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 extra-cellular 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

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

ROLES OF AKT IN DETERMINING THE HALLMARKS OF CANCER

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)

14

mTOR Inhibitors: Exploiting New Targets in Cancer

Vascular Cell Growth

Akt

PI3K

VEGFR PDGFR-

mTOR

Cancer Cell

Vascular Pericyte

Endothelial Cell

Tumor

Angiogenic Factors

Protein Synthesis

Bioenergetics

NutrientsGrowth Factors

mTOR

Cell Growth & Proliferation

15

mTOR

MG1

G2

S

Cell Cycle Activation

mTOR Coordinates Growth and Nutrient Signaling

IncreasedNutrient Uptake

Secretion of Angiogenic Growth Factors

Blood Vessel

Growth Factors

Nutrients

Nutrient Availability

16

mTOR is a Central Regulator of Growth and Metabolism

mTOR is an intracellular serine/threonine kinase

mTOR is a central regulator that senses changes in

– Availability of growth factors1,2

– Availability of nutrients1,2

– Availability of fuel/energy3

mTOR regulation can affect

– Angiogenesis4

– Cell growth3

– Nutrient uptake, utilization5

– Metabolism3

Cell Growth & Proliferation

Protein Synthesis

mTOR

Angiogenesis

Nutrients Growth Factors

Normal Cell

Bioenergetics

17

mTOR Integrates Growth Factor Signaling

mTOR pathway, PI3K-AKT-mTOR, is a downstream component of several growth factor signaling pathways1

mTOR activation turns on the synthesis of proteins involved in cell growth2

mTOR is a critical integrator of signaling that coordinates cell growth control3

mTOR

Growth Signaling

PI3K

AktTSC2

↑Glucose

TSC1

AMPK

Amino Acids

↑ATP

↓Glucose

↓ATP

Cell Growth & Proliferation

Protein Synthesis

Angiogenesis

Bioenergetics

18

mTOR Integrates Nutrient Signaling

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

mTOR

Growth Signaling

PI3K

AktTSC2

↑Glucose

TSC1

AMPK

Amino Acids

↑ATP

↓Glucose

↓ATP

Cell Growth & Proliferation

Protein Synthesis

Angiogenesis

Bioenergetics

19

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

20

mTOR Pathway is Deregulated by Mutations in Cancer

Normal cell growth, proliferation, and metabolism are maintained by a number of mTOR regulators1,2

Regulators of mTOR activity

mTOR activating

mTOR deactivating

Deregulation of mTOR can result in loss of growth control and metabolism1,3

Mutations in the mTOR pathway have been linked to specific cancers4

PTEN

TSC2

TSC1

mTOR

Cell Growth & Proliferation

Angiogenesis

Protein Synthesis

Bioenergetics

Akt

PI3K ERAbl

Ras

Ras

EGF

IGF

Nutrients

VEGF

Growth Signaling

Cancer Cell

21

mTOR Pathway is Deregulated in Many Cancers

Brain

Oral SCC

Breast

Pancreas

ColonUterus

Prostate

Skin

Ovary

BloodLung

Thyroid

Sarcoma

Kidney

22

mTOR Pathway is Deregulated in Select Cancers

Breast

NET

Colon

Lung

Kidney

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, 46%15

PI3K, 20%–32%13,41

PTEN, 35%41

Ras, 50%12

EGFR, 70%42

p-Akt, 23%–50%18

PTEN, 24%22

Ras, 30%12

EGFR, 32%–60%1

TSC1/TSC240

p-Akt, 38%38

PTEN, 31%39

TGF/TGF1, 60%–100%35

VHL, 30%–50%36,37

IGF-1/IGF-IR, 39%-69%9

% Incidence of mutation in select cancer

23

mTOR Activation Supports Cancer Cell Growth

Cancer cells have deregulated growth

Key proteins are regulated by mTOR activation:

– 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

Nutrients

Angio-genesis

Nutrient Uptake &

Metabolism

Glut 1LAT1

Cell Growth

mTOR

Protein Synthesis

Growth Signaling

4E-BP1

S6

S6K1

elF-4E

HIF-1Cyclin D

24

mTOR

mTOR Activates Cell Cycle Progression

Israels and Israels. Oncologist. 2000;5:510-513, with permission.

Restrictionpoint

G2

M

S

G1

Cyclin D1

Protein Synthesis

25

mTOR Pathway Activation Promotes AngiogenesisSecretion of Angiogenic Growth Factors

Angiogenesis enables cancer cells access to growth factors, nutrient and energy resources1

mTOR activation elevates protein synthesis of HIF-1 and HIF-22

HIF turns on several hypoxic stress genes including VEGF and PDGF-3

Cancer cells secrete the proangiogenic factors that promote the formation of new vessels1,4,5

HIF-1/2

mTOR

Hypoxic Stress Genes

Protein Synthesis

Angiogenic Factors

Secretion

VHL

26

mTOR Pathway Activation Promotes Angiogenesis

Growth Control of Vascular Cells

Vascular Cell Growth

Akt

PI3

K

VEGFR PDGFR-

mTOR

VEGF PDGF

Tumor

Angiogenesis

HIF-1/2

VHL

mTOR

Protein Synthesis

Hypoxic Stress Genes

AngiogenicGrowth Factors

Tumor

Cancer Cell

Vascular Pericyte

Endothelial Cell

27

mTOR Activation Increases Nutrient Uptake

mTOR

Protein Synthesis

AminoAcids Glucose

GLUT 1

Amino Acid and Glucose Transporters

Nutrients

LAT Cancer cells have increased

nutrient and metabolic needs

Adequate amino acids, glucose, and ATP are required to sustain cancer cell growth

Nutrients and metabolic fuel are taken up via nutrient transporters

mTOR activation can increase the expression of nutrient transporters

Cancer cell access to nutrients and metabolic fuel support unregulated cell growth

28

Production of Transporters

mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Coordinates Cancer Cell Growth

GlucoseTransporter

IncreasedNutrient Uptake

Nutrient Availability

Secretion of Angiogenic Growth Factors

Cancer Cell

Amino AcidTransporter

Mutations in Cancer

Blood Vessel

29

mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways

GlucoseTransporter

Secretion of Angiogenic Growth Factors

Cancer Cell

Amino AcidTransporter

Blood Vessel

DECREASED

Nutrient Availability

DECREASED

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)

41

mTOR Inhibitors Suppress Nutrient Availability

Vascular Cell Growth

Akt

VEGFR PDGFR-

mTOR

VEGF PDGF

Tumor

Protein Synthesis

Nutrient Uptake

NutrientsGrowth Factors

mTOR

NutrientTransporters

AngiogenicFactors

Secretion VEGF, PDGF

Angiogenesis

PI3K

42

mTOR Inhibition is a Novel Approach for Blocking Angiogenesis

Vascular Cell Growth

Akt

VEGFR

mTOR

VEGFPDGF

PDGFR-

Angiogenesis

Tumor

HIF1/2VHL

mTOR

Protein Synthesis

Hypoxic Stress Genes

AngiogenicGrowth Factors

TKI

VEGF mAb

PI3K

43

Growth factor inhibitors target either the growth factor or the receptor on the cell surface

mTOR inhibitors target cancer cell growth downstream of growth factor receptors

Combining an mTOR inhibitor with a growth factor receptor inhibitor may be a more effective strategy for cancer treatment

mTOR inhibitors may be effective in patients that are refractory to growth factor inhibition

mTOR

Cell Growth & Proliferation

Angiogenesis

Protein Synthesis

Akt

Growth FactormAb

TKI

Bioenergetics

mTOR Inhibition May Enhance the Antitumor Effects of Targeted Therapies

PI3K

44

mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies

mTORInhibition

Antiestrogens

RadiationChemotherapy

Growth Factor Signaling Inhibitors

Antiangiogenics

45

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 estrogen-dependent 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

Combination Therapy RationalemTOR Inhibition May Enhance the Antitumor Effects of Other Therapies

46

SummaryRationale 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