Novel biologic markers of treatment resistance in locally advanced cervical carci

描述（由申请人提供）：尽管有有效的细胞学筛查计划和治疗侵袭前宫颈发育不良的能力，但在全球范围内，宫颈癌是导致女性癌症死亡的第三大原因。虽然大约三分之二的女性在疾病局限于子宫颈时被诊断出来，并有可能通过手术治愈，但其余三分之一的女性癌症已经扩散到子宫颈以外的盆腔周围组织（称为局部晚期宫颈癌）。这些患者的主要治疗方式是铂化疗联合盆腔放射治疗（CRT）。不幸的是，肿瘤5年复发率仍然在30-40%之间。一小部分在联合CRT后复发的患者可以通过超根治性手术来挽救，但对于大多数女性来说，姑息性化疗是唯一的选择。放疗和基于pt的治疗后的高失败率为鉴定与耐药性相关的分子标记提供了令人信服的理由。对这些标记物的验证将使识别那些可能无法通过标准治疗的患者成为可能，从而引导临床医生寻求替代的非铂治疗方案，如靶向治疗、生物制剂和临床试验。我们的总体假设是肿瘤和正常组织细胞都有助于局部变化，影响肿瘤生长和对联合CRT的抵抗。我们预测血管生成过程中血管内皮细胞的变化将提供新的生物标志物，这将是治疗成功的预后。此外，不同的肿瘤蛋白也代表了预测肿瘤对CRT反应的生物标志物。因此，我们的研究计划旨在鉴定和验证参与血管生成的内皮来源蛋白，以及肿瘤特异性DNA修复蛋白作为预测肿瘤对原发性CRT耐药性的新生物标志物。我们的第三个目标是将这些标志物与标准的临床和病理预后和诊断参数结合起来，开发一个预测肿瘤对治疗反应和患者预后的复合指数。

DESCRIPTION (provided by applicant): Novel biologic markers of treatment resistance in locally advanced cervical carcinoma Cervical cancer is the third leading cause of cancer mortality in women worldwide, despite effective cytologic screening programs and the ability to treat pre-invasive cervical dysplasia. While approximately two-thirds of women will be diagnosed when their disease is confined to the cervix and will potentially be cured with surgery, the remaining one-third will have cancer that has spread beyond the cervix into the surrounding pelvic tissues (known as locally advanced cervical cancer). The main treatment modality for these patients is platinum (Pt) chemotherapy in combination with pelvic radiation therapy (CRT). Unfortunately, tumor recurrence rates at five years still range from 30-40%. A small percentage of these patients with recurrence following combined CRT can be salvaged with ultra-radical surgery, but for the majority of these women palliative chemotherapy is the only remaining option. High failure rates after radiation and Pt-based therapy provide a compelling rationale for the identification of molecular markers associated with resistance. Validation of such markers would make it possible to identify those patients who are likely to fail standard therapy, leading the clinician to pursue alternative non-Pt based regimens such as targeted therapies, biologics and clinical trials. Our overall hypothesis is that both tumor and normal tissue cells contribute to local changes that affect tumor growth and resistance to combined CRT. We predict that changes in the vascular endothelial cells that occur duing angiogenesis will provide novel biomarkers that will be prognostic for treatment success. Further, distinct tumor proteins also represent biomarkers that are prognostic for tumor response to CRT. Thus our research program aims to identify and validate endothelial-derived proteins involved in angiogenesis, as well as tumor- specific DNA repair proteins as novel biomarkers to predict tumor resistance to primary CRT. Our third aim is to combine these markers with standard clinical and pathologic prognostic and diagnostic parameters to develop a composite index that is predictive of tumor response to therapy and patient outcome. PUBLIC HEALTH RELEVANCE: Cervical cancer is the third leading cause of cancer mortality in women worldwide, despite effective cytologic screening programs and the ability to successfully treat pre-invasive cervical dysplasia. This research program aims to develop a composite biomarker and clinicopathologic index that is predictive of tumor persistence or durable response to cisplatin-based chemoradiation, in order to improve clinical decision-making for women with cervical carcinoma.