Novel targeted chemo/immunotherapy approach for localized and metastatic CaP

 描述（由申请方提供）：肿瘤细胞从原发组织扩散到远处器官，随后形成继发性肿瘤，是前列腺癌（CaP）男性死亡的主要原因。与原发性肿瘤相比，转移是特别具有挑战性的治疗，因为它的全身性质和经常与现有的治疗药物的耐药性。单一疗法在临床上失败，因为转移性CaP是一种多分子驱动的疾病，因此确定靶向转移性CaP发病机制中的关键分子的治疗方案非常重要。迫切需要鉴定参与转移的分子，这些分子为鉴定预防或治疗转移性CaP的新治疗方法创造了机会。我们已经鉴定了两种关键分子（i）S100 A4和（ii）Rac 1，它们在疾病从局部化到转移性CaP表型的进展中起作用。我们提供的证据表明，在人类和转基因小鼠模型中，S100 A4表达在CaP的进行性阶段增加，TRAMP和这种蛋白质调节转移性前列腺肿瘤细胞的迁移。重要的是，我们发现靶向S100 A4可以抑制TRAMP小鼠的转移。与该提议相关的重要信息是我们的数据，其显示了S100 A4的小分子抑制剂在体外的功效和抗S100 A4单克隆抗体（mAb-6 B12和5c 3-mAb）的开发，其具有在小鼠模型中抑制转移的潜力。我们还观察到Rac 1活性导致细胞骨架不稳定和原发性前列腺肿瘤细胞的迁移。基于这些发现，我们产生了我们的全球假设，即同时靶向S100 A4和Rac 1将是预防和治疗局部生长和转移性CaP疾病的理想方法。我们认为S100 A4靶向剂（如S100 A4抑制剂或抗S100 A4抗体）与Rac 1靶向剂（抑制剂）组合将抑制转移性和“潜在”侵袭性CaP细胞的转移能力。这些假设将在以下三个目标中进行检验：（aim#1）。使用CaP疾病的基于细胞的肿瘤跨内皮和骨髓转移模型确定基于S100 A4抑制剂和抗S100 A4抗体（6 B12和5C 3 mAb）的单一和组合疗法的抗转移功效。(aim#2）。确定特异性S100 A4抑制剂和抗S100 A4抗体对原位同基因和无胸腺小鼠模型中前列腺肿瘤细胞生长和转移的功效（目的3）。确定S100 A4和Rac 1靶向单一和联合治疗在TRAMP小鼠（CaP疾病的本地转基因模型）中的疗效。由于很少有治疗转移性CaP疾病的选择，该提案的成功结果将确定一种新的基于靶点的方法来预防和治疗男性转移性CaP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.