ASCO Connection

July 2017

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CANCER STEM CELLS RECURRING TUMOR Learn more at www.bostonbiomedical.com A key implication of the CSC model for cancer treatment is that both CSCs and non-stem cancer cells should be targeted to reduce tumor recurrence and metastasis. 15,16 The next generation of cancer therapeutics is in development with investigational agents designed to inhibit stemness pathways. 1 Targeting Stemness Stemness of CSCs may drive tumor growth Stemness is defined by the ability to self-renew and differentiate. 4 Unlike normal stem cells, which differentiate into healthy, mature cell types, CSCs differentiate into cancer cells. 4 The stemness of CSCs is maintained by various signaling pathways that are overactivated, including JAK/STAT, Wnt/β-catenin, Nanog, and Notch, depending on the tumor type. 5-9 Stemness may enable CSCs to metastasize and regrow tumors. 3 This makes CSCs phenotypically different from non-stem cancer cells and may confer therapy resistance. 3 Stemness can be acquired by non-stem cancer cells as they dedifferentiate in response to multiple stimuli, possibly including conventional cancer therapies. 10,11 The CSC model may help explain tumor recurrence In the clonal evolution model, all cells within a malignant tumor have similar tumorigenic activity. 12 By contrast, in the CSC model only a subset of tumor cells, CSCs, have tumor-initiating capability. 2 This may help to explain why early tumor shrinkage is often poorly predictive of overall survival. 13,14 While conventional therapies kill the bulk of non-stem cancer cells, resulting in tumor shrinkage, CSCs may remain viable and later reestablish the tumor, leading to relapse. 4 Not all cancer cells within a tumor are equal Despite current advances in cancer therapy, tumor recurrence and metastases remain clinical challenges. 1 A potential new approach to address these is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). 2 CSCs are highly tumorigenic, have high metastatic potential, and are resistant to conventional cancer therapies. 3 References: 1. Li Y, Rogoff H, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923-942. 3. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 4. Reya T, Morrison S, Clarke M, Weissman I. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 5. Kim J, Jeon H, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 6. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 7. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 8. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 9. Mo J, Park H, Guan K. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 10. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 11. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 12. Marjanovic N, Weinberg RC, CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59(1):168-179. 13. Coart E, Saad E, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 14. Zabor E, Heller G, Schwartz L, Chapman P. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 15. Visvader J, Lindeman G. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 16. Li X, Lewis M, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679. Boston Biomedical is a registered trademark of Sumitomo Dainippon Pharma Co., Ltd. ©2017 Boston Biomedical. All rights reserved. EDU-NPS-0119 6/2017 Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stemness pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis. CSCs are highly tumorigenic, have high metastatic potential, and are resistant to conventional cancer therapies. 3 TARGETING CANCER STEMNESS PATHWAYS

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