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

摘要 卵巢癌(OC)对于手术治疗后复发的患者来说是致命的和不可治愈的。 和以铂为基础的化疗。不幸的是，OC有很高的疾病复发率(70%-80%)和 大多数复发肿瘤对化疗药物耐药。目前，这些患者的治疗选择相当有限， 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 强调迫切需要新的和改进的疗法来消除和治疗复发和 抗药性疾病。在此背景下，我们的研究发现Hedgehog(HH)/GLI信号在 化疗耐药的OC细胞和肿瘤以及GLI1的表达与FA-BRCA上调显著相关 同源重组(HR)基因、肿瘤干细胞信号转导与OC患者预后不良有关。我们的 初步研究表明，GLI1调控DNA修复基因BRCA1、FANCD2和FANCD2的表达 RAD51在OC细胞和肿瘤中的表达及其抑制诱导了一种称为BRCAness的状态，其特征是 由于DNA双链断裂(DSB)修复效率低下。此外，HH/GLI1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。在这项建议中，我们的目的是阐明 HH/GLI1调节促进致癌复制的FA-BRCA和HR基因(目标1)，并确定 HH/GLI1抑制剂对卵巢癌细胞和卵巢癌BRCA熟练和缺陷OC细胞的作用 小鼠原位移植模型(目的2)。朝着确定有效的治疗组合的目标前进 协同作用和诱导合成致命性，我们将评估有效的治疗组合，包括 HH/GLI1和PARP抑制剂。最有效的药物组合将在小鼠的原位实验中得到检验。 和患者来源的OC异种移植模型评估其对抗获得性化疗耐药的效果 和OC疾病进展(目标3)。本提案中审查的化疗药物是FDA批准的或 目前正在进行临床和临床前评估(例如Vismodegib，sonidegib，GANT61，olaparib， Rucaparib，niraparib)；因此，发现的有效药物组合可以迅速过渡到临床 试验并发展成为OC患者的治疗方法。

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.