Abstract 4803: Limiting heme availability as an effective strategy to target lung cancer growth and progressionin vivo

Lung cancer is the leading cause of cancer-related death in the US. About 85% of cases are non-small cell lung cancer (NSCLC). Several chemotherapeutic and targeted therapeutic agents are approved for treating lung cancer, but the five-year survival rate remains low. Thus, alternative approaches for are required for treatment of lung cancer. Several studies demonstrate that enhanced mitochondrial respiration or oxidative phosphorylation (OXPHOS) is a key feature of NSCLC. Heme is a central metabolic molecule that serves as a prosthetic group in several proteins involved in oxygen transport, utilization, and storage. Previous studies from our lab show elevated levels of heme synthesis, uptake, and oxygen utilizing hemoproteins in NSCLC cells compared to normal cells. The results also demonstrate that inhibiting heme synthesis selectively inhibits proliferation of NSCLC cells. We hypothesize that elevated levels of heme are used as fuel for enhanced OXPHOS by NSCLC cells. Therefore, targeting heme flux and function can be an effective way of targeting NSCLC growth and progression. If elevated heme metabolism is crucial for the tumorigenic functions of NSCLC cells, limiting heme availability may be effective for suppressing lung tumor growth and progression. Therefore, we tried to lower heme availability by utilizing bacterial hemophores. We designed several heme-targeting peptides (HTAs) and tested their ability to inhibit heme uptake in NSCLC cell lines, subcutaneous xenografts, and lung orthotopic xenografts. NSCLC cells expressing luciferase were used to implant subcutaneous xenografts or lung orthotopic xenografts in NOD/SCID mice. The mice were treated with HTA to check if limiting heme availability would delay growth in NSCLC tumor xenografts. Also, mice with lung orthotopic xenografts treated with HTA were treated with a well-known chemotherapeutic agent, docetaxel, to determine if HTA pre-treatment improves survival in these mice. In vivo bioluminiscence imaging (BLI) was used to analyze growth and progression of orthotopic lung xenografts. Our BLI data show that HTA treatment causes a significant decrease in radiance (total photons/second) in subcutaneous xenografts and lung orthotopic xenografts. This is supported by Hematoxylin and Eosin (H & E) staining in paraffin-embedded tissue sections from lung orthotopic xenografts and tumor volumes of subcutaneous xenograft tumors resected from mice. Furthermore, in mice with lung orthotopic xenografts, HTA pre-treatment leads to a marked improvement in survival of mice further treated with docetaxel as compared to docetaxel treatment alone. Our results indicate that limiting heme availability can be an effective strategy to limit growth and progression of NSCLC and can be used to increase their vulnerability to chemotherapeutic agents like docetaxel. Citation Format: Poorva Ghosh, Sarada Preeta Kalainayakan, Sanchareeka Dey, Adnin Ashrafi, Li Zhang. Limiting heme availability as an effective strategy to target lung cancer growth and progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4803.