Transcript Key Concepts in Targeting Cancer Stem Cells to

Key Concepts in Targeting
Cancer Stem Cells
to Manage Disease
Moderator
Howard S. Hochster, MD
Professor of Medicine
Associate Director for Clinical Sciences
Clinical Research Program Leader, Gastrointestinal
Cancers Program
Yale Cancer Center
New Haven, Connecticut
Panelists
Max S. Wicha, MD
Madeline and Sidney Forbes Professor of Oncology
Founding Director Emeritus
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan
Manish A. Shah, MD
Associate Professor of Gastrointestinal Oncology
Director, Gastrointestinal Oncology Program
Co-Director, Center for Advanced Digestive Care
Weill Cornell Medical College of Cornell University/
New York-Presbyterian Hospital
New York, New York
Program Goals
• Define cancer stem cells (CSCs)
• Understand the role of CSCs in tumor
development, metastasis, and disease
progression
• Describe how CSCs resist chemotherapy
and other conventional treatments
• Review advances in CSC-directed therapies
This program will discuss investigational agents that the
FDA has not approved for use in the United States.
What Are CSCs?
"CSCs are cells within a tumor that possess the capacity to
self-renew and to cause the heterogeneous lineages of cancer
cells that comprise the tumor."
- AACR Consensus Workshop, 2006a
• CSCs (sometimes called tumor-initiating cells) are a small
subpopulation of cells in a tumorb
• CSCs were first identified in AML and have since been
found in most solid tumors and hematologic cancersb,c
• According to the CSC hypothesis, CSCs drive tumorigenesis
and metastasisa
a. Clarke MF, et al. Cancer Res. 2006;66:9339-9344; b. Bonnet D, Dick JE. Nat Med. 1997;3:730737; c. Al-Haji M, et al. Proc Natl Acad Sci U S A. 2003;100:3983-3988.
Types of Human Stem Cells
Embryonic
stem cells
• Pluripotent stem cells that can give rise to any type
of cell in the body
• Found in embryos
• Capable of self-renewal
Adult stem
cells
• Multipotent stem cells that can differentiate into
all the specialized cells needed to maintain their
dedicated tissue
• Found in all organs and in the blood
• Capable of self-renewal
Cancer
stem cells
• Multipotent stem cells that can differentiate into
all the cells within a tumor
• Found in the tumor microenvironment or "niche"
• May arise from a mutated ASC or progenitor cell
or from a reprogrammed differentiated cell
De Los Angeles A, et al. Nature. 2015;525:469-478.
Detecting CSCs
Serial Transplantation Assays
• This is the gold standard for definitively identifying CSCsa
• Suspected CSCs are injected into immunodeficient mice to see whether
they generate tumorsa
− Only a few CSCs are needed to initiate a tumor
− Drawback is differences in mouse vs human immune system
Cell Surface Markers
• Fluorescence-activated cell sorting and conjugating antibodies to
magnetic beads can identify CSC markers
• Colony-forming assays show whether a cell can self-renew
• Sphere-forming assays measure how many tumor spheres
a CSC produces in vitro (tumorigenic efficiency)b
• Cell surface markers are good surrogates but are not definitive
a. Bonnet D, Dick JE. Nat Med. 1997;3:730-737; b. Ajani JA, et al. Semin Oncol. 2015;42:S3-S17.
CSC Markers in Different Tumor Types
• CD133+ is 1 of the most common CSC markersa,b
− CD133+ CSCs were isolated first in brain tumors and later in
cancers of the colon, liver, breast, lung, ovary, prostate,
pancreas, eye, skin, and bone/soft tissue
− CD133+ may predict chemoresistance and worse survival
• Breast CSC markers include CD44+, CD24-, and ALDH
− Markers vary depending on histologic subtypec
− CD44+/CD24-/low phenotype predicts poor prognosis
• Some markers (eg, CD44 and CD24) are observed in
CSCs across many tumor typesa
a. Ajani JA, et al. Semin Oncol. 2015;42:S3-S17; b. Grosse-Gehling P, et al. J Pathol.
2013;229:355-378; c. De Beca FF, et al. J Clin Pathol. 2013;66:187-191.
CSC Model vs Stochastic Model
CSC (Hierarchical) Model
Asymmetric CSC
division
= oncogenic event
CSC = cancer stem cell
P = progenitor cell
M = mature cell
P
CSC
P
M
M
M
CSC
P CSC M
Stochastic (Clonal Evolution) Model
= oncogenic event
All tumor cells can self-renew
or differentiate.
CSC
M
CSC
P
M
CSC
Symmetric
division
CSC
P
P CSC M
CSC
M
P CSC
Tumor Heterogeneity
• Both the stochastic and CSC models start with 1 cell that
produces a tumor with genetically distinct cells
• The stochastic model attributes genetic heterogeneity in
tumors to clonal evolution, with no cell hierarchy
• The CSC model also accounts for tumor heterogeneity
− Mutations or epigenetic changes cause CSC subclones to
produce different progenitor cells from their parents
− Mature cells with acquired mutations dedifferentiate into stemlike cells and proliferate
− Migration of a CSC into another tissue microenvironment can
cause further diversification
Shackleton M, et al. Cell. 2009;138:822-829.
Seed-and-Soil Hypothesis
• In 1889, Paget noticed metastasis was more frequent in
certain organs and proposed it was not randoma-c
• Studies suggest metastasis results from signaling between the
cancer cell (seed) and the organ microenvironment at
metastatic sites (soil)b
• The microenvironment regulates angiogenesis, an important
component of metastasisd
"When a plant goes to seed, its seeds are carried in all
directions; but they can only live and grow if they fall on
congenial soil."
– Stephen Paget, 1889a,b
a. Paget S. Cancer Metastasis Rev. 1989;8:98-101; b. Langley RR, Fidler IJ. Int J Cancer.
2011;128:2527-2535; c. Chambers AF, et al. Nat Rev Cancer. 2002;2:563-572; d. Folkman J. N
Engl J Med. 1971;285;1182-1186.
Epithelial-to-Mesenchymal Transition
(EMT) Epithelial Cells
Mesenchymal Cells
Transition
Basement membrane
• EMT is important during embryogenesis and wound repaira
• Loss of epithelial markers like E-cadherin (CDH1) causes CSCs to
undergo EMT and lose their adhesive propertiesb
− The cells detach from the extracellular matrix and from each othera,b
− They progressively acquire mesenchymal-like traitsa,b
− The now free-floating mesenchymal cells enter the blood stream or
lymph nodes and metastasize to distant sitesa
a. Radisky DC, LaBarge MA. Cell Stem Cell. 2008;2:511-512; b. Thiery JP. Nat Rev Cancer.
2002;2:442-454.
Plasticity of CSCs and EMT
The plasticity of CSCs allows the cells to transition
between epithelial and mesenchymal states,
which is what gives them the ability to invade
tissue, disseminate, and grow at metastatic sites.
Qualities of CSCs in Epithelial-like vs Mesenchymal-like State
Epithelial-like State
• Express epithelial markers
• Have polarity
• Proliferate extensively
• Found more in tumor interior
Liu S, et al. Stem Cell Reports. 2013;2:78-91.
Mesenchymal-like State
• Express mesenchymal markers
• Remain relatively quiescent
• Found at tumor invasive front
• Invade the bloodstream
• Establish micrometastases
Drivers of Epithelial-Mesenchymal and
Mesenchymal-Epithelial Transitions
• Reversible EMT/MET transitions are regulated by the
tumor microenvironment
• Adverse tumor conditions that drive EMT includea,b
− Hypoxia (sometimes caused by antiangiogenic agents)
− Nutrient deprivation
− Mutations that cause E-cadherin loss
• microRNA regulates EMT/MET via multiple pathwaysb
• Myeloid precursor cells at the pre-metastatic site
(niche) send homing signals to attract CSCsc
a. Liu S, et al. Stem Cell Reports. 2013;2:78-91; b. Thiery JP. Nat Rev Cancer. 2002;2:442-454; c.
Kaplan RN, et al. Nature. 2005;438:820-827.
Therapeutic Targets for CSCs
• Therapies should target stemness pathways (internal
pathways that induce or maintain stemness properties in
CSCs)a
− Wnt receptors and ligands
− Notch receptors and ligands
− Hedgehog (ligands, Patched-Smoothened complex)
− JAK/STAT pathway, including STAT3
− TGF-β family of cytokines
− Hippo
− Crosstalk between Notch and other oncogenic pathways
• Inflammatory mediators (extracellular pathways), like IL-6
and IL-8, promote CSC self-renewal and are also good
treatment targetsb,c
a. Ajani JA, et al. Semin Oncol. 2015;42:S3-S17; b. Iliopoulous D, et al. Cell. 2009;139:693-706;
c. Ginestier C, et al. J Clin Invest. 2010;120:485-497.
Response of CSCs to Chemotherapy
20
CSC Population, %
• In preclinical models, the CSC
population increased after
chemotherapya
• Clinical studies have observed
enrichment of CSCs in patients
treated with chemotherapyb
• One proposed mechanism is
the cytokines that dying cells
release (eg, IL8) stimulate
development of CSCsa
In Vitro Assessment of CSCs
After Chemotherapya
16
12
8
4
0
a. Ginestier C, et al. J Clin Invest. 2010;120:485-487; b. Li X, et al. J Natl Cancer Inst.
2008;100:672-679.
Pilot Study of Reparixin Plus Paclitaxel
• Phase 1b study in HER2-negative MBC (N = 33)
− Reparixin loading dose (400, 800, or 1200 mg) 3 times/d for
3 days was followed by paclitaxel (80 mg/m2/wk) + reparixin
for 21 days
− Treatment continued until disease progression or toxicity
• Safety was assessed after 1 cycle
− 15 serious AEs occurred, none related to reparixin
− 30% of patients experienced a grade 3/4 AE
• Efficacy assessment included 18 patients
− 2 CR and 6 PR
− Duration of response: 2-20 mo
Schott AF, et al. SABCS 2014. Abstract P6-03-01.
Co-Targeting CSCs and Bulk Tumor Cells
• Targeting CSCs
− CSCs that survive treatment will repopulate the tumor
− CSCs can cause recurrence even years later
− Surviving CSCs have the potential to metastasize
• Targeting bulk non-tumorigenic cells
− In advanced cancer, the bulk tumor population is large
enough to constitute a huge burden or death
− Plasticity may allow mature tumor cells to
dedifferentiate and acquire stem-like properties
Effective treatment strategies must target the CSCs and the
cells that make up the bulk of the tumor.
Resistance of CSCs to Conventional
Therapy
CSCs have several pro-survival mechanisms that help them
resist chemotherapy, radiotherapy, and targeted drugs.
Intrinsic Mechanisms
Indirect Mechanisms
• Enhanced DNA repair
• Induction of EMT or
acquisition of CSC markers via
• High expression of drug
signaling pathways in the
efflux pumps
microenvironment
• Upregulation of anti• Hypoxia-triggered adaptive
apoptotic factors and
changes via HIF activation
detoxification enzymes
• Quiescence during treatment (eg, formation of new blood
vessels that are poor drug
to protect self-renewal ability
transporters)
a. Maugeri-Saccà M, et al. Clin Cancer Res. 2011;17:4942-4947; b. Skvortsova I, et al.
SeminCancer Biol. 2015 Sep 22. [Epub ahead of print]; c. Hashida S, et al. Cancer Sci. 2015 Jul
21. [Epub ahead of print]
Tumor Regression: Inadequate End Point
Tumor shrinkage by RECIST may not be useful
for evaluating response to CSC-directed therapies.
Little tumor
shrinkage
Tumor cannot
make new cells
Mature cells die,
tumor shrinks,
patient is cured.
CSC
CSC
CSC
Notable tumor
shrinkage
Reya T, et al. Nature. 2001;414:105-111.
Patient has a
relapse.
Efficacy End Points for CSC-Directed
Agents
Possible End Points for Trials of CSC-Directed Agents
End Point
Time to progression
(TTP)
CSC agents delay TTP, so patients will have
to take them until they have significant
progression to determine their effectiveness
Pathologic CR
to neoadjuvant
therapy
This is a well-defined predictor of recurrence; a
biopsy before and after neoadjuvant treatment
would show the direct effects of therapy on CSCs
Immune-related
response criteria
Measurable new lesions are incorporated into
total tumor burden because tumors may grow
before response is evident
Reduction in CSCs
A decrease in CSCs may predict better prognosis
Overall survival
CSC-directed agents must be shown to prolong
survival without compromising patient safety
CSCs as a Prognostic Marker
• Studies have linked CSC markers with an increased risk of
metastasis or recurrence, worse survival outcomes, and
treatment resistancea
• CSC markers have been found to have prognostic
significance in many solid tumors, including breast, colon,
brain, and head and neck cancers; and in hematologic
malignancies such as AMLa
• Breast cancer studies have shown higher proportions of
cells expressing CSC marker ALDH1+ after neoadjuvant
chemotherapy predicts early metastasis and worse survival
outcomesb-d
a. Ajani JA, et al. Semin Oncol. 2015;42:S3-S17; b. Charafe-Jauffret E, et al. Clin Cancer Res.
2010;16:45-55; c. Sakakibara M, et al. Cancer. 2012;118:3899-3910; d. Khoury T, et al. Mod
Pathol. 2012;25;388-397.
Circulating Tumor Cells and CSCs
• Circulating tumor cells (CTCs) can predict the risk of
metastasis and relapse in patients treated for cancera
• Analyzing the portion of CTCs that are CSCs may offer
clues to the efficacy of CSC-directed therapies
• The only FDA-approved method for isolating CTCs
uses the epithelial adhesion molecule EpCAMa
− ~50% of CTCs have undergone EMT and have low
expression of EpCAM or other epithelial markersb
− This method may fail to detect CSCs that survive therapy
• New technologies are being studied that use
microfluidics to isolate single cells by biomarkerc
a. Balic M, et al. Expert Rev Mol Diagn. 2012;12:303-312; b. Aktas B, et al. Breast Cancer Res.
2009;11:R46; c. Karabacak NM, et al. Nat Protoc. 2014;9:694-710.
CSC-Directed Agents in Clinical Trials
Several CSC-directed agents with various targets were shown
to be safe in phase 1 clinical trials.
Ipafricept
(OMP-54F28)
Demcizumab
(anti-DLL4)
DLL/JAG
Tarextumab
(OMP-59R5)
BBI608
WNT
Vantictumab
(anti-FZD)
NOTCH
LPR/FZD
β-CAT
β-CAT, STAT3, Nanog
TARGET DNA
IIIIIII
IL-8
IIIIIII
CXCR
CXCR1
1 IIIIIiI
IIiiiiiii
iiiiiiiii
FAK
FAK
iiiiiiiI
L-8II
Reparixin
Defactinib
Self-renewal, drug
resistance,
metastasis
Cancer stem cell
a. Liu S, Wicha MS. J Clin Oncol. 2010;28:4006-4012; b. Prud'homme GJ. Curr Pharm Des.
2012;18:2838-2849.
Forced Differentiation of CSCs
• CSC-directed agents that inhibit signaling along the
self-renewal pathway have been found to activate
quiescent CSCs, causing them to differentiatea
• Inducing CSCs to differentiate may represent a viable
CSC-directed treatment strategy
− Once differentiated, the CSCs would be susceptible to
chemotherapy
− You could potentially exhaust the population of CSCs
• Effective cancer treatment will likely require a
combination regimen with a CSC-directed agent and
an agent that targets the bulk non-tumorigenic cells
a. Guessous F, et al. Cell Cycle. 2010;9:1031-1036.
Immunotherapy and CSCs
• A small percentage of patients with cancer treated
with immunotherapy have durable remission
• Preclinical models suggest the immune system in
these patients eradicates the CSCs
• Anti-CSC vaccines are in development
− In a proof-of-concept study, a dendritic cell-based vaccine
gave immunocompromised mice antitumor immunitya
− Preliminary evidence from a phase 1/2 study (N = 90) of a
novel lung cancer CSC vaccine found it safe and effectiveb
• Combining vaccines with checkpoint inhibitors may
improve cure rates in some cancers
a. Teitz-Tennenbaum S, et al. Oncoimmunology. 2012;1:1401-1403; b. Lin M, et al. Immunol
Res. 2015;62:16-22.
Summary
• Growing evidence shows CSCs contribute to the
development, growth, and metastasis of cancer
• CSCs may originate from a mutated ASC or a mature
cell that acquires stem-like properties
• Many novel agents that target CSC signaling
pathways or cytokines are being studied in clinical
trials, and early data suggest these drugs are
relatively safe
• More research is needed to identify appropriate end
points for CSC-directed therapies and to identify safe
combinations that target CSCs and bulk tumor cells
Abbreviations
AE = adverse event
ALDH = aldehyde dehydrogenase
AML = acute myelogenous leukemia
ASC = adult stem cell
CDH1 = cadherin-1
CR = complete response
CSC = cancer stem cells
CTC = circulating tumor cell
EMT = epithelial-to-mesenchymal transition
EpCAM = epithelial cell adhesion molecule
ERK= extracellular signal-regulated kinase
IL = interleukin
GI = gastrointestinal
HER2 = human epidermal growth factor receptor 2
JAK = Janus kinase
M = mature cell
MAPK = mitogen-activated protein kinase
Abbreviations (cont)
MBC = metastatic breast cancer
MSI = microsatellite instability
P = progenitor cell
PD-1 = programmed cell death 1
PD-L1 = programmed death ligand 1
PR = partial response
RECIST = Response Evaluation Criteria In Solid Tumors
STAT = signal transducer and activator of transcription
TGF-β = transforming growth factor-β
TTP = time to progression
Abbreviations (cont)
MBC = metastatic breast cancer
MSI = microsatellite instability
P = progenitor cell
PD-1 = programmed cell death 1
PD-L1 = programmed death ligand 1
PR = partial response
RECIST = Response Evaluation Criteria In Solid Tumors
STAT = signal transducer and activator of transcription
TGF-β = transforming growth factor-β
TTP = time to progression
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