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非常差的预后相关。对于晚期黑色素瘤（AJCC III期和IV期），5年生存率分别小于45%和5%。我们已经开发了一种用于晚期黑色素瘤患者的治疗方案，称为生物化学疗法（BC）和维持生物疗法，其由多种生物和化学治疗药物同时组成。该方案的独特之处在于它非常有效，产生50-60%的反应率，毒性更小，并且比历史联合疗法减少了住院治疗。然而，晚期治疗方案的一个常见问题是早期识别可能受益于这种积极治疗的患者。目前评估治疗反应的方法是基于常规成像技术和体格检查。不幸的是，这些技术可能是昂贵的、耗时的，并且需要存在大量的肿瘤体积用于测定，这延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效用。需要改进监测患者反应的方法，以在治疗过程的早期确定治疗效果，并避免在无反应患者中产生不必要的治疗费用和毒性。血液检测提供了一种容易获得的途径，可以快速监测可能与疾病进展和治疗反应相关的系列事件，这可能具有临床意义。我们已经在来自黑素瘤患者的无细胞血清/血浆中发现了基因型标记物作为疾病结果的预后基因型标记物（PGM）。已经开发了使用多重毛细管阵列电泳（CAE）的测定来评估黑色素瘤患者血清中特异性标志物的基因型变化。这些包括具有杂合性丢失（洛）和特定基因的CpG启动子区域甲基化的微卫星标记。我们的假设是，血清中的基因型标记物可用作疾病结局的PGM，并在患者治疗过程的早期作为对治疗反应的预测因子。这种方法的新奇在于，可以在治疗期间收集连续血液并评估两种类型的PGM。在R21阶段，将建立两种PGM检测试剂盒的高通量、特异性、耐用性、重现性和灵敏度。R33阶段将专注于验证PGM并确定其在AJCC IV期黑色素瘤患者的正在进行的前瞻性多中心II期BC和维持生物治疗试验中的临床效用。

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.