Published OnlineFirst September 19, 2017; DOI: 10.1158/0008-5472.CAN-17-0054 Cancer Meeting Report Research New Advances and Challenges of Targeting Cancer Stem Cells Nurmaa K. Dashzeveg1, Rokana Taftaf1, Erika K. Ramos1, Luke Torre-Healy2, Anastasia Chumakova2, Daniel J. Silver2, Tyler J. Alban2, Maksim Sinyuk2, Praveena S. Thiagarajan2, Awad M. Jarrar2, Soumya M. Turaga2, Caner Saygin2, Erin Mulkearns-Hubert2, Masahiro Hitomi2, Jeremy N. Rich3,4,5, Stanton L. Gerson4,5,6, Justin D. Lathia2,4,5, and Huiping Liu1,4,5,7,8 Abstract The second International Cancer Stem Cell Conference in peutic resistance, and emerging novel concepts. The confer- Cleveland, Ohio, on September 20–23, 2016, convened 330 ence hosted 35 renowned speakers, 100 posters, 20 short attendees from academic, industrial, and clinical organiza- talks, and a preconference workshop. The reported advances tions. It featured a debate on the concepts and challenges of of CSC research and therapies fostered new collaborations the cancer stem cells (CSC) as well as CSC-centered scientific across national and international borders, and inspired the sessions on clinical trials, genetics and epigenetics, tumor next generation's young scientists. Cancer Res; 77(19); 5222–7. microenvironment, immune suppression, metastasis, thera- Ó2017 AACR. Cancer Stem Cell Overview Yogen Saunthararajah. The heated debate covered the defini- tion, impact, and clinical implications of CSCs in cancer med- Over the last 20 plus years, cancer stem cells (CSC) have been icine, and more. On an achieved consensus, CSCs are function- functionally identified in human leukemia (1) and many solid ally identified by their self-renewal and tumorigenic capacity, tumors, such as breast, ovarian, prostate, brain, colon, lung, and whereas heterogeneous markers may be used to enrich CSCs others. Increasing evidence supports that CSCs remain the root of across cancers. Both intrinsic and extrinsic signaling pathways cancer, seeds of metastasis, and sources of therapy resistance (2). from genetic, epigenetic, and microenvironmental alterations Although the concept of CSCs has provided an opportunity to converge to regulate stemness of cells, thereby featuring the assess the complexity of cancer using a developmental-biology– plasticity of CSCs. Stemness signature genes are clearly associ- inspired paradigm, the big question remains to what level and ated with clinical outcomes of cancer patients (3), but strategies how CSCs would affect cancer medicine. CSC Conference 2016 targeting CSCs would need to be combined with other targeted provided a forum to challenge and foster the forefront research and immunotherapies to eradicate cancer and achieve durable and clinical applications of CSCs. disease status. At the opening session, a forum debate about the beliefs and The keynote speakers set up the high standard of the state-of- challenges on CSCs followed between two groups, including the the art research reports as well as challenges to the CSC field. believers Drs. John E. Dick, Luis Parada, and Tannishtha Reya, Dr. John E. Dick (University Health Network, Toronto, Ontario, and the challengers Drs. Mina Bissell, Geoffrey M. Wahl, and Canada), who pioneered the CSC field by first identifying human leukemia stem cells (LSC; ref. 1) and colon CSCs, shared the dark side of stem cells (SC) where his latest research has 1 Department of Pharmacology, Feinberg School of Medicine, Northwestern identified that a preleukemic SC with DNMT3A mutations 2 University, Chicago, Illinois. Department of Cellular and Molecular Medicine, may be the first step in initiating disease and also the culprit Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. 3Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research evading therapy and triggering relapse in patients with AML (4). Institute, Cleveland, Ohio. 4The Case Comprehensive Cancer Center, Cleveland, Dr. Robert Weinberg (Massachusetts Institute of Technology, Ohio. 5The National Center for Regenerative Medicine, Cleveland, Ohio. 6The Cambridge, MA) described normal and neoplastic SCs and University Hospitals Cleveland Medical Center, Cleveland, Ohio. 7Department of the epithelial–mesenchymal transition (EMT) program. EMT Medicine (Hematology and Oncology Division) and Robert H. Lurie Compre- transcription factors, such as Slug, Snail, Sox9, and Zeb1, coop- hensive Cancer Center, Feinberg School of Medicine, Northwestern University, eratively act to determine the mammary SC state and CSC Chicago, Illinois. 8Deparmtent of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio. plasticity (5). Dr. Luis Parada (Memorial Sloan Kettering, New York, NY) emphasized that CSCs are defined by function not N.K. Dashzeveg, R. Taftaf, and E.K. Ramos contributed equally to this article. by epitopes or surrogate assays. His work explored the stem Corresponding Author: Huiping Liu, Northwestern University, 303 E Superior St, cell origin of CSCs in malignant glioma and utilized the CDG Lurie 5-119, Chicago, IL 60611. Phone: 312-503-5248; Fax: 312-503-0189; E-mail: transgene in specific promoter elements to target both CSCs [email protected] and transit-amplifying cells. This discovery implicates that same doi: 10.1158/0008-5472.CAN-17-0054 genetic drivers in different cells of origin develop distinct glio- Ó2017 American Association for Cancer Research. blastoma multiforme (GBM) tumor types (6). 5222 Cancer Res; 77(19) October 1, 2017 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst September 19, 2017; DOI: 10.1158/0008-5472.CAN-17-0054 Advances of Targeting Cancer Stem Cells Taken together with the work that identified DNMT3, TET2, using cellular DNA barcoding with multiplexed, high-resolution and ASXL1 as predictive markers for myeloid malignancy (7) techniques to better study the heterogeneity of human malig- and preleukemic mutations in hematopoietic stem cells (8) in nant tumors (17, 18). The frequencies of clone-initiating cells leukemic development, these findings support that SCs can be the vary from 1/10 to 1/10,000, and the carcinogenic process in cell-of-cancer-origin and sources of CSCs. human normal epithelia requires the acquisition of multiple driver mutations (18). Clinical Trials of CSC Targeting As discussed in the conference, cancer arises from the populations with self-renewal and multipotent properties. Therapeutics Dr. Geoffrey M. Wahl (Salk Institute, La Jolla, CA) examined The evolution of clinical trials that target CSCs holds promise of the plasticity of the fetal mammary SCs (fMaSC) as their affecting cancer medicine. CSC functions have been linked to transcriptome is significantly enriched in basal-A human breast dysregulated stem cell pathways such as Wnt, Notch, and Hedge- cancers. They exhibit characteristics of both luminal and hog signaling (9), which are fundamental for normal SCs. Despite basal cells. While their transcriptomes are different from 'CSC,' the great challenges to specifically target CSCs, two hedgehog they can be induced to undergo an atypical EMT that is also pathways inhibitors targeting SMO (LDE225/sonidegib and reversible and reflects that found in metastatic breast cancers. GDC-0449/vismodegib) have received FDA approval for treating Differentiation by inflammation, oncogenes, or both, likely basal cell carcinoma (10). Notable approaches have been devel- will present challenges to therapies intended to selectively oped to target cancer-specific fusion receptors (11) and CD47 target CSCs (19). In addition, Dr. Benjamin Spike (Univer- (12). Ongoing CSC-targeting clinical trials are being conducted to sity of Utah, Salt Lake City, UT) discussed the SC transcrip- evaluate their efficacy in a variety of cancers. tional continuum in mammary development and implications Dr. Max S. Wicha (University of Michigan, Ann Arbor, MI) for CSCs with embryonic SC and fMaSC-like signatures. His discussed the therapeutic targeting of breast CSCs and outlined studies also showed that MCAM, Cripto-GRP78 pathways some of the therapeutic agents currently used in clinical trials regulate breast cancer development (20). including demcizumab (anti-Notch ligand DLL4 antibody), Moreover, Dr. Xiling Shen (Duke University, Durham, NC) ipafricept (Fzd8 fusion protein OMP-54F28), vantictumab addressed how asymmetric division determines cell fate, SC or (anti-Frizzled), reparixin (CXCR1 inhibitor), defactinib [focal non-SC, through miR-34a-Numb-Notch signaling cascade. A long adhesion kinase (FAK) inhibitor], tarextumab (OMP-59R5), noncoding RNA suppresses miR-34a by recruiting DNA methyl- and BBI608 (targets STAT3). His small-molecule and high- transferase Dnmt3a via prohibitin-2 and histone deacetylase 1 throughput siRNA screenings also discovered novel agents that (161). Dr. Marcus E. Peter (Northwestern University, Chicago, IL) target CSC regulatory pathways (13). Dr. Jonathan Pachter reported that chronic stimulation of CD95 results in lower levels (Verastem, Inc.) presented CSC-targeting strategies in clinical of miR-200c, monitored using a sensor plasmid for miR-200c, trials using selective inhibitors of FAK and PI3K/mTOR increasing the CD24 low stem-like population in breast cancer (14). Although targeting CSC alone may not be sufficient to cells (22). This is driven by a type I interferon/STAT1 pathway remove the bulk tumor, combining FAK inhibitors with other (23). Dr. Dean Tang (Roswell Park Cancer Institute, Buffalo,