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

非小细胞肺癌靶向治疗：体内可行性研究

• 批准号: 8312247
• 负责人: Ginette Serrero
• 金额: $ 19.39万
• 依托单位: A AND G PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312247
• 关键词: A549; Adverse effects; Antibodies; Biological; Cancer Etiology; Cancer Model; Cancer Patient; Categories; Cell Line; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; Companions; Development; Diagnosis; Diagnostic; Disease; Dose; EGF gene; Epidermal Growth Factor Receptor; Feasibility Studies; Future; Goals; Growth; Growth Factor; H1299; Human; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medical Surveillance; Mono-S; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nude Mice; Outcome; PC cell-derived growth factor; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Population; Production; Progranulin; Property; Protein Tyrosine Kinase; Quality of life; Recurrence; Regimen; Resistance; Risk; Role; Serum; Small Business Innovation Research Grant; Small Cell Carcinoma; Staging; System; Therapeutic; Therapeutic Effect; Tissues; Treatment Protocols; Woman; Xenograft Model; Xenograft procedure; angiogenesis; autocrine; cancer cell; cancer diagnosis; cancer therapy; chemotherapeutic agent; chemotherapy; clinical toxicology; cost; docetaxel; gemcitabine; high risk; improved; in vivo; lung small cell carcinoma; malignant breast neoplasm; men; mortality; neoplastic cell; novel; novel therapeutics; outcome forecast; overexpression; phase 1 study; pre-clinical; preclinical study; receptor; standard of care; theranostics; therapy development; tumor; tumor growth; tumorigenesis; tumorigenic

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.

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，美国诊断出222，520例肺癌新发病例，其中85%为非小细胞肺癌（NSCLC），157，300例肺癌相关死亡。显然，需要额外的和新的治疗选择。抗EGF-R和抗v-EGF治疗的使用已经证明了靶向治疗和单克隆抗体方法的潜力。针对癌细胞而非正常组织的关键和特异性靶点的新疗法的开发预计是有效的，并使对健康细胞的损害最小化。A&G制药公司致力于确定癌症的治疗诊断靶点，以开发具有伴随诊断的生物靶向治疗。这些活性导致发现了88 kDa颗粒蛋白前体（GP 88），一种临床前验证为在NSCLC肿瘤发生中发挥作用的自分泌生长因子。我们已经证明：1）GP 88是NSCLC的自分泌生长/存活因子; 2）NSCLC中GP 88表达增加与NSCLC的致瘤性增加正相关; 3）GP 88介导肿瘤细胞血管生成和侵袭性; 4）过表达GP 88的NSCLC对当前疗法有抗性; 5）恶性组织中GP 88表达增加与预后不良的参数相关，而正常组织为阴性; 6）GP 88的高表达与早期NSCLC中复发风险的增加相关; 7）预后不良的肺癌患者具有升高的GP 88血清水平; 8）我们实验室已经开发了中和抗人GP 88单克隆抗体（AG 1），并且先前在我们的乳腺癌异种移植系统中进行了验证。使用NSCLC的初步结果表明，AG 1消除GP 88功能活性。I期SBIR申请的重点是充分表征AG 1对NSCLC异种移植物的作用。具体目标是：1）测定抗人GP 88单克隆抗体AG 1在裸鼠移植瘤模型中对非小细胞癌的单一治疗的功效和效力。我们将确定AG 1在异种移植模型中的最佳治疗剂量，其中H1299和A549细胞广泛用作NSCLC模型; 2）确定AG 1抗体与NSCLC标准治疗中使用的化疗剂（多西他赛、顺铂和吉西他滨）联合治疗的效果。最初，将在单药治疗方案中使用A549和NCI-H1299异种移植物确定多西他赛、顺铂和吉西他滨的最佳治疗剂量。我们将确定AG 1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GP 88是否是NSCLC靶向治疗的候选者，并确定AG 1对NSCLC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NSCLC患者的生存结局和生活质量。 公共卫生关系： 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，在肿瘤生长、存活和对当前疗法的抵抗中起着关键作用。该实验室已经开发出可以阻断这种生长因子对肿瘤形成的作用的药物。本申请提出了可行性研究以调查该药剂是否可以抑制肺癌，特别是小细胞肺癌。在第一阶段SBIR研究结束时，我们将建立可行性研究，以开发肺癌的新疗法。

项目成果

GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma.

• DOI: 10.1016/j.humpath.2014.05.011
• 发表时间: 2014-09
• 期刊: HUMAN PATHOLOGY
• 影响因子: 3.3
• 作者: Edelman, Martin J.;Feliciano, Josephine;Yue, Binbin;Bejarano, Pablo;Ioffe, Olga;Reisman, David;Hawkins, Douglas;Gai, Qiwei;Hicks, David;Serrero, Ginette
• 通讯作者: Serrero, Ginette