Novel therapeutic inhibition of the Rac oncogene in pancreatic cancer

描述（由申请人提供）：胰腺癌是美国第四大癌症死亡原因，5年生存率仅为5%。目前的治疗方法已被证明无效，因此确定新的药物靶点至关重要。最近发现的一个细胞靶点是致癌的小GTPase Rac1，它被认为可以维持细胞的生长和侵袭。有趣的是，一种鸟嘌呤核苷酸交换因子（GEF）和Rac致癌基因的激活因子，称为Vav1，是一类广泛的Rac GEF的成员，最近被证明在胰腺癌中异位表达。虽然Vav1的表达通常局限于造血细胞，但其在胰腺癌中的表达已被证明与患者死亡率增加相关，并促进小鼠培养和肿瘤发生中的转化增加。药物硫唑嘌呤是一种公认的抗炎剂，最近被证明可以抑制造血细胞中的Vav1-Rac活性。我们的初步数据表明，该药物还能减弱胰腺癌细胞的生长，并显著阻止其在培养中的侵袭潜力。因此，本提案的中心假设预测，硫唑嘌呤靶向胰腺癌中异位表达的VAV1，以减少体外侵袭性和体内转移。在本初步研究中提出的研究将在细胞培养（SA#1）和裸鼠模型（SA#2）中定义胰腺癌细胞中支持转移的药物敏感细胞过程，如细胞增殖、侵袭性基质降解和细胞迁移。这种蛋白在大多数胰腺肿瘤中的异位表达使得这种治疗方法特别有吸引力。从该提案中收集的信息将为治疗这种致命疾病的令人兴奋、重要和新颖的临床前试验提供基础。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a 5-year survival rate of only 5%. Current therapies have proven ineffective, making the identification of new drug targets essential. A recently identified cellular target is the oncogenic small GTPase Rac1, which is known to sustain cell growth and invasion. Interestingly, a guanine nucleotide exchange factor (GEF) and activator of the Rac oncogene, termed Vav1, is a member of a broad class of Rac GEFs that has recently been shown to be ectopically expressed in pancreatic cancers. Although Vav1 expression is normally restricted to hematopoietic cells, its expression in pancreatic cancer has been shown to correlate with increased mortality in patients and promote increased transformation in culture and tumorigenesis in mice. The drug azathioprine is a well-established anti-inflammatory agent that has recently been shown to inhibit Vav1-Rac activity in hematopoietic cells. Our preliminary data indicate that this drug also attenuates growth of pancreatic cancer cells and markedly prevents their invasive potential in culture. Therefore, the CENTRAL HYPOTHESIS of this proposal predicts that azathioprine targets ectopically expressed VAV1 in pancreatic cancers to reduce invasive properties in vitro and metastasis in vivo. The research proposed in this pilot study will define the drug-sensitive cellular processes in pancreatic cancer cells that support metastasis, such as cell proliferation, invasive matrix degradation, and cell migration, both in cell culture (SA#1) and in nude mouse models (SA#2). The ectopic expression of this protein in a majority of pancreatic tumors makes this therapeutic approach particularly attractive. The information gathered from this proposal will provide the basis of an exciting, important, and novel pre-clinical trial toward treating this lethal disease. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a 5-year survival rate of only 5%. Current therapies are generally ineffective against pancreatic cancer; therefore, new therapeutic approaches are critically needed. The research described in this proposal will determine if a well-established anti-inflammatory drug could be a potential therapy for pancreatic cancers by testing its effects in pancreatic cancer cells and in mice.