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。尽管治疗取得了进步，但5年生存率低至15%。目前的非小细胞肺癌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，包括只有适度的生存率增加和对患者的显著毒性。非小细胞肺癌现有治疗方法在疗效和安全性方面的局限性突出了对新治疗方法的需求。近年来研究发现，髓细胞上表达的触发受体（TREM-1）在NSCLC的进展中起着重要作用。巨噬细胞中短发夹RNA （shRNA）抑制TREM-1可抑制癌细胞侵袭。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抑制可以提高NSCLC患者的生存率。该项目的长期目标是开发一种靶向治疗非小细胞肺癌的新方法。I期研究的主要目标是证明TREM-1的特异性失活与新型抑制肽在动物模型系统中抑制肿瘤进展并提高生存率。第一阶段的具体目标是：1)生成和表征TREM-1抑制肽的可注射配方，2)在非小细胞肺癌小鼠模型中测试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。这些肽采用新颖的、不依赖于配体的作用机制，预计副作用较小。为了提高肽的溶解度、生物利用度和靶向tam，我们将利用SignaBlok专有的纳米系统来靶向巨噬细胞递送水不溶性和低水溶性药物。我们将使用非小细胞肺癌的NCI-H292异种移植小鼠模型来测试自由和颗粒形式的肽抑制癌症进展和促进生存的能力。预计该研究将发现新的抗癌先导化合物，为开发新的非小细胞肺癌靶向治疗奠定基础，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的项目中进一步改进这项技术。重要的是，TREM-1可能不仅在NSCLC的进展中起作用，而且在其他肿瘤的进展中也起作用。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。

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.