Inhibition of Lung Cancer Metastasis in mice by inhaled aerosolized anti-MARCKS peptides

Q. Yin1, A. Crews1, S. Fang1, J. Park, I. Parikh2, C. Chen3, R. Wu3, K. Adler1
1 North Carolina State University, Raleigh, North Carolina 27607;
2BioMarck Pharmaceuticals, Durham, North Carolina 27713; and 3University of California, Davis, California 95817

Abstract

We have previously reported that intraperitoneal administration of peptides that inhibit the function of
MARCKS (myristoylated alanine-rich C Kinase Substrate) protein also inhibit metastasis of human lung
cancer cells orthotopically-injected into the left lobe of SCID mice [1,2] Here, we administered an anti-
MARCKS peptide, BIO 11006, (the active portion of the MANS peptide identical to the N-terminal region of
MARCKS) via the inhaled aerosol route in 2 models of lung cancer in SCID mice: PC-9 cells orthotopically
injected into the left lobe, and A549 cells injected into the tail vein which go on to seed in the lung and form metastatic tumors. 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 significant attenuation of tumor metastasis into the lung, heart or diaphragm, with almost identical attenuation whether the peptides were administered IP or via inhaled aerosol. In additional studies with the orthotopic model, administration of the peptide IP starting at day 15 post orthotopic injection of cells, a point where metastasis had already started, resulted in apparent inhibition of further metastasis. Carrying this study further, we waited until day 26 post orthotopic cell injection to begin daily treatment with BIO 11006 via inhaled aerosol, and found that, even at this advanced time of metastasis, there appeared to be complete inhibition of further tumor metastasis when the animals were examined at day 42 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 peptide treatments, either with MANS or BIO 11006. The results suggest that inhaled aerosolized BIO 11006, already approved and utilized in clinical trials in patients with COPD, appears to have potent anti-metastatic effects in two different mouse models of lung cancer.