DNA Markers As Surrogates:Melanoma Patient Response

描述(由申请人提供) 转移性黑色素瘤的诊断通常与预后非常差有关。对于晚期黑色素瘤(AJCC期ILL和IV期)，5年生存率分别不到45%和5%。我们已经开发出一种用于晚期黑色素瘤患者的治疗方案，称为生物化疗(BC)和维持生物疗法，该疗法同时包括多种生物和化疗药物。这种疗法的独特之处在于它非常有效，与以往的联合疗法相比，它的有效率为50%-60%，毒性更小，住院时间更少。然而，晚期治疗方案的一个常见问题是及早识别可能从这种积极治疗的补充中受益的患者。目前评估治疗反应的方法是基于传统的成像技术和体检。不幸的是，这些技术可能昂贵、耗时，并且需要大量肿瘤体积来进行检测，这推迟了治疗的开始，并限制了它们作为疾病反应的早期指标的实用性。需要改进监测患者反应的方法，以便在疗程早期确定治疗效果，并避免无应答患者不必要的治疗成本和毒性。血液检测提供了一种快速监测可能与疾病进展和治疗反应相关的系列事件的简便途径，这可能具有临床意义。我们已经在黑色素瘤患者的无细胞血清/血浆中发现了作为疾病预后的预后基因标记(PGM)的基因标记。采用多重毛细管阵列电泳法(CAE)检测黑色素瘤患者血清中特异性标志物的基因变化。这些包括杂合性缺失(LOH)的微卫星标记和特定基因的CpG启动子区域的甲基化。我们的假设是，在患者治疗的早期，血清中的基因类型标记物可以作为疾病结局的预测指标和治疗反应的预测因子。这种方法的新奇之处在于，可以在治疗期间收集系列血液，并对两种类型的妊娠期高危妊娠进行评估。在R21阶段，将建立两种PGM检测方法，以实现高通量、特异性、稳健性、重复性和敏感性。R33阶段将专注于验证PGMS，并在正在进行的针对AJCC IV期黑色素瘤患者的预期多中心II期BC和维持生物治疗试验中确定它们的临床有效性。

DESCRIPTION (provided by applicant) The diagnosis of metastatic melanoma is often associated with a very poor prognosis. For advanced stage melanoma (AJCC stage ill and IV) the 5-year survival rate is less than 45% and 5%, respectively. We have developed a treatment regimen for advanced stage melanoma patients referred to as Biochemotherapy (BC) and maintenance Biotherapy that consists of multiple biological and chemotherapeutic drugs concurrently. This regimen is unique in that it is highly effective, producing response rates of 50-60% with less toxicity and reduced hospitalization than historical combination therapies. However, a common problem with advanced stage treatment protocols is the early identification of patients who may benefit from the addition of such aggressive therapy. Current methods to assess treatment response are based on conventional imaging techniques and physical examination. Unfortunately, these techniques can be expensive, time consuming, and requires the presence of a substantial tumor volume for deteion, which delays therapeutic initiation and limits their utility as early indicators of disease response. Improvements in methods to monitor patient response are needed to determine therapeutic efficacy early in the treatment course and avoid unnecessary treatment costs and toxicity in non-responder patients. Blood testing offers an easily accessible route to rapidly monitor serial events that may be associated with disease progression and response to therapy, which may be of clinical significance. We have discovered genotypic markers in acellular serum/plasma from melanoma patients as prognostic genotypic markers (PGM) of disease outcome. Assays using multiplex capillary array electrophoreis (CAE) have been developed to assess genotypic changes of specific markers in melanoma patients in serum. These include microsatellite markers with loss of hetrozygosity (LOH) and methylation of CpG promoter regions of specific genes. Our hypothesis is that genotypic markers in serum can be used as PGM for disease outcome and as predictors of response to therapy early in the course of patient treatment. The novelty of this approach is that serial bloods can be collected during therapy and assessed for both types of PGM. In the R21 phase, the two PGM assays will be established for high throughput, specificity, robustness, reproducibility, and sensitivity. The R33 phase will focus on validating the PGMs and determining their clinical utility in an ongoing prospective multicenter Phase II BC and maintenance Biotherapy trial for AJCC stage IV melanoma patients.