Drug Development for Metastasis Prevention

Overview

Journal Crit Rev Oncog

Publisher Begell House

Specialty Oncology

Date 2016 Jun 10

PMID 27279241

Citations 23

Authors

Yari Fontebasso

Steven M Dubinett

Affiliations

Soon will be listed here.

Abstract

Metastatic disease is responsible for 90% of death from solid tumors. However, only a minority of metastasis-specific targets has been exploited therapeutically, and effective prevention and suppression of metastatic disease is still an elusive goal. In this review, we will first summarize the current state of knowledge about the molecular features of the disease, with particular focus on steps and targets potentially amenable to therapeutic intervention. We will then discuss the reasons underlying the paucity of metastatic drugs in the current oncological arsenal and potential ways to overcome this therapeutic gap. We reason that the discovery of novel promising targets, an increased understanding of the molecular features of the disease, the effect of disruptive technologies, and a shift in the current preclinical and clinical settings have the potential to create more successful drug development endeavors.

Citing Articles

Molecular principles underlying aggressive cancers.

Nussinov R, Yavuz B, Jang H Signal Transduct Target Ther. 2025; 10(1):42.

PMID: 39956859 PMC: 11830828. DOI: 10.1038/s41392-025-02129-7.

3D tumor spheroids: morphological alterations a yardstick to anti-cancer drug response.

Senrung A, Lalwani S, Janjua D, Tripathi T, Kaur J, Ghuratia N In Vitro Model. 2025; 2(6):219-248.

PMID: 39872501 PMC: 11756486. DOI: 10.1007/s44164-023-00059-8.

Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment.

Anandi L, Garcia J, Ros M, Janska L, Liu J, Carmona-Fontaine C Life Sci Alliance. 2024; 8(1).

PMID: 39419548 PMC: 11487089. DOI: 10.26508/lsa.202403053.

Cancer metastases: Tailoring the targets.

Pote M, Singh D, M A A, Suchita J, Gacche R Heliyon. 2024; 10(15):e35369.

PMID: 39170575 PMC: 11336595. DOI: 10.1016/j.heliyon.2024.e35369.

Gα2 Protein Inhibition Blocks Chemotherapy- and Anti-Androgen-Induced Prostate Cancer Cell Migration.

Caggia S, Johnston A, Walunj D, Moore A, Peer B, Everett R Cancers (Basel). 2024; 16(2).

PMID: 38254786 PMC: 10813862. DOI: 10.3390/cancers16020296.

References

Ouatas T, Halverson D, Steeg P . Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res. 2003; 9(10 Pt 1):3763-72. View

Korpal M, Ell B, Buffa F, Ibrahim T, Blanco M, Celia-Terrassa T . Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011; 17(9):1101-8. PMC: 3169707. DOI: 10.1038/nm.2401. View

Takenaga M, Tamamura H, Hiramatsu K, Nakamura N, Yamaguchi Y, Kitagawa A . A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma. Biochem Biophys Res Commun. 2004; 320(1):226-32. DOI: 10.1016/j.bbrc.2004.05.155. View

Giancotti F . Mechanisms governing metastatic dormancy and reactivation. Cell. 2013; 155(4):750-64. PMC: 4354734. DOI: 10.1016/j.cell.2013.10.029. View

Loges S, Mazzone M, Hohensinner P, Carmeliet P . Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009; 15(3):167-70. DOI: 10.1016/j.ccr.2009.02.007. View

Halder S, Beauchamp R, Datta P . A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia. 2005; 7(5):509-21. PMC: 1501161. DOI: 10.1593/neo.04640. View

Toiyama Y, Yasuda H, Saigusa S, Matushita K, Fujikawa H, Tanaka K . Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int J Cancer. 2011; 130(12):2912-21. DOI: 10.1002/ijc.26330. View

Yanase T, Tamura M, Fujita K, Kodama S, Tanaka K . Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo. Cancer Res. 1993; 53(11):2566-70. View

Gao H, Chakraborty G, Lee-Lim A, Mo Q, Decker M, Vonica A . The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell. 2012; 150(4):764-79. PMC: 3711709. DOI: 10.1016/j.cell.2012.06.035. View

10.

Kobayashi A, Okuda H, Xing F, Pandey P, Watabe M, Hirota S . Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011; 208(13):2641-55. PMC: 3244043. DOI: 10.1084/jem.20110840. View

11.

Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M . DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005; 24(14):2375-85. DOI: 10.1038/sj.onc.1208429. View

12.

Kim Y, Koo K, Sung J, Yun U, Kim H . Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol. 2012; 2012:306879. PMC: 3296207. DOI: 10.1155/2012/306879. View

13.

Ocana O, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S . Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012; 22(6):709-24. DOI: 10.1016/j.ccr.2012.10.012. View

14.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

15.

Pantel K, Speicher M . The biology of circulating tumor cells. Oncogene. 2015; 35(10):1216-24. DOI: 10.1038/onc.2015.192. View

16.

Wang T, Hsu S, Feng H, Huang R . Folate deprivation enhances invasiveness of human colon cancer cells mediated by activation of sonic hedgehog signaling through promoter hypomethylation and cross action with transcription nuclear factor-kappa B pathway. Carcinogenesis. 2012; 33(6):1158-68. DOI: 10.1093/carcin/bgs138. View

17.

Vandenbroucke R, Libert C . Is there new hope for therapeutic matrix metalloproteinase inhibition?. Nat Rev Drug Discov. 2014; 13(12):904-27. DOI: 10.1038/nrd4390. View

18.

Aguirre-Ghiso J . Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007; 7(11):834-46. PMC: 2519109. DOI: 10.1038/nrc2256. View

19.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

20.

Ebos J, Lee C, Cruz-Munoz W, Bjarnason G, Christensen J, Kerbel R . Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009; 15(3):232-9. PMC: 4540346. DOI: 10.1016/j.ccr.2009.01.021. View