A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-driven Non-small Cell Lung Cancer

• Published in: Molecular cancer therapeutics
• Main Authors: Cina, Cima, Majeti, Bharat, O'Brien, Zhihong, Wang, Li, Clamme, Jean Pierre, Adami, Roger, Tsang, Kwok Yin, Harborth, Jens, Ying, Wenbin, Zabludoff, Sonya
• Format: Journal Article
• Language: English
• Published: United States 17.10.2024
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0915

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25-30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-Transferase P (GSTP) known as a Phase II detoxification enzyme has more recently been identified as a modulator of MAP kinase-related cell-signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle (LNP) comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared to liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose dependent anti-tumor growth inhibition. Further, quantitative image analysis of PCNA and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P <0.005) as compared to the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.