Molecular Mechanisms in Gastrointestinal Stromal Tumor

描述(由申请人提供)：靶向分子制剂是癌症治疗中的一项里程碑式的成就。特别是，酪氨酸激酶抑制剂甲磺酸伊马替尼针对胃肠道间质瘤(GIST)的突变KIT蛋白，这是一种肠道肉瘤。虽然伊马替尼非常有效，但它几乎从未引起完全反应，肿瘤进展的中位数约为20个月。在我们5年的资助中，我们确定了常规病理变量和KIT突变类型与人类原发GIST切除后预后的关系，并确定了对伊马替尼获得性耐药的机制。我们的重点已经演变，现在我们的目标是将免疫疗法与伊马替尼结合起来，以改善GIST的结果。我们推测，伊马替尼诱导的肿瘤快速破坏所导致的肿瘤抗原释放可以通过同期的免疫治疗来利用。在自发发生GIST的转基因小鼠中，我们发现伊马替尼的抗肿瘤作用部分是由免疫介导的。我们发现，伊马替尼可以减少肿瘤中吲哚胺2，3-双加氧酶(IDO)的产生，IDO是一种关键的免疫抑制蛋白。我们还发现，当伊马替尼与抗体介导的阻断CTLA-4相结合时，可以增强抗肿瘤效果。CTLA-4是一种由激活的T细胞表达的免疫调节蛋白，由调节性T细胞组成。在目标1中，我们将证明伊马替尼在GIST中的抗肿瘤作用依赖于对IDO的抑制。在目标2中，我们将确定糖皮质激素诱导的肿瘤坏死因子受体配体如何调节伊马替尼的抗肿瘤作用。在目标3中，我们将明确CTLA-4阻断如何在GIST中增强伊马替尼的抗肿瘤作用。我们的发现将促进我们对GIST的理解，并可能导致使用分子和免疫联合治疗的新的临床试验。 公共卫生相关性：在这项提案中，我们将调查免疫反应在抗癌靶向分子治疗效果中的作用。我们将在胃肠道癌症的小鼠模型中结合分子治疗和免疫治疗。我们的研究可能会找到一种更有效的方法来治疗癌症患者。

DESCRIPTION (provided by applicant): Targeted molecular agents are a landmark achievement in cancer treatment. In particular, the tyrosine kinase inhibitor imatinib mesylate targets mutant KIT protein in gastrointestinal stromal tumor (GIST), an intestinal sarcoma. While imatinib is remarkably effective, it almost never induces a complete response and tumor progression occurs at a median of approximately 20 months. During our 5 years of funding, we defined the relationship of conventional pathologic variables and the type of KIT mutation to outcome following the resection of primary GIST in humans and identified the mechanism of acquired resistance to imatinib. Our focus has evolved and now our goal is to combine immunotherapy with imatinib to improve outcomes in GIST. We hypothesize that tumor antigen release resulting from the rapid tumor destruction induced by imatinib can be exploited by using concomitant immunotherapy. In a transgenic mouse that develops GIST spontaneously, we have found that the anti-tumor effects of imatinib are partially immune-mediated. We have discovered that imatinib decreases tumor production of indoleamine 2,3-dioxygenase (IDO), a key immunosuppressive protein. We have also found that imatinib has enhanced anti-tumor efficacy when combined with antibody-mediated blockade of CTLA-4, an immunomodulatory protein expressed by activated T cells and constitutively by regulatory T cells. In Aim 1, we will demonstrate that the anti-tumor effects of imatinib in GIST depend on inhibition of IDO. In Aim 2, we will determine how glucocorticoid-induced tumor necrosis factor receptor ligand modulates the anti-tumor effects of imatinib. In Aim 3, we will define how CTLA-4 blockade enhances the anti-tumor effects of imatinib in GIST. Our findings will advance our understanding of GIST and may lead to a novel clinical trial using combined molecular and immune therapy. PUBLIC HEALTH RELEVANCE: In this proposal, we will investigate the role of the immune response in the effects of targeted molecular therapy against cancer. We will combine molecular therapy with immunotherapy in a mouse model of gastrointestinal cancer. Our investigations may identify a more effective approach to treating patients with cancer.