Effect of an anti-MARCKS peptide (BIO-11006) on metastasis of lung cancer in vivo.

Abstract

e23017 Background: We have previously reported that administration of peptides that inhibit the function of MARCKS (myristoylated alanine-rich C Kinase Substrate) inhibit metastasis of human lung cancer cells orthotopically-injected into the left lung of SCID mice (Chen et al: Oncogene 33:3696–3706, 2014; Chen et al: Am J Resp Crit Care Med 190:1127-1138, 2015). Methods: Here, we administered an anti-MARCKS peptide, BIO-11006, as an inhaled aerosol in 2 models of lung cancer in SCID mice: PC-9 cells orthotopically injected into the left lung, and A549 cells injected into the tail vein. In the orthotopic model, initiation of treatment with BIO-11006 at day 4 post injection of cells and treatment every day thereafter for 4 weeks resulted in dramatic attenuation of tumor metastasis into the lung, heart and diaphragm, with similar attenuation whether the peptides were administered IP or via inhaled aerosol. In additional studies with this model, we waited until day 26 post orthotopic cell injection, a time when there was already extensive metastasis to the lung and distal organs, to begin daily treatment with BIO-11006 via inhalation. Results: There was complete inhibition of further metastasis and primary tumor growth when the animals were examined at day 38 post orthotopic injection of cells. Similar results with the tail vein model were observed: when the peptide was administered by aerosol starting at day 3 post tail vein inoculation, metastasis observed 8 weeks later in distal organs was inhibited by ~ 95% by treatment with inhaled BIO-11006. When PC-9 cells were examined via confocal microscopy, BIO-11006 was seen to cause a cytoskeletal rearrangement so that the cells took on a morphology favoring adherence to the substrate rather than movement. Conclusions: The results suggest that inhaled BIO-11006, already completed in phase 2 clinical trials in patients with COPD, appears to have potent antimetastatic effects in two different mouse models of lung cancer. Clinical trials of inhaled BIO-11006 in patients with advanced lung cancer were initiated in January of 2017.