarkably vulnerable to further suppression of such neighboring essential genes. We revealed that POLR2A is such an essential gene that is often partially co-deleted with TP53 in human cancers. Such hemizygous loss of TP53/POLR2A occurs in 53, 60, and 41% of colorectal, breast, and pancreatic cancers, respectively. The POLR2A activity is specifically inhibited by α-Amanitin (Ama), a cyclic peptide of 8 amino acids found in the mushroom Amanita phalloides. We demonstrate that low doses of Ama conjugated with anti-epithelial cell adhesion molecule (EpCAM) antibody for targeting CRC can result in much enhanced tumor regression in murine models of human CRC with hemizygous deletion of POLR2A without evident systemic toxicity. However, a small fraction of CRC cells are found to be resistant to Ama in a dose-dependent manner. These drug-resistant cells are often called cancer stem-like cells (CSCs) or tumor initiating cells (TICs). A common feature of the CSCs in many cancers (e.g., CRC together with breast and pancreatic cancers) is that they overexpress the variant CD44. Our preliminary data show that the Ama-resistant CRC cells are indeed enriched with CD44, but not EpCAM. Moreover, our studies show that human breast and prostate CSCs can be effectively destroyed in vitro and in vivo using anticancer agent-laden nanoparticles that target the variant CD44 (but not the normal or non-variant CD44 on normal stem cells) with no evident systemic toxicity. Here, we hypothesize that targeted delivery of Ama and/or clinically used anticancer drugs to the variant CD44+ cancer cells with nanoparticles can overcome their drug resistance. We will test this hypothesis with two specific aims: 1, to determine the mechanisms of resistance to the Ama-based POLR2A-targted therapy of human CRCs with hemizygous loss of TP53 and 2, to determine if the combined therapy of Ama and clinically used anticancer drugs co-delivered with the variant CD44-targeting nanoparticles can overcome the drug resistance of human CRCs. It is expected that this project may result in a novel approach to targeting TP53 and could have a major impact on the treatment of colorectal and other cancers harboring TP53 deficiency.

项目概要/摘要过去几十年来，人类结直肠癌（CRC）的死亡率几乎没有变化目前，结直肠癌和大多数其他人类癌症的治疗选择仍然非常有限。肿瘤抑制基因TP53经常因突变或缺失而失活，影响巨大。人们已努力恢复 p53 活性以用于癌症治疗，但尚未出现基于 p53 的疗法。由于p53信号传导的复杂性，成功转化为临床癌症治疗。因此，不是恢复 p53 活动，而是识别 TP53 删除或在最近的一项研究中，突变是对抗人类癌症中 p53 缺陷的一种新策略。发表在 Nature 上，我们证实 TP53 的基因组缺失经常伴随着部分丢失具有半合子 TP53 缺失的邻近必需基因和癌细胞非常容易受到我们发现 POLR2A 就是这样一个重要基因。在人类癌症中，TP53/POLR2A 经常与 TP53 部分共同缺失。结直肠癌、乳腺癌和胰腺癌的发病率分别为 53%、60% 和 41%。 POLR2A 活性可被 α-鹅膏菌素 (Ama) 特异性抑制，α-鹅膏菌素是一种由 8 个氨基酸组成的环肽在蘑菇鹅膏菌中，我们证明低剂量的鹅膏菌与抗上皮细胞结合。用于靶向 CRC 的细胞粘附分子 (EpCAM) 抗体可大大增强肿瘤消退 POLR2A 半合子缺失的人类 CRC 小鼠模型，无明显的全身毒性。然而，一小部分 CRC 细胞被发现对 Ama 具有剂量依赖性耐药性。这些耐药细胞通常被称为癌症干细胞样细胞（CSC）或肿瘤起始细胞（TIC）。许多癌症（例如结直肠癌以及乳腺癌和胰腺癌）中 CSC 的共同特征是我们的初步数据表明，Ama 抗性 CRC 细胞确实是 CD44 变体。富含 CD44，但不富含 EpCAM。此外，我们的研究表明，人类乳腺和前列腺 CSC 可以。使用针对变体的载有抗癌剂的纳米颗粒在体外和体内有效地破坏 CD44（但不是正常干细胞上的正常或非变异 CD44），没有明显的全身毒性。在这里，我们将 Ama 和/或临床使用的抗癌药物靶向递送至变体带有纳米颗粒的 CD44+ 癌细胞可以克服其耐药性，我们将用两种方法来检验这一假设。具体目标： 1、确定Ama为基础的POLR2A靶向治疗的耐药机制具有 TP53 和 2 半合子缺失的人类 CRC，以确定 Ama 和临床联合治疗是否有效使用过的抗癌药物与靶向CD44的纳米颗粒共同传递可以克服该药物预计该项目可能会产生一种针对 TP53 的新方法。并可能对结直肠癌和其他存在 TP53 缺陷的癌症的治疗产生重大影响。