Abstract 786: To examine the effect of limiting heme bioavailability on lung tumor growth & progression
Authors: Ghosh Poorva , Kalainayakan Sarada Preeta , Dey Sancharika , Sohoni Sagar , Zhang Li 
Published: August 2018

Numerous epidemiological studies in the past have shown that increased heme intake is associated with higher risk of several cancers, including lung cancer. Previous studies from our lab have demonstrated a significant increase in heme uptake, synthesis, and expression of oxygen utilizing hemoproteins in non -small cell lung cancer cells (NSCLCs) as compared to normal cells. Also, inhibition of heme synthesis was shown to negatively impact proliferation of NSCLCs specifically. This led us to hypothesize that heme fuels proliferation of NSCLC cells and promotes lung tumor growth. Heme is a central molecule for mitochondrial function and for all processes involved in oxygen utilization. Also, it serves as a prosthetic group in several oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Most human cells synthesize heme de novo and uptake heme from the circulation. The purpose of the study is to employ various strategies to limit bioavailability of heme and evaluate whether altering heme availability impacts NSCLC tumor growth and development in vivo.

To limit heme availability, we designed an agent (Heme targeting agent 1or HTA1) to sequester heme from circulation and thereby limit heme available for uptake. A well-known inhibitor of heme synthesis was used to limit heme synthesis. NSCLC cells that express luciferase was implanted in NOD/SCID mice to generate subcutaneous and lung orthotopic xenografts. The mice were treated with the HTA1 alone and HTA1 in combination with an inhibitor. We designed another agent (Heme targeting agent 2 or HTA2) that is thought to have higher heme binding affinity compared to HTA1. Treatment with HTA2 caused significantly greater reduction in growth and proliferation of NSCLCs in vitro as compared to HTA1. To assess its anti-tumor efficacy in comparison to HTA1 in vivo above-mentioned mice were treated with HTA2. Tumor growth was monitored by non-invasive bioluminescence imaging (BLI) using Perkin Elmer's IVIS Lumina III Imager.

In lung orthotopically implanted xenografts, BLI data show that there is a significant reduction in radiance (total flux in photons per second) in the treatment groups that received the HTA1 in combination with the inhibitor compared to HTA1 alone. Also, HTA2 caused a more effective reduction in radiance compared to HTA1. Immunohistochemistry was performed on lung tissues from the mice treated with the heme limiting agents mentioned above.

Our results indicate that combination of heme limiting agents works effectively in inhibiting lung tumor growth and progression by limiting both heme uptake and synthesis. Further studies to evaluate the potential of these heme limiting agents in inhibiting lung cancer growth and progression are underway.

Citation Format: Poorva Ghosh, Sarada Preeta Kalainayakan, Sancharika Dey, Sagar Sohoni, Li Zhang. To examine the effect of limiting heme bioavailability on lung tumor growth & progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 786.