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Emerging strategies for treating metastasis

Abstract

The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune-activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.

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Fig. 1: Five-year survival rates of patients diagnosed with select cancer types in the time period from 2000–2017.
Fig. 2: Metastatic ability, therapeutic resistance and plasticity are intrinsically linked by genetic, epigenetic and metabolic pathways that offer promising therapeutic nodes for drug development.
Fig. 3: Development of metastasis competency requires additional malignant properties beyond primary tumorigenesis.
Fig. 4: Targeting the immune microenvironment of metastatic cancers.

Data availability

The human cancer mortality data in Fig. 1 were derived from the SEER database with 2017 as the most recently annotated 5-year survival date: https://seer.cancer.gov/data/. Source data are provided with this paper. All other data are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the members of our laboratory for helpful discussions. We also apologize to the many investigators whose important studies could not be cited directly here owing to space limitations. The work in the authors’ laboratories is supported by grants from the Brewster Foundation, the American Cancer Society, the Susan G. Komen Foundation, the Breast Cancer Research Foundation, the NIH and the US Department of Defense to Y.K. S.G. is supported by grants from the NCI, the US Department of Defense, the Breast Cancer Research Foundation, Hugs for Brady, AHEPA, the Val Skinner Foundation and the Gertrude Fogarty Trust.

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Correspondence to Yibin Kang.

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M.E. holds equity interest and a management position in KayoThera, a company developing cancer therapeutics. Y.K. holds equity interest in KayoThera and Firebrand Therapeutics and is a member of the scientific advisory boards of KayoThera, Firebrand Therapeutics and Cytocares. Y.K. has consulted for Merck, Amgen and Ono Pharma and has previously received funding support from Merck, Amgen, Johnson & Johnson, Janssen, Glycomimetics and Ono Pharma. S.G. has consulted for Merck, Roche, Foundation Medicine, Foghorn Therapeutics, Novartis, Silagene, EQRX and Inspirata, has received research funding from M2GEN and has equity interest in Inspirata and Silagene.

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Peer review information Nature Cancer thanks Salvador Benitah and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Fig. 1 5-year survival rates for the select cancers shown in Fig. 1 extracted from the SEER database (2020).

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Esposito, M., Ganesan, S. & Kang, Y. Emerging strategies for treating metastasis. Nat Cancer 2, 258–270 (2021). https://doi.org/10.1038/s43018-021-00181-0

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