Transcript MODULAZIONE FARMACOLOGICA DI SEGNALI …

PI3K/Akt/mTOR
ROLES OF AKT IN DETERMINING
THE HALLMARKS OF CANCER
Self-sufficiency in growth signals and insensitivity to
anti-growth signals:
Akt overexpression can mediate an increase in
cellular response to growth factors in the extracellular space
Akt promotes cytoplasmic localization of CKIs,
such as p21 and p27, thereby inhibiting their
function
Akt stabilizes cyclin D1 e D3 levels
Akt facilitates MDM2 nuclear localization and its
inhibitory action on p53
ROLES OF AKT IN DETERMINING
THE HALLMARKS OF CANCER
Inhibition of apoptosis
Akt inactivates the proapoptic factors Bad and
(pro)caspase-9
Akt activates IKK enhancing NFκB transcriptional
activity on antiapoptotic genes
Akt inactivates Forkhead transcription factors,
inhibiting FasL synthesis
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Potenziale replicativo illimitato:
Akt aumenta l’attività telomerasica fosforilando
hTERT
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Angiogenesi:
Akt attiva la nitrossido sintetasi endoteliale
(eNOS), promuovendo il processo angiogenico
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Invasività e metastasi :
Akt contribuisce al potenziale invasivo
stimolando la produzione di metalloproteinasi
della matrice (MMPs)
mTOR Inhibitors: Exploiting New
Targets in Cancer
Endothelial Cell
Cancer Cell
Growth
Factors
Nutrients
VEGFR
PDGFR-b
PI3K
mTOR
Akt
Protein Synthesis
Cell Growth
& Proliferation
mTOR
Tumor
Bioenergetics
Angiogenic
Factors
Vascular Cell
Growth
Vascular Pericyte
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mTOR Coordinates
Growth and Nutrient Signaling
Blood Vessel
Nutrient Availability
Growth Factors
Increased
Nutrient Uptake
Nutrients
mTOR
Secretion of Angiogenic
Growth Factors
M
G1
G2
Cell Cycle Activation
S
15
mTOR is a Central Regulator
of Growth and Metabolism
Growth Factors
Nutrients
 mTOR is an intracellular
serine/threonine kinase
 mTOR is a central regulator that
senses changes in
– Availability of growth
factors1,2
mTOR
– Availability of nutrients1,2
– Availability of fuel/energy3
Protein Synthesis
 mTOR regulation can affect
Cell Growth
& Proliferation
Bioenergetics
Angiogenesis
Normal Cell
– Angiogenesis4
– Cell growth3
– Nutrient uptake, utilization5
– Metabolism3
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mTOR Integrates Growth Factor Signaling
↓Glucose
↑Glucose
↓ATP
PI3K
AMPK
TSC1
↑ATP
TSC2
Akt
Growth
Signaling
Amino
Acids
 mTOR activation turns on the
synthesis of proteins involved in
cell growth2
mTOR
Protein Synthesis
Cell Growth
& Proliferation
 mTOR pathway, PI3K-AKTmTOR, is a downstream
component of several growth
factor signaling pathways1
 mTOR is a critical integrator of
signaling that coordinates cell
growth control3
Bioenergetics
Angiogenesis
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mTOR Integrates Nutrient Signaling
↓Glucose
↑Glucose
↓ATP
PI3K
AMPK
TSC1
↑ATP
TSC2
Growth
Signaling
Akt
Amino
Acids
mTOR
Protein Synthesis
Cell Growth
& Proliferation
 mTOR senses availability of
amino acids, metabolic fuel, and
energy1
 Nutrients and energy stores are
essential for protein synthesis,
cell growth, proliferation, and
survival1,2,3
 mTOR activation supports
growth and survival by
increasing cell access to
nutrients and metabolic fuels4
Bioenergetics
Angiogenesis
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mTOR Pathway Regulates Bioenergetics
 Bioenergetics refers to nutrient utilization and metabolism
 mTOR senses nutrient and energy availability in a cell
 mTOR pathway activation controls bioenergetics by
increasing nutrient transporter expression and production of
angiogenic growth factors
 mTOR pathway activation controls bioenergetics by
enabling the influx of glucose, amino acids, and other
important molecules that are metabolic fuels used to
generate ATP
 Targeting the mTOR pathway can impact the bioenergetics
of the cell
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mTOR Pathway is Deregulated
by Mutations in Cancer
IGF
EGF
Growth
Signaling
VEGF
Nutrients
Ras
 Normal cell growth, proliferation,
and metabolism are maintained by
a number of mTOR regulators1,2
PTEN
Abl
ER
PI3K
 Regulators of mTOR activity
Ras
TSC1
mTOR activating
Akt
TSC2
mTOR deactivating
 Deregulation of mTOR can result
in loss of growth control and
metabolism1,3
mTOR
Protein Synthesis
Cell Growth
& Proliferation
Bioenergetics
 Mutations in the mTOR pathway
have been linked to specific
cancers4
Angiogenesis
Cancer Cell
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mTOR Pathway is Deregulated in Many Cancers
Brain
Thyroid
Oral
SCC
Breast
Lung
Blood
Kidney
Ovary
Pancreas
Colon
Uterus
Prostate
Skin
Sarcoma
21
mTOR Pathway is Deregulated in Select Cancers
p-Akt, 23%–50%18
PTEN, 24%22
Ras, 30%12
EGFR, 32%–60%1
Breast
Lung
NET
TSC1/TSC240
p-Akt, 42%16
PI3K, 18%–26%27,28
PTEN, 15%–41%25
HER2, 30%–36%26,27
TSC1/TSC231,32
IGF-1/IGF-1R33
VHL34
p-Akt, 38%38
PTEN, 31%39
TGFa/TGFb1,
60%–100%35
VHL, 30%–50%36,37
IGF-1/IGF-IR,
39%-69%9
Kidney
% Incidence of mutation in select cancer
Colon
p-Akt, 46%15
PI3K, 20%–32%13,41
PTEN, 35%41
Ras, 50%12
EGFR, 70%42
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mTOR Activation Supports Cancer Cell Growth
Nutrients
Growth
Signaling

Cancer cells have deregulated
growth

Key proteins are regulated by
mTOR activation:
mTOR
S6K1
4E-BP1
elF-4E
S6
Protein Synthesis
Cyclin D
HIF-1a
Cell
Growth
Angiogenesis
Glut 1
LAT1
Nutrient
Uptake &
Metabolism

–
Cell cycle regulators1
–
Proangiogenic factors2
–
Amino acid and glucose
transporters3,4
mTOR activation supports
cancer cell growth by
stimulating the synthesis of
proteins important for cell
growth, angiogenesis, nutrient
uptake, and metabolism
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mTOR Activates Cell Cycle Progression
mTOR
M
G2
Protein Synthesis
G1
S
Restriction
point
Cyclin D1
Israels and Israels. Oncologist. 2000;5:510-513, with permission.
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mTOR Pathway Activation Promotes Angiogenesis
Secretion of Angiogenic Growth Factors
mTOR
VHL
 Angiogenesis enables cancer
cells access to growth factors,
nutrient and energy resources1
Protein Synthesis
 mTOR activation elevates protein
synthesis of HIF-1a and HIF-2a2
HIF1/2
 HIF turns on several hypoxic
stress genes including VEGF and
PDGF-b3
Hypoxic Stress Genes
Angiogenic Factors
 Cancer cells secrete the
proangiogenic factors that
promote the formation of new
vessels1,4,5
Secretion
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mTOR Pathway Activation Promotes Angiogenesis
Growth Control of Vascular Cells
VEGF
PDGF
Endothelial Cell
VEGFR
Cancer Cell
PI3
PDGFR-b
K
mTOR
Akt
Protein Synthesis
mTOR
VHL
HIF1/2
Hypoxic Stress Genes
Angiogenic
Growth Factors
Tumor
Tumor
Vascular Cell Growth
Angiogenesis
Vascular Pericyte
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mTOR Activation Increases Nutrient Uptake
Amino
Acids
Glucose
Nutrients
GLUT 1
LAT
 Cancer cells have increased
nutrient and metabolic needs
 Adequate amino acids, glucose,
and ATP are required to sustain
cancer cell growth
mTOR
 Nutrients and metabolic fuel are
taken up via nutrient transporters
 mTOR activation can increase the
expression of nutrient transporters
Protein Synthesis
Amino Acid and
Glucose Transporters
 Cancer cell access to nutrients
and metabolic fuel support
unregulated cell growth
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mTOR Coordinates Cancer Cell Growth
Blood Vessel
Nutrient Availability
Glucose
Transporter
Production
Increasedof
Transporters
Nutrient
Uptake
mTOR
Secretion of Angiogenic
Growth Factors
Mutations in
Cancer
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
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mTOR Inhibition May Disrupt
Cancer Cell Growth by Various Ways
Blood Vessel
Nutrient Availability
DECREASED
Secretion of Angiogenic
Growth Factors
Glucose
Transporter
mTOR
DECREASED
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
29
Sabatini Nature Reviews Cancer advance online publication;
published online 17 August 2006 | doi:10.1038/nrc1974
Figure 16.44b The Biology of Cancer (© Garland Science 2007)
Figure 16.44c The Biology of Cancer (© Garland Science 2007)
mTOR Inhibitors Suppress Nutrient Availability
VEGF
Growth
Factors
Nutrients
PDGF
VEGFR
PDGFR-b
PI3K
mTOR
Akt
mTOR
Protein Synthesis
Angiogenic
Nutrient
Factors
Transporters
Secretion
VEGF, PDGF
Nutrient
Uptake
Tumor
Vascular Cell Growth
Angiogenesis
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mTOR Inhibition is a Novel Approach for
Blocking Angiogenesis
VEGF mAb
PDGF
VEGF
TKI
PDGFR-b
VEGFR
mTOR
PI3K
Protein Synthesis
Akt
VHL
HIF1/2
Tumor
mTOR
Hypoxic Stress Genes
Angiogenic
Growth Factors
Vascular Cell Growth
Angiogenesis
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mTOR Inhibition May Enhance the
Antitumor Effects of Targeted Therapies
Growth Factor
mAb
TKI
 Growth factor inhibitors target
either the growth factor or the
receptor on the cell surface
PI3K
 mTOR inhibitors target cancer
cell growth downstream of growth
factor receptors
Akt
 Combining an mTOR inhibitor
with a growth factor receptor
inhibitor may be a more effective
strategy for cancer treatment
mTOR
Protein Synthesis
Cell Growth
& Proliferation
Bioenergetics
 mTOR inhibitors may be effective
in patients that are refractory to
growth factor inhibition
Angiogenesis
43
mTOR Inhibition May Enhance the
Antitumor Effects of Other Therapies
Radiation
Chemotherapy
mTOR
Inhibition
Growth Factor
Signaling
Inhibitors
Antiestrogens
Antiangiogenics
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Combination Therapy Rationale
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies
Agent
Rationale
EGFR inhibitors
Defects in the mTOR signaling pathway may counter the effects of
EGFR inhibitors on cell growth and proliferation. Combined treatment
has been beneficial in preclinical studies1
Cytotoxic
chemotherapy
Cytotoxic drugs such as the platinum derivatives, taxanes,
anthracyclines, and gemcitabine have shown improved antitumor
effects in preclinical models when used in combination with mTOR
inhibitors2-4
Antiangiogenic
agents
mTOR inhibition affects angiogenesis through mechanisms that
enhance and complement those of anti-VEGF/anti-VEGFR signaling
inhibitors5
Antiestrogens
Defects in the mTOR signaling pathway may render estrogendependent tumor cells resistant to antiestrogens and aromatase
inhibitors. Combinations effective preclinically6-8
Radiation
In preclinical studies, mTOR inhibition enhances cell killing induced
by radiation, possibly by interfering with repair of damage to DNA9
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Summary
Rationale for Targeting mTOR
 Targeting deregulated pathways has been a successful clinical
strategy
 mTOR is a central regulator of cancer cell growth and metabolism
 Deregulation of components of the mTOR pathway occurs in many
types of hematologic and solid tumors
 Targeting the mTOR pathway can impact the bioenergetics of the
cell, a new approach in the treatment of cancer
 mTOR is a unique target in cancer that may provide therapeutic
benefit to patients with disease refractory to currently approved
therapies
 Therapeutic strategies combining mTOR inhibitors with other
targeted therapies or cytotoxic agents may provide enhanced
anticancer activity
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