Metarrestin: a new approach to targeting the leading cause of cancer mortality

2018

Challenge

The spreading of cancer from the site of the initial tumor to other organs and tissues in the body, known as metastasis, remains the leading cause of cancer mortality. This is largely due to the lack of therapies that specifically inhibit metastasis.

Advance

One feature unique to metastatic cancer cells is the development of a specialized structure within the nucleus called the perinucloelar compartment (PNC), making it an attractive target for therapeutics. A group of IRP scientists, led by Juan Marugan, Ph.D., teamed up with IRP investigator Udo Rudloff, M.D., Ph.D., and outside partners to identify compounds that interact with the PNC. The researchers further optimized the drug-like properties of those compounds to obtain Metarrestin, a molecule able to selectively disrupt the PNC structure, thereby targeting metastatic cancer cells while sparing healthy cells. In several animal models of human cancers, Metarrestin robustly reduced cancer metastasis or prevented it completely, resulting in increased life span.

Impact

Metarrestin represents a new class of cancer therapeutics specifically designed to prevent or eliminate metastasis with broad applicability in solid tumors. Metarrestin will soon be tested in human clinical trials for pancreatic cancer at the NIH Clinical Center.

Publications

Vilimas T, Wang AQ, Panaik S, Hughes EA, Singleton MD, Knotts Z, Li D, Frankowski K, Schlomer JJ, Guerin TM, Springer S, Drennan C, Dextras C, Wang C, Southall N, Ferrer M, Huang S, Kozlov S, Marugan J, Xu X, Rudloff U. (2018). Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer. Cancer Chemother Pharmacol. 82(6):1067-1080.

Frankowski K, Wang C, Patnik S, Schoenen F, Southall N, Teper Y, Sun W, Kandela I, Hu D, Dextras C, Norton J, Titus S, Lewandowska M, Wen Y, Farley K, Mathews Greiner L, Sultan J, Meng Z, Zhou M, Fang M, Long C, Khanolkar O, Chen W, Kang J, Huang H, Chow E, Goldberg E, Feldman C, Xi R, Quadri H, Rim Kim H, Sahagian G, Baserga S, Mazar A, Ferrer M, Zheng W, Shilatifard A, Aubé J, Rudloff U, Marugan JJ, Huang S. (2018). Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Sci. Transl. Med. 10(441): eaap8307.