Novel targeted chemo/immunotherapy approach for localized and metastatic CaP

 描述(申请人提供)：肿瘤细胞从原发组织扩散到远处器官，继而形成继发肿瘤是前列腺癌(CAP)患者死亡的主要原因。与原发肿瘤相比，转移性肿瘤的治疗尤其具有挑战性，因为它具有全身性，而且经常与现有治疗药物的耐药性有关。单一疗法在临床上失败了，因为转移性CAP是一种多分子驱动的疾病，因此确定一种针对转移性CAP发病机制中关键分子的治疗方案非常重要。迫切需要确定与转移有关的分子，以创造机会确定预防或治疗转移CAP的新的治疗方法。我们已经确定了两个关键分子(I)S100A4和(II)rac1，它们在疾病从局限型到转移性帽子表型的发展过程中发挥作用。我们提供的证据表明，S100A4在人和转基因小鼠模型TRAMP的进展期表达增加，该蛋白调节转移性前列腺癌细胞的迁移。重要的是，我们发现靶向S100A4可以抑制TRAMP小鼠的转移。与这一建议相关的重要信息是，我们的数据显示了小分子S100A4抑制剂在体外的有效性，以及抗S100A4单抗(mAb-6B12和5C3-mAb)的发展，这些单抗可能在小鼠模型中抑制转移。我们还观察到，rac1活性导致原代前列腺肿瘤细胞的细胞骨架不稳定和迁移。基于这些发现，我们提出了我们的全球假设，即同时靶向S100A4和rac1将是预防和治疗局部区域生长和转移性帽子疾病的理想方法。我们假设S100A4靶向药物(如S100A4-抑制剂或抗S100A4抗体)与rac1靶向药物(抑制剂)联合使用将抑制转移和潜在的侵袭性CAP细胞的转移能力。这些假设将在以下三个目标中得到检验：(目标1)。采用CAP病的细胞肿瘤跨内皮细胞转移和骨髓转移模型，确定S100A4抑制剂和抗S100A4抗体(6B12和5C3单抗)为基础的单一和联合治疗的抗转移效果。(目标2)。检测特异性S100A4抑制物和抗S100A4抗体对同种异体原位和裸鼠前列腺癌细胞生长和转移的影响(AIM 3)。确定S100A4和rac1靶向单一和联合治疗在流浪鼠身上的疗效，流浪鼠是帽子病的本土转基因模型。由于治疗转移性帽子病的选择很少，这项提案的成功结果将确定一种新的以靶点为基础的方法来预防和治疗男性转移性帽子疾病。

 DESCRIPTION (provided by applicant): Dissemination of tumor cells from primary tissue to distant organs with subsequent formation of secondary tumors is the major cause of mortality in men suffering from prostate cancer (CaP). In contrast to the primary tumor, metastasis is especially challenging to treat because of its systemic nature and frequent association with resistance to existing therapeutic agents. Monotherapies have failed at clinics because metastatic CaP is a multiple molecule-driven disease, making it important to identify a therapeutic regimen that would target key molecules in the pathogenesis of metastatic-CaP. There is an urgent need to identify molecules involved in metastasis that create opportunities to identify new therapeutic approaches to prevent or treat metastatic CaP. We have identified two key molecules (i) S100A4 and (ii) Rac1, which play role in the progression of disease from localized to metastatic CaP-phenotype. We provide evidence that S100A4 expression is increased during progressive stages of CaP in humans and transgenic mouse model, TRAMP and this protein regulates the migration of metastatic prostate tumor cells. Importantly, we found that targeting S100A4 could inhibit metastasis in TRAMP mice. The important information pertinent to this proposal is our data showing the efficacy of small molecule inhibitors of S100A4 in vitro and development of anti-S100A4 monoclonal antibodies (mAb-6B12 & 5c3-mAb) that has potential to inhibit metastasis in a mouse model. We also observed Rac1 activity leads to cytoskeleton instability and migration of primary prostate tumor cells. Based on these findings we generated our global hypothesis that targeting S100A4 and Rac1 simultaneously will be an ideal approach to prevent and treat locoregional growth and metastatic-CaP disease. We posit that S100A4-targeting agents (such as S100A4-inhibitor or anti-S100A4 antibody) in combination with Rac1-targeting agents (inhibitor) would inhibit the metastatic ability of both metastatic and "potential" invasive CaP cells. These hypotheses will be tested in the following three Aims: (aim#1). Determine the anti-metastatic efficacy of S100A4-inhibitor and anti- S100A4 antibodies (6B12 & 5C3 mAb)-based mono and combination therapies using cell-based tumor transendothelial and bone-marrow metastasis models of CaP disease. (aim#2). Determine the efficacy of the specific S100A4-inhibitor and anti-S100A4 antibody on the growth and metastasis of prostate tumor cells in orthotopic syngeneic and athymic mouse models (aim 3). Determine the efficacy of S100A4 and Rac1 targeted mono- and combination therapies in TRAMP mice, the autochthonous transgenic model of CaP-disease. Since very few options are available to treat metastatic-CaP disease, the successful outcome of this proposal will identify a new target-based approach to prevent and treat metastatic CaP disease in men.