Molecular Mechanisms in Gastrointestinal Stromal Tumor

描述（由申请人提供）：靶向分子药物是癌症治疗的里程碑式成就。特别是，酪氨酸激酶抑制剂甲磺酸伊马替尼靶向胃肠道间质瘤（GIST）（一种肠肉瘤）中的突变型KIT蛋白。虽然伊马替尼非常有效，但它几乎从未诱导完全反应，肿瘤进展发生在中位数约20个月。在我们5年的资助期间，我们确定了常规病理变量和KIT突变类型与人类原发性GIST切除术后结局的关系，并确定了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联合收割机免疫治疗与伊马替尼结合，以改善GIST的结局。我们假设，伊马替尼诱导的快速肿瘤破坏导致的肿瘤抗原释放可以通过使用伴随免疫治疗来利用。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免疫介导的。我们已经发现伊马替尼减少了吲哚胺2，3-双加氧酶（IDO）的肿瘤产生，IDO是一种关键的免疫抑制蛋白。我们还发现，伊马替尼与抗体介导的CTLA-4（一种由活化T细胞表达并由调节性T细胞组成型表达的免疫调节蛋白）阻断联合使用时，可增强抗肿瘤疗效。在目的1中，我们将证明伊马替尼在GIST中的抗肿瘤作用取决于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，我们将定义CTLA-4阻断如何增强伊马替尼在GIST中的抗肿瘤作用。我们的研究结果将促进我们对GIST的理解，并可能导致一种新的使用分子和免疫联合治疗的临床试验。

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.