Development of novel targeted agents in lung cancer

描述（由申请人提供）：非小细胞肺癌（NSCLC）每年影响超过222，000名美国人。尽管治疗取得了进展，但5年生存率低至15%。目前NSCLC的治疗包括细胞毒性化疗和靶向生物治疗。它们都有多种缺点，包括仅适度增加存活率和对患者的显著毒性。与NSCLC可用治疗相关的疗效和安全性的局限性突出了对新治疗的需求。如最近发现的，髓样细胞上表达的触发受体（TREM-1）在NSCLC进展中起作用。通过巨噬细胞中的短发夹RNA（shRNA）抑制TREM-1显示出抑制癌细胞侵袭。在临床环境中，肿瘤相关巨噬细胞（TAM）上TREM-1低表达患者的4年生存率为60%，而高表达患者的4年生存率为20%。我们假设TREM-1抑制可以改善NSCLC患者的生存。该项目的长期目标是开发一种新的靶向治疗NSCLC的方法。I期研究的主要目标是证明用新型抑制肽特异性灭活TREM-1抑制动物模型系统中的肿瘤进展并提高存活率。I期的具体目标是：1）产生和表征TREM-1抑制肽的可注射制剂，和2）在NSCLC的小鼠模型中测试TREM-1抑制肽。这些肽将使用SignaBlok专有的TREM-1信号模型进行设计。这些肽采用新的、配体非依赖性的作用机制，预计副作用较轻。为了增加肽的溶解度、生物利用度和靶向TAM，我们将利用SignaBlok的专有纳米系统，用于水不溶性和水溶性差的药物的巨噬细胞靶向递送。我们将使用NSCLC的NCI-H292异种移植小鼠模型来测试游离和颗粒形式的肽抑制癌症进展和促进存活的能力。预计拟议的研究将确定新的抗癌先导化合物，为开发新的NSCLC靶向治疗奠定基础，从而提高患者的生存率。第一阶段的数据将用于在第二阶段计划中进一步改进这项技术。重要的是，TREM-1不仅在NSCLC的进展中发挥作用，而且在其他肿瘤的进展中也发挥作用。因此，第一阶段的成功完成将为可能适用于各种肿瘤的假设提供概念证明。 公共卫生相关性：非小细胞肺癌的死亡人数超过乳腺癌、结肠癌和前列腺癌的总和，5年生存率为15%。目前的治疗有许多缺点，包括生存率只有适度的提高和对患者的显著毒性。这项拟议的研究预计将导致开发新的抗癌疗法，可以大大改善这种类型癌症的治疗，从而提高患者的生存率。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) affects over 222,000 Americans annually. Despite advances in therapy, the 5-year survival rate is as low as 15%. Current treatments of NSCLC include cytotoxic chemotherapy and targeted biologic therapies. They all have multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The limitations in efficacy and safety associated with availabe treatments for NSCLC highlight the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1) plays a role in NSCLC progression. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages is shown to suppress cancer cell invasion. In clinical setting, the 4-year survival rate in patients with low expression of TREM-1 on tumor-associated macrophages (TAMs) is 60%, compared with 20% in those with high expression. We hypothesize that TREM-1 inhibition can improve survival of NSCLC patients. The long-term objective of the proposed project is to develop a novel approach to targeted treatment of NSCLC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel inhibitory peptides suppresses tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test the TREM-1 inhibitory peptides in a mouse model of NSCLC. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These peptides employ novel, ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use a NCI-H292 xenograft mouse model of NSCLC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival. It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of NSCLC, thereby leading to a higher survival rate of the patients. The Phase I data will be used to further improve this technology in a Phase II program. Importantly, TREM-1 may play a role in the progression of not only NSCLC but also other tumors. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer kills more patients than breast, colon, and prostate cancer combined, and the 5- year survival rate is 15%. Current treatment has multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.