Identification of novel drugs to target dormant micrometastases

• Published in: BMC cancer Vol. 15; no. 1; p. 404
• Main Authors: Hurst, Robert E, Hauser, Paul J, You, Youngjae, Bailey-Downs, Lora C, Bastian, Anja, Matthews, Stephen M, Thorpe, Jessica, Earle, Christine, Bourguignon, Lilly Y W, Ihnat, Michael A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.05.2015; BioMed Central
• Subjects: Analysis; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Chemotherapy; Drug therapy; Female; Health aspects; Inhibitory Concentration 50; Maximum Tolerated Dose; Metastasis; Mice, Inbred BALB C; Mice, Nude; Neoplasm Micrometastasis - drug therapy; Physiological aspects; Xenograft Model Antitumor Assays
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-015-1409-4

Cancer-specific survival has changed remarkably little over the past half century, mainly because metastases that are occult at diagnosis and generally resistant to chemotherapy subsequently develop months, years or even decades following definitive therapy. Targeting the dormant micrometastases responsible for these delayed or occult metastases would represent a major new tool in cancer patient management. Our hypothesis is that these metastases develop from micrometastatic cells that are suppressed by normal extracellular matrix (ECM). A new screening method was developed that compared the effect of drugs on the proliferation of cells grown on a normal ECM gel (small intestine submucosa, SISgel) to cells grown on plastic cell culture plates. The desired endpoint was that cells on SISgel were more sensitive than the same cells grown as monolayers. Known cancer chemotherapeutic agents show the opposite pattern. Screening 13,000 compounds identified two leads with low toxicity in mice and EC50 values in the range of 3-30 μM, depending on the cell line, and another two leads that were too toxic to mice to be useful. In a novel flank xenograft method of suppressed/dormant cells co-injected with SISgel into the flank, the lead compounds significantly eliminated the suppressed cells, whereas conventional chemotherapeutics were ineffective. Using a 4T1 triple negative breast cancer model, modified for physiological metastatic progression, as predicted, both lead compounds reduced the number of large micrometastases/macrometastases in the lung. One of the compounds also targeted cancer stem cells (CSC) isolated from the parental line. The CSC also retained their stemness on SISgel. Mechanistic studies showed a mild, late apoptotic response and depending on the compound, a mild arrest either at S or G2/M in the cell cycle. In summary we describe a novel, first in class set of compounds that target micrometastatic cells and prevent their reactivation to form recurrent tumors/macrometastases.