SBIR-STTR Award

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.

Public Health Relevance Statement:
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.

NIH Spending Category:
Biotechnology; Cancer; Lung; Lung Cancer

Project Terms:
A549; Adverse effects; angiogenesis; Antibodies; autocrine; Biological; cancer cell; cancer diagnosis; Cancer Etiology; Cancer Model; Cancer Patient; cancer therapy; Categories; Cell Line; Cells; Cessation of life; chemotherapeutic agent; chemotherapy; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; clinical toxicology; Clinical Trials; Combined Modality Therapy; Companions; cost; Development; Diagnosis; Diagnostic; Disease; docetaxel; Dose; EGF gene; Epidermal Growth Factor Receptor; Feasibility Studies; Future; gemcitabine; Goals; Growth; Growth Factor; H1299; high risk; Human; improved; in vivo; Laboratories; lung small cell carcinoma; Malignant - descriptor; malignant breast neoplasm; Malignant neoplasm of lung; Malignant Neoplasms; Mediating; Medical Surveillance; men; Mono-S; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mortality Vital Statistics; Mus; neoplastic cell; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; novel; novel therapeutics; Nude Mice; Outcome; outcome forecast; overexpression; Patients; PC cell-derived growth factor; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Play; Population; pre-clinical; preclinical study; Production; Progranulin; Property; Protein Tyrosine Kinase; Quality of life; receptor; Recurrence; Regimen; Resistance; Risk; Role; Serum; Small Business Innovation Research Grant; Small Cell Carcinoma; Staging; standard of care; System; theranostics; Therapeutic; Therapeutic Effect; therapy development; Tissues; Treatment Protocols; tumor; tumor growth; tumorigenesis; tumorigenic; Woman; Xenograft Model; Xenograft procedure

Significance: In 2016, 224,390 new cases of LC and 158,080 related deaths are expected in the US. Of new LC cases ~85% are non-small cell lung cancer (NSCLC) and 70% of these are diagnosed with metastatic/ locally advanced/ inoperable LC with a 5-yr survival of less than 17%. A new approach is required to reduce the overall death rates in this devastating disease. Efficacious therapies targeting EGFR, ALK and ROS translocations and vEGF are used in standard of care (SoC). However, they are only effective in <10% of the overall NSCLC population. FDA approved companion diagnostics are used to identify patients that may receive benefit from these drugs. In spite of these advances, no therapy is curative in advanced disease and median life expectancy for metastatic NSCLC remains at ~12 mths. Hypothesis: We have identified GP88, an 88 kDa glycoprotein autocrine intimately involved in cellular deregulated growth leading to tumor formation. The PI, demonstrated GP88’s critical role in the biological process of cancer tumorigenesis and survival, its overexpression in LC tumors while it is not expressed in normal lung tissue, its secretion into biological fluids at increased levels in LC patients compared to healthy individuals. Thus using a tissue test to identify tumors that express GP88 and then treating these patients with an antibody that neutralizes GP88 and therefore blocks its autocrine effect on cancer cells will a) inhibit tumor growth and b) increase the efficacy of current LC drugs. Supporting Evidence: Pathological studies established GP88 tumor expression as a predictive marker for recurrence. Clinical studies showed LC patients with progressive disease have elevated GP88 serum levels compared to healthy individuals. In Vivo studies demonstrated that AG1, a recombinant anti-GP88 can reduce the growth of human LC xenografts in mice and potentiate the effect of SoC drugs. Strategy and Approach: We will carry out a phase I clinical trial using AG1 to determine safety and recommended phase 2 dose. In addition, we will require tissue collection and serial blood sampling on all patients to evaluate for GP88 expression (tissue) and concentration (blood) in enrolled patients and expansion cohorts of NSCLC and mesothelioma, diseases demonstrated to express GP88 correlated with outcome. The IHC test measures GP88 expression in tumor tissue to identify patients with tumors expressing GP88. The serum GP88 EIA test can provide real time monitoring of disease status in the SoC. Specific aim 1: Manufacture 300gms of GMP AG1 for the Phase I clinical studies Specific Aim 2: Perform a Phase I clinical study in (a) patients with solid tumors to determine maximum tolerated dose/ optimum biological dose and (b) expansion cohorts with LC and mesothelioma patients. Overall Impact: Blocking the action of GP88 in aggressive cancer such as LC using a neutralizing antibody will 1) inhibit tumor growth 2) potentiate standard of care drugs. There is compelling biological and clinical evidence to suggest that GP88 is therapeutic target with companion diagnostics for NSCLC that could impact LC treatment and improve survival of patients with NSCLC. Lay outline In 2016, 224,390 new cases of LC and 158,080 related deaths are expected in the US. The majority of these are non-small cell lung cancer (NSCLC) that are diagnosed with metastatic cancer and only 17% of these will be alive at 5yrs post diagnosis. Drugs that are effective in this disease are only useful in less than 10% of the NSCLC population and no curative therapies exist. A new approach that will benefit a larger population and provides increased life expectancy needs to be developed. We have identified GP88, a glycoprotein that is produced by cancer cells and stimulates growth and survival of the same cancer cells leading to tumor formation. GP88 is found in LC but not normal lung tissue. There is compelling biological and clinical evidence to suggest that GP88 is therapeutic target with companion diagnostics for NSCLC that could impact treatment and improve survival of patients with NSCLC. We have developed a tissue test to identify which tumors express GP88 and an anti-GP88 (AG1) to block the action of GP88 on tumor tissues to a) inhibit tumor growth and b) increase the efficacy of current LC drugs. Additionally, a blood test has been developed to monitor patients while on treatment. Using AG1 as the therapy with two companion diagnostic tests we will carry out a phase I clinical trial to determine safety of AG1 in humans and will collect tumor tissue and blood on all patients to evaluate for GP88 expression (tissue) and concentration (blood).

Public Health Relevance Statement:
In 2016, 224,390 new cases of LC and 158,080 related deaths are expected in the US. The majority of these are non-small cell lung cancer (NSCLC) that are diagnosed with metastatic cancer and only 17% of these will be alive at 5yrs post diagnosis. Drugs that are effective in this disease are only useful in less than 10% of the NSCLC population and no curative therapies exist. A new approach that will benefit a larger population and provides increased life expectancy needs to be developed. We have identified GP88, a glycoprotein that is produced by cancer cells and stimulates growth and survival of the same cancer cells leading to tumor formation. GP88 is found in LC but not normal lung tissue. There is compelling biological and clinical evidence to suggest that GP88 is therapeutic target with companion diagnostics for NSCLC that could impact treatment and improve survival of patients with NSCLC. We have developed a tissue test to identify which tumors express GP88 and an anti-GP88 (AG1) to block the action of GP88 on tumor tissues to a) inhibit tumor growth and b) increase the efficacy of current LC drugs. Additionally, a blood test has been developed to monitor patients while on treatment. Using AG1 as the therapy with two companion diagnostic tests we will carry out a phase I clinical trial to determine safety of AG1 in humans and will collect tumor tissue and blood on all patients to evaluate for GP88 expression (tissue) and concentration (blood).

Project Terms:
Acute; Address; advanced disease; autocrine; Biological; Biological Process; Biotechnology; Blood; Blood specimen; Blood Tests; cancer cell; cancer diagnosis; Cell Line; Cessation of life; Clinical; Clinical Research; cohort; companion diagnostics; curative treatments; Data; Death Rate; design; Diagnosis; Diagnostic tests; Disease; Disseminated Malignant Neoplasm; Documentation; Dose; Drug resistance; efficacy study; Eligibility Determination; Enrollment; Epidermal Growth Factor Receptor; FDA approved; Glycoproteins; Growth; Human; improved; in vivo; Individual; Institutional Review Boards; Laboratories; Life Expectancy; Liquid substance; Lung Neoplasms; Malignant Neoplasms; manufacturing process; Maximum Tolerated Dose; Measures; Mesothelioma; Monitor; Mus; Neoplasm Metastasis; neutralizing antibody; new therapeutic target; Non-Small-Cell Lung Carcinoma; nonhuman primate; novel strategies; Outcome; overexpression; Pathologic; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Phase I Clinical Trials; Population; preclinical study; predictive marker; Process; Progressive Disease; Publishing; Recombinants; Recurrence; Risk; Role; Safety; Serum; Small Business Innovation Research Grant; Solid Neoplasm; standard of care; Structure of parenchyma of lung; System; targeted treatment; Technology Transfer; Testing; therapeutic target; Time; Tissue Banks; Tissues; Toxicology; Treatment Efficacy; tumor; tumor growth; Tumor Tissue; tumorigenesis; Vascular Endothelial Growth Factors; Xenograft procedure