Targeted Therapy for Non Small Cell Lung Carcinoma: In vivo Feasibility Studies

描述(由申请人提供)： 肺癌仍然是全球男性和女性癌症和死亡的主要原因。2010年，美国新诊断的肺癌病例有222,520例，其中85%是非小细胞肺癌(NSCLC)，与肺癌相关的死亡人数为157,300人。显然，需要更多和新的治疗选择。抗EGF-R和抗v-EGF治疗的使用已经证明了靶向治疗和单抗方法的潜力。针对癌细胞而不是正常组织的靶向、关键和特异的新疗法的发展有望是有效的，并将对健康细胞的损害降至最低。A&G制药公司专注于确定癌症的治疗靶点，以便开发具有伴随诊断的生物靶向治疗。这些活动导致了88 kDa颗粒蛋白前体(GP88)的发现，这是一种临床前被证实在非小细胞肺癌肿瘤发生中发挥作用的自分泌生长因子。结果表明：1)GP88是非小细胞肺癌的自分泌生长/生存因子；2)GP88高表达与NSCLC的致瘤性呈正相关；3)GP88介导肿瘤细胞的血管生成和侵袭性；4)高表达GP88的NSCLC对现有治疗方案耐药；5)在恶性组织中高表达的GP88与预后不良的参数相关，而正常组织为阴性；6)GP88的高表达与早期NSCLC复发的风险增加有关；7)预后不良的肺癌患者血清GP88水平升高；8)本实验室研制了一种中和抗人GP88的单抗(AG1)，并已在我们的乳腺癌异种移植系统中得到验证。NSCLC的初步结果表明，AG1取消了GP88的功能活性。第一阶段SBIR应用的重点是充分表征AG1对非小细胞肺癌异种移植的影响。其具体目的是：1)检测抗人GP88单抗AG1对裸鼠非小细胞癌裸鼠移植瘤模型的单一治疗效果和效力。我们将在以H1299和A549细胞作为非小细胞肺癌模型的异种移植模型中确定AG1的最佳治疗剂量；2)确定AG1抗体与非小细胞肺癌治疗标准中使用的化疗药物(多西紫杉醇、顺铂和吉西他滨)联合治疗的效果。最初，多西他赛、顺铂和吉西他滨的最佳治疗剂量将在单一疗法中使用A549和NCI-H1299异种移植来确定。我们将确定AG1与每种化疗药物联合是否会增强其效果。在第一阶段结束时，我们将证明GP88是否是非小细胞肺癌靶向治疗的候选药物，并确立了AG1对非小细胞肺癌的最佳治疗效果。如果成功，这种新的治疗方法将有可能改善治疗，提高非小细胞肺癌患者的生存结果和生活质量。 公共卫生相关性： 肺癌仍然是全球男性和女性癌症和死亡的主要原因。A&G制药公司发现了一种新的靶点，该靶点在肿瘤生长、生存和对当前疗法的耐药性方面发挥着关键作用。该实验室已经开发出可以阻断这种生长因子在肿瘤形成中的作用的试剂。本申请提出了可行性研究，以调查该药物是否可以抑制肺癌，特别是对小细胞肺癌。在这项第一阶段SBIR研究结束时，我们将确定开发肺癌新疗法的可行性研究。

DESCRIPTION (provided by applicant): Lung Cancer remains the leading cause of cancer and mortality for men and women worldwide. In 2010, there were 222,520 new cases of lung cancer diagnosed in the US, 85% being non small cell lung cancer (NSCLC) and 157,300 lung cancer related deaths. Clearly, there is a need for additional and novel therapeutic options. The use of anti-EGF-R and anti v-EGF therapies has proven the potential of targeted therapies and monoclonal antibody approaches. The development of novel therapy against target critical and specific to the cancer cells but not to the normal tissues is expected to be efficacious and minimize damage to healthy cells. A&G Pharmaceutical Inc. is focused on identifying theranostic target for cancer in order to develop biological targeted therapy with companion diagnostics. These activities have led to the discovery of the 88 kDa granulin precursor (GP88), an autocrine growth factor preclinically validated as playing a role in NSCLC tumorigenesis. We have shown that: 1) GP88 is an autocrine growth/survival factor for NSCLC; 2) increased GP88 expression in NSCLC positively correlates with increased tumorigenic properties of NSCLC; 3) GP88 mediates tumor cell angiogenesis and invasiveness; 4) NSCLC overexpressing GP88 are resistant to current therapies; 5) increased GP88 expression in malignant tissue correlates with parameters of poor prognosis while normal tissue is negative; 6) high expression of GP88 is associated with increased risk of recurrence in early stage NSCLC; 7) lung cancer patients with poor prognosis have elevated GP88 serum levels; 8) a neutralizing anti-human GP88 monoclonal antibody (AG1) has been developed in our laboratory and been validated previously in our breast cancer xenograft system. Preliminary results using NSCLC indicated that AG1 abrogates GP88 functional activity. The phase I SBIR application focuses on fully characterizing AG1 effect on NSCLC xenografts. The specific aims are: 1) Determine the efficacy and potency of anti-human GP88 monoclonal antibody AG1 in mono-therapy for non small cell carcinoma in nude mice xenograft models. We will determine the optimal therapeutic dose of AG1 in xenograft models with H1299 and A549 cells widely used as NSCLC models; 2) Determine the effect of AG1 antibody in combination therapy with chemotherapeutic agents (docetaxel, cisplatin and gemcitabine) that are used in the standard of care for NSCLC. Initially, optimal therapeutic dose for docetaxel, cisplatin and gemcitabine will be determined using A549 and NCI-H1299 xenografts in a monotherapy regimen. We will determine if AG1 combined with each chemotherapeutic drug will potentiate its effect. At the conclusion of this Phase I, we will have demonstrated whether GP88 is a candidate for NSCLC targeted therapy and established the optimal therapeutic effects of AG1 for NSCLC. If successful, such novel therapy will have the potential to improve treatment and increase the survival outcomes and quality of life of NSCLC patients. PUBLIC HEALTH RELEVANCE: Lung Cancer remains the leading cause of cancer and mortality for both men and women worldwide. A&G Pharmaceutical Inc. has discovered a novel target that plays a critical role in tumor growth, survival and resistance to current therapies. The laboratory has developed agents that can block the action of this growth factor on tumor formation. The present application proposes feasibility studies to investigate if this agent can be inhibit lung cancer, particularly on small cell lung carcinoma. At the end of this phase I SBIR study, we will have established feasibility studies to develop novel therapies for lung cancer.