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率的主要原因。 2010年，美国诊断出222,520例新的肺癌病例，85％是非小细胞肺癌（NSCLC）和157,300例与肺癌相关的死亡。显然，需要其他新颖的治疗选择。抗EGF-R和抗V-EGF疗法的使用证明了靶向疗法和单克隆抗体方法的潜力。针对癌细胞至关重要的靶标的新型治疗的发展，但预计不针对正常组织有效，并最大程度地减少对健康细胞的损害。 A＆G Pharmaceutical Inc.专注于识别癌症的治疗靶标，以开发具有伴侣诊断的生物学靶向治疗。这些活性导致发现了88 kDa颗粒蛋白前体（GP88），这是一种自分泌生长因子，其临时性证明是在NSCLC肿瘤中发挥作用。我们已经表明：1）GP88是NSCLC的自分泌生长/生存因子； 2）NSCLC中GP88的表达增加与NSCLC的肿瘤性特性呈正相关； 3）GP88介导肿瘤细胞血管生成和侵袭性； 4）过表达GP88的NSCLC对当前疗法有抵抗力； 5）gp88在恶性组织中的表达增加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复发风险增加有关； 7）预后不良的肺癌患者的血清水平升高； 8）中和抗人GP88单克隆抗体（AG1）已在我们的实验室中开发出来，并在我们的乳腺癌异种移植系统中得到了验证。使用NSCLC的初步结果表明，AG1废除了GP88功能活性。 I期SBIR应用的重点是完全表征AG1对NSCLC异种移植物的影响。具体目的是：1）确定抗人GP88单克隆抗体AG1在单疗法中对裸小鼠异种移植模型非小细胞癌的疗效和效力。我们将确定具有H1299和A549细胞广泛用作NSCLC模型的异种移植模型中AG1的最佳治疗剂量； 2）确定AG1抗体与化学治疗剂（多西他赛，顺铂和吉西他滨）在NSCLC标准中使用的作用。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AG1是否与每种化疗药物合并会增强其作用。在本第I阶段结束时，我们将证明GP88是否是NSCLC靶向治疗的候选者，并确定了AG1对NSCLC的最佳治疗作用。如果成功，这种新型疗法将有可能改善治疗方法并提高NSCLC患者的生存结果和生活质量。 公共卫生相关性： 肺癌仍然是全球男女癌症和死亡率的主要原因。 A＆G Pharmaceutical Inc.发现了一个新的目标，该目标在肿瘤生长，生存和对当前疗法的耐药性中起关键作用。该实验室开发了可以阻止该生长因子对肿瘤形成的作用的药物。本应用提出可行性研究，以研究该药物是否可以抑制肺癌，尤其是在小细胞肺癌上。在这一阶段I SBIR研究结束时，我们将建立可行性研究，以开发新的肺癌疗法。

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