Hedgehog/Gli1-targeted therapies to overcome ovarian cancer chemoresistance and disease recurrence

摘要 卵巢癌（OC）是致命的，无法治愈的患者复发后，原发癌手术治疗 和含铂化疗。不幸的是，OC的疾病复发率很高（70-80%）， 大多数复发性肿瘤是化学抗性的。目前，这些患者的治疗选择非常有限， 因此，与其他癌症不同，OC的死亡率几十年来没有改善。这种可怕的情况 强调了对新的和改进的治疗方法的迫切需要，以消除和治疗复发性和 化学抗性疾病在这种情况下，我们的研究确定了Hedgehog（Hh）/GLI信号转导在小鼠中的增加。 化疗耐药OC细胞和肿瘤，GLI 1表达与上调FA-BRCA显著相关 和同源重组（HR）基因、癌症干细胞信号传导和OC患者的不良预后。我们 初步数据表明，GLI 1调节DNA修复基因BRCA 1、FANCD 2和 OC细胞和肿瘤中的RAD 51及其抑制诱导称为“BRCAness”的状态，其特征在于 DNA双链断裂（DSB）的修复效率低下。此外，Hh/GLI 1抑制或下调 降低细胞存活率和形成肿瘤球体的能力（干细胞特征），并使合成 PARP抑制剂的致命性。在这个建议中，我们的目标是阐明分子机制， Hh/GLI 1调节促进致癌复制的FA-BRCA和HR基因（Aim 1），并决定细胞增殖。 Hh/GLI 1抑制剂在BRCA-活性和缺陷OC细胞系和卵巢癌中的功效 原位小鼠模型（Aim 2）。为了确定有效的治疗组合， 协同和诱导合成致死性，我们将评估有效的治疗组合， Hh/GLI 1和PARP抑制剂。最有效的药物组合将在小鼠原位 和患者来源的OC异种移植物模型，以评价它们在对抗获得性化学抗性中的功效 和OC疾病进展（Aim 3）。本提案中审查的化学药品是FDA批准的， 目前正在进行临床和临床前评价（例如，vismodegib，sonidegib，GANT61，olaparib， rucaparib，niraparib）;因此，发现的有效药物组合可以快速过渡到临床 临床试验，并开发成治疗OC患者的方法。

Abstract Ovarian cancer (OC) is deadly and incurable for patients that recur after primary cancer is treated with surgery and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and most recurrent tumors are chemoresistant. Currently, therapeutic options are quite limited for these patients, and thus unlike with other cancers, the mortality in OC has not improved in decades. This dreadful situation highlights a drastic need for new and improved therapeutics to eliminate and treat recurrent and chemoresistant disease. In this context our studies identified increased Hedgehog (Hh)/GLI signaling in chemoresistant OC cells and tumors, and GLI1 expression significantly correlated with upregulated FA-BRCA and homologous recombination (HR) genes, cancer stem cell signaling and poor prognosis of OC patients. Our preliminary data demonstrate that GLI1 regulates expression of DNA repair genes BRCA1, FANCD2 and RAD51 in OC cells and tumors and its inhibition induces a state known as “BRCAness”, which is characterized by inefficient repair of DNA double strand breaks (DSB). Additionally, Hh/GLI1 inhibition or downregulation decreased cell survival and ability to form tumor spheroids (stem cell characteristic), and enabled synthetic lethality with PARP inhibitors. In this proposal we aim to elucidate the molecular mechanisms by which Hh/GLI1 regulates FA-BRCA and HR genes that promote oncogenic replication (Aim 1), and determine the efficacy of Hh/GLI1 inhibitors in both BRCA-proficient and deficient OC cells in cell line and ovarian cancer orthotopic mouse models (Aim 2). Towards the goal of identifying effective therapeutic combinations that work synergistically and induce synthetic lethality, we will evaluate effective therapeutic combinations involving Hh/GLI1 and PARP inhibitors. The most efficient drug combinations will be examined in a mouse orthotopic and patient derived xenograft models of OC to evaluate their efficacy in combatting acquired chemoresistance and OC disease progression (Aim 3). Chemotherapeutic drugs examined in this proposal are FDA approved or currently undergoing clinical and preclinical evaluation (ex. vismodegib, sonidegib, GANT61, olaparib, rucaparib, niraparib); thus, the effective drug combinations discovered can quickly be transitioned into clinical trials and developed into treatments for OC patients.