EGFR antisense DNA added to cetuximab and radiotherapy for head and neck cancer

描述(申请人提供)：表皮生长因子受体(EGFR)在头颈部鳞状细胞癌(SCCHN)中表达上调，并与不良预后有关。我们已经开发了肿瘤内EGFR反义寡核苷酸基因疗法(EGFR AS)，作为一种安全且潜在有效的治疗SCCHN的方法，正如匹兹堡大学进行的前一阶段研究所显示的那样。在目前的提案中，我们正在将EGFR AS用于治疗潜在的可治愈的局部晚期SCCHN。近年来，随着全身化疗药物的加入，局部晚期SCCHN的标准治疗方案得到了改善。然而，局部区域控制和生存仍然是次优的。此外，以顺铂为基础的放化疗与严重毒性反应的发生率很高。西妥昔单抗(Erbitux或C225)是一种嵌合的EGFR单抗，在SCCHN的III期试验中显示出生存益处，并被FDA批准用于治疗局部晚期SCCHN。放疗加西妥昔单抗目前被认为是标准疗法，特别是对那些不适合顺铂化疗的患者。在拟议的II期研究中，我们计划在30名老年(即70岁或以上)或不符合顺铂条件的局部晚期SCCHN患者中，通过将EGFR与标准西妥昔单抗合并西妥昔单抗同时使用来评估双重EGFR抑制作用。我们将评估局部区域无进展生存率(主要终点)、其他疗效参数和毒性。EGFR AS将通过临床确定的直接可视化或内窥镜直接瘤内注射，每周给予一次。为了研究双重EGFR抑制的抗肿瘤机制，我们将利用逆相蛋白芯片(RPPA)和免疫组织化学方法对治疗前后的肿瘤标本进行包括EGFR通路相关信号蛋白在内的肿瘤组织生物标志物的检测。如果联合使用EGFR AS、西妥昔单抗和放射治疗符合预先指定的疗效标准，将被提交进一步的临床试验。我们的目标是开发一种新颖、有效和安全的联合疗法，特别适合不能耐受化疗的SCCHN患者。公共卫生相关性：该项目涉及针对表皮生长因子受体(EGFR)的基因治疗，EGFR是头颈部癌细胞生长的重要分子。我们计划在标准放疗和西妥昔单抗治疗期间，将抗EGFR基因注射到头颈癌肿瘤中。我们的目标是开发一种新的、有效和安全的晚期头颈癌联合疗法，特别适合不能耐受化疗的老年或虚弱患者。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinoma of the head and neck (SCCHN) and has been associated with poor prognosis. We have developed intratumoral EGFR antisense oligonucleotide gene therapy (EGFR AS) as a safe and potentially efficacious treatment for SCCHN as shown in a previous phase I study conducted at the University of Pittsburgh. In the current proposal, we are incorporating EGFR AS in the treatment of potentially curable, locally advanced SCCHN. In recent years, standard therapeutic options for locally advanced SCCHN have improved with the addition of systemic agents to radiation. However, locoregional control and survival remain suboptimal. Moreover, cisplatin-based chemoradiotherapy is associated with a high incidence of serious toxicities. Cetuximab (Erbitux or C225) is a chimerized EGFR monoclonal antibody that has demonstrated survival benefit in a phase III trial in SCCHN and was approved by the FDA for the treatment of locally advanced SCCHN. Radiation plus cetuximab is currently considered standard therapy, especially for patients who are not good candidates for cisplatin chemotherapy. In the proposed phase II study, we plan to evaluate dual EGFR inhibition by adding intratumoral EGFR AS to standard cetuximab with concurrent cetuximab in 30 patients with previously untreated locally advanced SCCHN who either elderly (i.e. 70 years or older) or cisplatin-ineligible. We will evaluate the locoregional progression-free survival (primary endpoint), other efficacy parameters, and toxicities. EGFR AS will be administered weekly by direct intratumoral injection using direct visualization or endoscopy as clinically determined. In order to study the antitumor mechanism of dual EGFR inhibition we will evaluate tumor tissue biomarkers, including EGFR pathway-related signaling proteins, using reverse phase protein microarrays (RPPA) and immunohistochemistry in tumor samples taken before and after therapy. If combination therapy with EGFR AS, cetuximab, and radiation meets the prespecified efficacy criteria will be forwarded to further clinical testing. Our goal is to develop a novel, efficacious and safe combination therapy that will be particularly suitable for patients with SCCHN who cannot tolerate chemotherapy. PUBLIC HEALTH RELEVANCE: This project involves the use of gene therapy against the epidermal growth factor receptor (EGFR), an important molecule for the growth of head and neck cancer cells. We plan to inject an anti-EGFR gene into head and neck cancer tumors during treatment with standard radiation and cetuximab. Our goal is to develop a novel, efficacious and safe combination therapy for advanced head and neck cancer that will be particularly suitable for elderly or frail patients who cannot tolerate chemotherapy.