New Advances and Challenges of Targeting Cancer Stem Cells Nurmaa K

Home , Sonidegib, Tannishtha Reya, Vismodegib

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- 2017 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- 2017 American Association for Cancer Research. blastoma multiforme (GBM) tumor types (6).

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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, NY) therapies such as the immune checkpoint blocking anti- emphasized NANOG-mediated reprograming in prostate cancer bodies is a promising strategy that is currently being tested (24). Dr. Marius Wernig (Stanford University, Stanford, CA) in several clinical trials (ClinicalTrials.gov NCT02546531, demonstrated that ASCL1, MYT1L, and BRN2 mediate direct con- NCT02758587, NCT02943317). CSC-targeting ChemoID drug version reprogramming of mouse embryonic fibroblasts and other response assays served as correlative endpoints and stratifica- cell types to functional neurons bypassing the induced pluripotent tion variables for glioblastoma (Pier Paolo Claudio, University stem cells. His group found that ASCL1 is sufficient to generate of Mississippi, Oxford, MS; ref. 15), which could lead to more functional neurons, whereas MYT1l (repressing nonneuronal pro- efficient and personalized anticancer therapy in the future. grams) and BRN2 enhance the maturation process (25). FABP5 drives self-renewal of triple-negative breast CSCs by A few short talks updated that DDB2 can limit the ovarian enhancing the transcriptional activity of PPARd to induce CSC population, probably through suppressing the transcrip- NANOG, SOX2, and OCT4 (Dr. Liraz Levi, Cleveland Clinic tion of ALDH1A1 as a transcription regulator (Qi-En Wang, þ Foundation, Cleveland, OH). FABP5 inhibitor-F19 was devel- Ohio State University, Columbus, OH; ref. 26). OLIG2 marks þ oped to decrease tumorigenesis and stemness (16). SOX2 quiescent SCs and mediates medulloblastoma growth Although different therapeutic strategies targeting CSCs are through altering the epigenetic landscape to activate oncogenic being evaluated in clinical trials, combination therapies consist- pathways in adult mice (Q. Richard Lu, Cincinnati Children's ing of existing agents and CSC pathway inhibitors are to be Hospital, Cincinnati, OH). PRMT6- dependent CRAF/ERK sig- optimized to affect cancer care. Furthermore, high-throughput naling regulates CSC plasticity in liver cancer (Stephanie Ma, screenings may help better determine the best personalized University of Hong Kong, Hong Kong). A subset of connexin approach to treat patients. In addition, examining genomic altera- proteins drives self-renewal in triple-negative breast cancer by tions at premalignant stages (6, 7) could identity malignancy- forming an aberrant intracellular complex with FAK and specific targets. NANOG (Praveena Thiagarajan, Cleveland Clinic Foundation).

Genetics, epigenetics, and development Tumor microenvironment Accumulation of genetic and epigenetic alterations contributes Although both intrinsic and extrinsic factors merge to frame to the self-renewal and drug-resistant capacity of CSCs. Dr. Con- CSC plasticity, microenvironment inﬂuences play a pivotal nie Eaves (BC Cancer Agency), a keynote speaker, reported the role in the signaling cascades during CSC progression and clonal analysis of human breast cancer origins and progression, differentiation. Based on the pioneering work of keynote

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speaker Dr. Mina Bissell (Lawrence Berkeley National Labora- ford University) highlighted that the MYC oncogene regulates tory, Berkeley, CA), tumor growth and malignant behavior are immune checkpoints through inducing CD47 and PD-L1 expres- regulated at the level of tissue organization and dependent on sion (33). MYC inactivation enhanced antitumor immune the extracellular matrix. Extracellular glucose determines response; therefore, reducing MYC expression and activity may malignant tumor phenotype via EPAC/RAP1 and O-GlcNAc restore immune response against cancer cells (33). pathways (27). The p53 association with laminin 5 induces Dr. Shideng Bao (Cleveland Clinic Foundation) described the dormancy of cancer cells, resulting in drug resistance. In GBM interplay between glioma SCs (GSC) and tumor-associated CSC studies, Dr. Jeremy Rich (Cleveland Clinic Foundation) macrophages (TAM). GSCs recruit tumor-supportive TAMs concluded that various microenvironmental niche factors, (M2) by secreting periostin, which binds to avb3 integrin on such as acidic conditions, glucose restriction, and iron meta- TAMs (34). Dr. Jeffrey Rosen (Baylor College of Medicine, Hous- bolism, modulate CSC functions. CSC-targeting strategies ton, TX) emphasized the cooperative role of WNT and FGF would be specifically tailored to the microenvironment. signaling pathways in the immune microenvironment in tumor Keynote speaker Dr. Carla F. Kim (Boston Children's Hospital, dormancy, recurrence, and metastasis. Inhibition of FGF receptor Boston, MA) spearheaded successful three-dimensional (3D) leads to regression of Wnt1/iR1 tumors and decreases recruitment cocultures of bronchioalveolar SCs (BASC) with endothelial cells of myeloid-derived suppressor cells (MDSC), promoting EMT, and demonstrated that endothelium-derived Tsp1 influences tumor invasion, angiogenesis, and metastasis. BASC alveolar differentiation under control of Bmp4-stimulated Dr. Justin D. Lathia (Cleveland Clinic Foundation) identified NFATc1 in a lung endothelium-specific manner (28). In addition, CSC-driven and immune-suppressive MDSCs in the brain of her recent work revealed the chromatin regulation of lung ade- GBM patients. CSC-derived MIF in GBM suppresses immune nocarcinoma tumor-propagating cells and BASCs via H3K9 rejection by recruiting MDSCs via immune suppressive enzyme methyltransferases G9a/Glp. Dr. Antonio Iavarone (Columbia arginase-1 in CXCR2-dependent manner (35). In addition, TLR4 University, New York, NY) described a mechanism where hypoxia decreases SC properties in CSCs by controlling retinoblastoma- drives the CSC state in GBM through inhibitor of differentiation binding protein 5 in GBM CSCs. In a separate study, autologous (ID), which is often amplified in both adult and pediatric gliomas dendritic cells loaded with antigens from autologous ovarian for tumor maintenance or upregulated in hypoxic conditions CSCs serve as an adjunctive treatment for advanced ovarian through the PHD1–DYRK1–ID2 signaling axis (29). His group cancer (Bob Dillman, AVITA Biomedical). developed a peptide that blocks the interaction between ID2 and the VHL ubiquitin ligase complex. Therapeutic resistance and heterogeneity Additional short talks further emphasized the role of micro- The role of CSCs in therapy resistance has been well estab- environmental signals in CSC regulation. Oncostatin-M in nor- lished based on previous studies (36). Dr. Tannishtha Reya mal human epithelial cells induces senescence marker GLB1 and (University of California San Diego, San Diego, CA) presented Snail expressions, which are related to EMT and CSC properties her work on SC signals in cancer heterogeneity and therapy (Benjamin Bryson, Case Western Reserve University, Cleveland, resistance. She reported that the SC determinant Musashi is a OH). Additional mechanisms include oncostatin-M–driven, critical driver of pancreatic cancer progression, and Musashi Zeb1-dependent induction of EMT and CSC properties in pan- reporters are a distinctive tool to identify therapy resistance creatic ductal adenocarcinoma (Neetha Parameswaran, Case (37). Dr. Peter Dirks (Hospital for Sick Children, Toronto, Western Reserve University), cancer-associated fibroblast regula- Ontario, Canada) reported that driving GBM cells into termi- tion on tumor-initiating cell (TIC) plasticity in hepatocellular nally differentiated neuronal lineage is important to reduce carcinoma (Yuen-Ting Eunice Lau, University of Hong Kong; resistance. Dr. Keith Chan (Baylor College of Medicine) ref. 30), and stearoyl-CoA desaturase as a mediator of TICs in reported that COX2-mediated PGE2 release contributes to þ hepatospheres (Terence Kin-Wah Lee, The Hong Kong Polytech- recruitment of CK14 cells following treatment, and that nic University, Hong Kong). Based on a mouse model for non– blockade of PGE2 release inhibits the accumulation of resis- small cell lung carcinoma, the alterations in the KEAP1/NRF2 tance to bladder cancer therapy (38). In addition, CD117 is a pathway may serve as predictive biomarkers for personalized sensitive marker for tumor grade and recurrence in prostate therapies against non–small cell lung cancers (Youngtae Jeong, cancer (Bethany Kerr, Wake Forest University; ref. 39). Inhibi- Stanford University; ref. 31). tion of CD55 holds great promise as a CSC-targeted therapy for cisplatin-resistant endometrioid tumor patients (Caner Saygin, Immune suppression and stemness Cleveland Clinic Foundation). Novel connexin-43 mimetic Studying the innate and adaptive immune response to cancer peptide (JM2) decreases connexin-43–mediated microtubule cells and CSCs has promoted one of the most promising thera- interaction in GSCs and reduces temozolomide resistance peutic approaches in the cancer field—immunotherapy. Dr. and neurosphere formation (Samy Lamouille, Virginia Tech Thomas F. Gajewski (University of Chicago, Chicago, IL) intro- Carillion Research Institute, Roanoke, VA; ref. 40). A 3D GBM- duced T-cell inflamed versus noninflamed tumor microenviron- CSC organoid culture system has been developed to preserve þ ments in melanoma. A CD8 T-cell infiltrate is ineffective at the cell heterogeneity and microenvironmental gradients in eradicating tumor cells unless the immune-suppressive Tregs, patient tumors and will aid in the development of new ther- PD1/PD-L1, and IDO (tryptophan metabolizing enzyme) are apies to treat the heterogeneity of GBM (Chris Hubert, Cleve- inhibited in combination. His work demonstrated that melano- land Clinic Foundation; ref. 41). ma-intrinsic b-catenin activation or PTEN loss prevents host antitumor immune response with reduced T-cell dynamics Metastasis, novel technologies, and new concepts (recruitment), a lack of T-cell–inflamed phenotype, and resistance Increasing evidence supports the mediation of CSCs in to anti–PD-1 immunotherapy (32). Dr. Dean W. Felsher (Stan- metastasis. The detection of a subpopulation of circulating

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tumor cell (CTC) with putative stem cell progenitor markers in Recognition of young scientists and career development patients with metastatic breast cancer and liver cancer impli- workshop þ cates circulating CSCs in metastasis. Lgr5 colorectal CSCs The young investigator awards recognized five outstanding werefoundtobemediatingcancer metastasis (42). Increased scientists. Their presentations featured (i) molecular mechanisms metastatic potential was later observed in breast cancer of CTC clustering in breast cancer (Xia Liu, Case Western Reserve patient–derived CTCs expressing putative CSC markers (43). University); (ii) a 3D culture system to model ovarian tumor Dr. Arnold I. Caplan (Case Western Reserve University) therapeutic resistance (Geeta Mehta, University of Michigan); (iii) emphasized the molecular control of melanoma metastasis CSC regulation of MDSC functions in GBM immune evasion into bone, demonstrating that mesenchymal stem cell/pericyte (Daniel Silver, Cleveland Clinic Foundation; ref. 35); (iv) PKA presence is required for efficient melanoma cancer cell intra- regulation of tumorigenicity and chemotherapy resistance vasation and extravasation to bone (44). A notable study was through activating PHF2 in immortalized human mammary cells shared by Dr. Simona Parrinello (Imperial London College, (Diwakar Pattabiraman, Massachusetts Institute of Technology; London, United Kingdom) that in a murine GBM model, ref. 49); and (v) genetic imprinting of CpG methylation state ephrin-B2 drives perivascular invasion and proliferation of influences Hippo signaling through miR-127-SETD8-LAT2 path- glioma stem-like cells (45). way in stem/progenitor cells (Maider Zabala Ugalde, Stanford Recent evidence suggests that CTC clusters are present in the University). blood of cancer patients and correlated with metastasis and At the beginning of the preconference workshop, an NIH grant drug resistance in various cancers (46). CTC clusters showed workshop with talks from Dr. Michael Espey (NIH, Bethesda, 23- to 50-fold increase in metastatic ability compared with MD), Dr. Nywana Sizemore (NIH), and Dr. Ming Lei (NIH) single CTCs (46). Dr. Huiping Liu (Case Western Reserve covered trainee career development strategies, discussion of grant University) studies cluster formation of CTCs in breast cancer opportunities, and career options discussions. At the Meet-the anddiscussedtheroleofbreastCSCsinmetastasisusingPDX Editors session, Dr. Christine Weber and Dr. Deborah J. Sweet models. Her team demonstrated the cellular and molecular gave a brief overview of publishing in the Nature journals and Cell mechanisms (such as miR-206) via which CSCs promote Press, respectively. metastasis (36, 47). Dr. Sumanta Goswami (Yeshiva University, New York, NY) showed that Wnt mediates a cross-talk between Conclusions tumor microenvironment of metastasis and CSCs, suggesting a Although the link between developmental and cancer biology potential role of CSCs in metastasis. has long been appreciated, the assessment of stem cell programs A few presentations featured recent advances in new tech- in cancer has provided insight into cancer progression and pro- nologiestocaptureCTCsandimageCSCsaswellasin vided opportunities to develop next-generation cancer therapies. understanding of CSC-mediated recurrence and therapy resis- Cellular heterogeneity and plasticity represent significant chal- tance. CTC detection in the clinical samples has been challenges in understanding stem cell biology. Given the intrinsic lenging. Dr. Sunitha Nagrath's lab (University of Michigan) attributes of CSCs and stemness signaling shown to suppress developed the GO-Chip made of graphene oxide and anti- immune response and mediate immunotherapy resistance, we body-coated microposts to rapidly separate CTCs from blood expect that targeting CSCs and modulating the tumor microen- samples (48). She demonstrated that 50% of patients with vironment to augment immune attacks on cancer would be a lungcancerwerefoundtohaveCTCsinclusters,andtheir promising strategy to combine with existing approaches against initial data show that these clusters correlate with survival. A cancer. new minimally invasive technique of intravital imaging using a lung window visualized the fate and microenvironment of tumor cells and CSCs in lung metastasis (Sonia Voiculescu, Disclosure of Potential Conflicts of Interest Albert Einstein College of Medicine, New York, NY). An No potential conflicts of interest were disclosed. optimized CTC isolation technique was employed to establish three cell lines of circulating colorectal cancer cells with CSC Acknowledgments hallmarks and chemoresistance (Julie Pannequin, Institute of We acknowledge the National Center for Regenerative Medicine and Functional Genomic, Montpellier, France). A newly designed Case Comprehensive Cancer Center for hosting the conference. We gold nanoparticle, Smart Flare, was coated with a probe to appreciate the executive administrative team led by Charlene Mitchell who organized and made the conference a successful platform for scientific bind mRNA transcripts of interest in the living cells as well as exchange and new initiations of breakthrough research and clinical in CSCs (Steven McClellan, University of South Alabama, applications. Mobile, AL). Dr. Stanton L. Gerson (Case Western Reserve University and Grant Support University Hospitals) reported that autologous transplants of 6 The CSC 2016 and the meeting report were partially supported by hematopoietic progenitor cells with mutant O -alkylguanine NIH/NCIR13CA206377 (S.L. Gerson), P30 CA043703 (S.L. Gerson), and DNA alkyltransferase (MGMT) (P140K) overcome the side R00CA160638 (H. Liu). effects of combination therapies for GBM with temozolomide The costs of publication of this article were defrayed in part by the 6 and MGMT inhibitor O -benzylguanine (BG). This approach payment of page charges. This article must therefore be hereby marked will allow patients to tolerate temozolomide and BG treat- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate ment with minimal bone marrow toxicity due to the coupled this fact. low affinity of P140K mutant to BG. Preliminary results demonstrated that this chemoprotection strategy is tolerable Received January 6, 2017; revised May 25, 2017; accepted July 18, 2017; and safe. published OnlineFirst September 19, 2017.

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www.aacrjournals.org Cancer Res; 77(19) October 1, 2017 5227

New Advances and Challenges of Targeting Cancer Stem Cells

Nurmaa K. Dashzeveg, Rokana Taftaf, Erika K. Ramos, et al.

Cancer Res 2017;77:5222-5227. Published OnlineFirst September 19, 2017.

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