This document discusses cancer stem cells (CSCs) and potential therapies targeting them. It begins with introductions to stem cells and CSCs, then covers the history of discovering CSCs. New therapies discussed include targeting CSC-specific markers, signal pathways like Wnt and Notch, CSC metabolism, and epithelial-mesenchymal transition. Clinical trials targeting CSC pathways are also summarized. The document provides an overview of CSCs and recent research into developing treatments focused on these cells.

1. Role of Cancer Stem Cells In Cancer Therapy
GUIDED BY
Dr. G. CHANDRAIAH
ASSISTANT PROFESSOR
NIPER-HYD.
PRESENTED BY
G.NARESH
M.S (PHARMACOLOGY
AND TOXICOLOGY)
PC2016206.4/10/2017 1

2. Contents
• Introduction
• History of CSCs
• New Therapies to Target Cancer Stem Cells
• CSCs Specific Markers Therapy
• Targeting Signal Pathways
• Targeting CSCs Metabolism
• Epithelial– mesenchymal Transition (EMT)
• Summary
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3. Stem Cells Introduction
Stem cells are the foundation cells for our bodies. The highly specialized cells
that make up our organs and tissues originally came from an initial pool of
stem cells that formed shortly after fertilization
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4. Characters of stem cells
Stem cells can be broadly defined by two characteristics, sometimes referred
to as the “cardinal property ,
1. Capacity to self-renew (divide in a way that generates more stem cells)
2. To differentiate (to turn into mature, specialized cells that make up our
tissues and organs).
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5. Types of Stem Cells
 Embryonic stem cells are pluripotent stem cells, meaning they can give rise
to all cell types of the body.
• They can be grown indefinitely in vitro if the correct conditions are met,
• Embryonic stem cells are obtained from a very early stage in development,
usually the blastocyst stage, which in the human forms about 5 days after
fertilization of an egg.
 Adult or ‘tissue-specific’ stem cells are multipotent, meaning they can give
rise to a limited number of mature cell types
• Usually corresponding to the tissues in which they reside.
 induced pluripotent stem cells or iPS cells
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6. Cancer Stem Cells
• Cancer stem cells (CSCs) are a small subpopulation of tumor cells with
capabilities of self-renewal, dedifferentiation, tumorogenicity, and inherent
chemo-and radiotherapy resistance, which ultimately results in tumor relapse
that lead to the failure of conventional and traditional therapies.
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7. con..
Deshmukh et al. Molecular Cancer (2016) 15:69, 2
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8. con…
•
• Tao Wang1,2, Sarah Shigdar2, Michael P. Gantier3,4
Oncotarget; 2016, 6, 42-xx
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9. Comparison of Somatic And Cancer Stem Cells
Somatic stem cell
• Self-renew, highly regulated
differentiate, produces mature
tissue
• Migrate to distant tissues
• Long lifespan
• Resistant to apoptosis
Cancer stem cell
• Self-renew, poorly regulated
differentiate, produces tumor
• Metastasize to distant sites
• Long lifespan
• Resistant to apoptosis
JOHN B. SPILLANE et al , CANCER STEM CELLS: A REVIEW ,2007 ,165.
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10. Characters Of CSCs
• Self-renewal and differentiation to heterogeneous lineage (definition)
• Small number in cancer cells
• Chemo resistance
• Resistance to radiation therapy
• Stay in the resting phase of the cell cycle
• High metastatic ability
• Sphere forming ability
• Expression of cancer stem cell markers
• High ABC transporter expression
Toshiyuki Ishiwata, Review Article, Cancer stem cells and epithelial-mesenchymal transition: Novel therapeutic targets
for cancer,2016
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11. HISTORY OF CSCs
• 1868 — The term “stem cell” appears in scientific literature, when German
biologist Ernst Haeckel uses the phrase stem cell to describe the fertilized egg
that becomes an organism
• 1886 — William Sedgwick uses the term “stem cells” to describe the parts of a
plant
• June 1, 1909 — Russian academic Alexander Maxi mow lectures at the Berlin
Hematological Society on a theory that all blood cells come from the same
ancestor cell
• February 2, 1963 — Canadian scientists Ernest McCulloch and James Till
perform experiments on the bone marrow of mice and observe that different
blood cells come from a special class of cells. This is one of the first pieces of
evidence of blood stem cells.
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12. Con..
• In 1968, the first bone marrow transplant was performed to successfully treat
two siblings with severe combined immunodeficiency
• 1978: Stem cells were discovered in human cord blood
• 1981: First in vitro stem cell line developed from mice
• 1988: Embryonic stem cell lines created from a hamster
• 1995: First embryonic stem cell line derived from a primate
• 1997: Cloned lamb from stem cells
• 1997: Leukemia origin found as hematopoietic stem cell, indicating possible
proof of cancer stem cells
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13. Origion Of CSCs
Atena, M., Reza, A.M. and Mehran, G. (2014) A Review on the Biology of Cancer Stem Cells. Stem
Cell Discovery, 4, 83-89.4/10/2017 13

14. Arokia Priyanka Vaz et al, a Department of Biochemistry and Molecular Biology, University of Nebraska Medical
Center,Omaha, NE, U.S.A.2013 ,14
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14

15. Identification of CSCs
• Sphere formation assay
• Flow cytometry (efflux of fluorescent compounds)
• Cell surface markers
• Sphere formation indicates their high proliferating ability without cell
attachment.
• SP cells indicate their high drug efflux capacity and
• CSC markers are highly expressed proteins specific to CSCs.
Toshiyuki Ishiwata, Review Article, Cancer stem cells and epithelial-mesenchymal transition:
Noveltherapeutic targets for cancer,2016
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16. Isolation Of CSCs
• FACS, and MACS (magnetic cell sorting) are the main techniques used to isolate
CSCs.
• CSCs enrichment can be done using the FACS (Fluorescence-activated cell
sorting) technique
• Magnetic Cell Sorting (MACS): This technology isolates cells with a high quality
and is regarded as a standard method for cell isolation. This technique can
isolate cells based on expression of special stem cell markers like CD 24, CD133,
ALDH1 and CD44.
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17. New Therapies To Target Cancer Stem Cells
Yapeng Hu, Liwu Fu et al ,Targeting cancer stem cells , 2012;2(3):340-356 .
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18. Con..
Chen K et al, Act Pharma Sinica 2013
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19. CSC Markers Therapy
A number of CSC markers including
• CD44, CD133,
• receptor tyrosine kinase,
• aldehyde dehydrogenase
• epithelial cell adhesion molecule/epithelial specific antigen,
• ATP-binding cassette subfamily G member 2
have been proved as the useful targets for defining CSC population in solid tumors.
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Peyman Ranji1 & Tayyebali Salmani Kesejini1 et al,review, Targeting cancer stem cell-specific markers and/or
associated signaling pathways for overcoming cancer drug resistance .aug2016.

20. Potential Surface Biomarker Based Therapy
Arokia Priyanka Vaz et al, a Department of Biochemistry and Molecular Biology, University of Nebraska Medical
Center,Omaha, NE, U.S.A.2013 ,13
20

21. MARKER Cancer type
CD133 Brain, Prostate, Pancreas ,Melanoma ,Colon, Liver, Lung, Ovary
CD44 Colon ,Breast, Prostate ,Pancreatic
ABCG2 Pancreas ,breast ,Lung , Limbal epithelium ,Brain prostate, Liver,
Ovarian, Retinoblastoma
ALDH Breast ,Lung ,Head and neck , Colon, Liver ,Pancreas ,Gastric ,Prostate
ABCB5 Melanoma
CD90 T-acute lymphoblastic leukemia , Gliomas ,Liver
Yapeng Hu, Liwu Fu Review Article Targeting cancer stem cells: a new therapy to cure cancer
Patients Am J Cancer Res 2012;2(3):340-356
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22. • Differences as well as signaling pathways and metabolic alterations can
hopefully distinguish between CSCs and SSCs and may be exploited for the
selective tumor-targeted therapies
• The innovative treatment methods such as nano , immuno , gene, and
chemotherapy approaches for targeting CSC specific markers and/or their
associated signaling pathways.
• CSC markers are attractive targets for novel cancer-targeting therapy
• Since the high expression of these markers has been observed in most human
tumor Slight surface antigen
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23. CD44
• CD44 is a major surface hyaluronic (HA) receptor
• both HA and CD44 involve in chemotherapeutic resistance
• CD44 can interact with P-gp to promote cell migration and invasion of tumor
cells
CD133
• CD133, a member of prominin family, consists of five transmembrane single-
chain glycoproteins
• CD133 can play a dominant role in drug resistance
• CD133 can enhance the activity of histone deacetylase 6 (HDAC6) via Wnt/β-
catenin signaling pathway
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24. Receptor tyrosine kinases
• RTKs have attractive features. Structurally, RTKs consist of an extracellular domain
that serves as the ligand-binding region
• EGFR, PDGFR, and CSF-1R
• increase phosphorylation of both JAK ,STAT.
ABCG2
• ABCG2 belongs to ABC transporter family as one of the most common drug
resistance mechanism
• consists of four domains; two nucleotide-binding and two transmembrane
• ABCG2 has an important physiological function in tissue protection against toxins
and xenobiotics through drug elimination
• It has been shown to participate in the multidrug resistance of tumors and lead to
the cancer relapse.
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25. Aldehyde dehydrogenase
• Aldehyde dehydrogenase (ALDH), a multifunctional enzyme with 11 families and
4 subfamilies,
• ALDH via retinoid signaling pathways can play a key role in regulation of gene
expression and cell differentiation.
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26. MARKER DRUGS
CD44+ Paclitaxel ,DOX , PTX, Taxol, ADR , Methotrexate
CD133+ Trifluoperazine , Gefitinib / Cisplatin , GSI-18(γ-secretase
inhibitor) Bafilomycin A1 (BafA1) , dCD133KDEL(an antiCD133
targeted toxin)
RTK Combination of METF and SAL , PTX , Dasatinib, DNR (
daunorubicin, Lapatinib, sunitini, or dasatinib)CK6 (a fully
human IgG1 monoclonal
antibody), Figitumumab.
ABCG2 PPARγ agonists ( telmisartan, pioglitazone, and rosiglitazone) ,
Isoliquiritigenin (ISL) , PZ-39 In , DOX PTX Cisplatin, ABCG2
siRNA , Sorafenib , Tunicamycin/Cisplatin .
ALDH Salinomycn, Histone deacetylase inhibitor (LBH589) , Dickkopf-
1 (Dkk-1) , Ellipticine PTX , RNA aptamer
Peyman Ranji1 & Tayyebali Salmani Kesejini1 et al,review, Targeting cancer stem cell-specific markers and/or
associated signaling pathways for overcoming cancer drug resistance aug 2016 ,5-17.
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27. Target Signal Pathways
Notch
• highly conserve developmental pathway, which plays a critical role in cell-fate
decision, tissue patterning and morphogenesis
Hedgehog
• Initially identified in Drosophila as a critical mediator of segmental patterning during
embryonic development, and it regulates the proliferation, migration, and
differentiation
• Sonic hedgehog pathway is also linked to transcription factor NF-κB signaling
Wnt
• Wnt is a group of secreted signaling proteins that bind receptor molecules on the
surface of target cells.
• β-Catenin the essential mediator of Wnt signaling
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28. Update On Clinical Trials For CSC Mole Targets
Target Drug Cancer Target Phase
Wnt vitaminD3
PRI-724
CWP232291
Basal Cell Carcinoma
advanced solid tumors
AML
β-catenin
CBP/β-catenin
β-catenin
III
I
I
Notch MK0752
RO4929097
PF-03084014
Advanced Breast
Cancer
Lung Cancer
Leukemia
γ-secretase
γ-secretase
γ-secretase
I
II
I
Hh GDC-0449
BMS-833923
IPI-926
Solid tumors
Colorectal
Basal cell
Primary Myelofibrosis
Fibrosis, Bone Marrow
PTCH and/or
SMO
SMO
SMO
I
I
II
Yapeng Hu, Liwu Fu Review Article Targeting cancer stem cells: a new therapy to cure cancer Patients Am J Cancer
Res 2012;2(3):340-356
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29. Targeting CSC Metabolism
• Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic
and biosynthetic requirements.
• They are largely dependent on aerobic glycolysis for their energy production and
also are associated with increased fatty acid synthesis and increased rates of
glutamine utilization .
• Resistance to cancer treatment may arise due to dysregulation in glucose
metabolism, fatty acid synthesis, and glutaminolysis
• CSCs undergo metabolic alterations that include low mitochondrial respiration and
high glycolytic activity.
• Tumor cells alter their metabolism to ensure survival, evade host immune attack,
and proliferate
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30. Deshmukh et al. Molecular Cancer (2016) 15:69 ,3.
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31. • Impact of glucose utilization by CSCs and non CSCs highlights the difference in
their metabolic profiles.
• Pyruvate enters the TCA cycle to initiate the precursor or supply towards
biosynthetic reactions.
• The Warburg effect in turn activates aerobic glycolysis and lessens mitochondrial
respiration, suggesting a preferred choice for proliferation
• cancer cells predominantly produce energy by a high rate of glycolysis followed
by lactic acid fermentation in the cytosol.
• Glutamine acts as a source of carbon and nitrogen for biosynthetic reactions of
cancer cells
• Glutaminase is highly expressed in rapidly growing tumor cells
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32. Epithelial– mesenchymal Transition (EMT)
• During cancer metastasis, CSCs undergo epithelial– Mesenchymal transition (EMT),
thereby acquiring mesenchymal features, migrating to adjacent stromal tissues and
invading blood or lymph vessels.
• cancer stem cells (CSCs) and epithelial- mesenchymal transition (EMT) play major
roles in cancer recurrence and metastasis.
• inhibition of mesenchymal variants or regulation of EMT in cancer cells as novel
therapies for cancer recurrence and metastasis
• Suppression of the mesenchymal variant of fibroblast growth factor (FGFR)-2, FGFR-
2 IIIc, and regulation of the EMT using epithelial splicing regulatory protein 1
(ESRP1) are effective in the treatment of immune deficient mice with pancreatic
cancer
Toshiyuki Ishiwata, Review Article, Cancer stem cells and epithelial- mesenchymal transition: Novel therapeutic
targets for cancer,2016
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33. Nanoparticle Mediated Targeting Of VEGFR
• Angiogenesis is a crucial process in tumor pathogenesis
• Angiogenesis is the formation of new blood vessels from the pre-existing vasculature.
• Angiogenesis is controlled by pro- angiogenic and antiangiogenic factors in the body.
• The regulatory factors may be several growth factors like VEGF, FGF, PDGF, EGF, placental
growth factor, Angiopoietin-1, Angiogenin, Interleukin 8.
• Angiogenesis is driven due to hypoxic conditions in the tumor. The hypoxic condition activates
the production of VEGF.
• The natural anti- angiogenic factor presents in the body are Angiostatin, Endostatin
Vasostatin, Prolactin, Angiopoietin-2, Interferon, -a and g Interleukin 12, Fibronectin, Platelet
factor-4.
• A finely tuned equilibrium exists between these pro-angiogenic and anti-angiogenic factors in
vivo.
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34. Ambasta et al. Vascular Cell 2011, 3:26
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35. VEGF Inhibitors
• Bevacuzimab is a humanized monoclonal antibody which binds to VEGF-A.
• Another monoclonal antibody used to target VEGF pathway is IMC-1121B which
selectively binds and inhibits the VEGFR-2.
• chimeric IgG1 antibody and its binding prevents the formation of ligand-
receptor.
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36. THANK YOU
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