SBIR-STTR Award

Aromatase Inhibitors (AI) are the preferred hormonal treatment for estrogen receptor positive Breast Cancer (BC) in postmenopausal women and are used to treat approximately 140,000 patients annually in the US. However, ~40% of patients will be, or become resistant to AIs. If sensitivity to AI can be re-established in patients that have become resistant, this would be a major step forward in treating ER+ BC patients. The PI has characterized a growth factor, GP88, and demonstrated its critical role in the development, proliferation and survival of cancer cells. Importantly, the PI has demonstrated using in vitro studies that GP88 is a driver in controlling cancer cell resistance to AIs such as Letrozole. The PI has developed a neutralizing monoclonal anti-GP88 antibody, shown in vitro to return BC cell sensitivity to AIs in previously AI resistant cell lines. This application seeks to prove through the use of xenograft studies that anti-GP88 is effective in vivo in restoring AI sensitivity in previously resistant tumors. If successful, anti-GP88 in conjunction with AI therapy in AI resistant patients would be a major advancement in treating BC patients that currently have systemic chemotherapy as their only option and could improve overall BC survival.

NIH Spending Category:
Aging; Biotechnology; Breast Cancer; Cancer; Estrogen

Project Terms:
Antibodies; Aromatase Inhibitors; Breast Cancer Cell; cancer cell; Cancer Patient; Cell Line; chemotherapy; Development; Drug resistance; Estrogen Antagonists; Estrogen receptor positive; Estrogen Therapy; Growth Factor; Hormonal; hormone therapy; improved; In Vitro; in vivo; Letrozole; malignant breast neoplasm; Monitor; novel; Nude Mice; Patients; Postmenopause; Resistance; Role; Tamoxifen; tumor; tumor growth; tumor xenograft; Woman; Xenograft procedure

Our Phase I Contract demonstrated that AG1, an anti-GP88 (Progranulin) recombinant antibody potentiated the efficacy of anti-estrogen (AE) based therapy to inhibit tumor growth in breast cancer xenografts. Additionally we have demonstrated that AG1 is efficacious as a single agent in lung cancer xenografts. The significant: >50% of estrogen positive (ER+) breast cancer patients are, or become insensitive to AE therapy and ~50% lung cancer patients die even when disease is detected at an early stage. Thus potentiating efficacy of AE in ER+ breast cancer potentially offers a treatment solution for AE resistant patients and improving treatment options for early stage lung cancer may reduce the number of deaths. These biological data, together with the complete manufacturing process and stability studies that we have developed for AG1, supports moving AG1 into final pre-clinical studies. The PI is requesting support in form of a Phase II contract to enable the production of a batch of AG1, complete dosing studies, and perform repeat-dose in life toxicology (Acute dose previously performed), pharmacokinetics and dose assessment in non-human primates and file an IND with the US FDA for first in human safety and efficacy studies for indications of breast and lung cancer. Acute; Anti-Idiotypic Antibodies; Antineoplastic Agents; base; Biological; Cancer Patient; Cessation of life; Clinical; Clinical Research; Contracts; Data;Development; Development Plans; Disease; Dose; Drug Kinetics; efficacy trial; Estrogen Antagonists; Estrogen Therapy; Estrogens; Human; improved ;Life; malignant breast neoplasm; Malignant neoplasm of lung; manufacturing process; Measures; Non-Small-Cell Lung Carcinoma; nonhuman primate; novel; Nude Mice; Patients; Phase; pre-clinical; reclinical study; Preparation; Production; Progranulin; Recombinant Antibody; Resistance; Safety; Solutions; Staging; Toxicology tumor growth; Xenograft Model; Xenograft procedure;