PI3K/Akt/mTOR. I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Autosufficienza rispetto ai...

PI3K/Akt/mTOR

I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT

Autosufficienza rispetto ai segnali di crescita e insensibilità ai segnali antiproliferativi :

La sovraespressione di Akt può mediare un aumento della risposta cellulare ai livelli di fattori di crescita presenti nell’ambiente extracellulare

Akt promuove la localizzazione nucleare di Mdm2, favorendone l’azione di inibizione su p53

Akt promuove la localizzazione citoplasmatica di CKI quali p21 e p27, inibendone la funzione

Akt stabilizza i livelli di cicline D1 e D3


Inibizione del processo apoptotico:

Akt inattiva i fattori proapoptotici Bad e (pro)caspasi-9

Akt attiva IKK promuovendo la trascrizione di geni antiapoptotici da parte di NFκB

Akt inattiva i fattori di trascrizione Forkhead, inibendo la sintesi di FasL


Potenziale replicativo illimitato:

Akt aumenta l’attività telomerasica fosforilando hTERT


Angiogenesi:

Akt attiva la nitrossido sintetasi endoteliale (eNOS), promuovendo il processo angiogenico


Invasività e metastasi :

Akt contribuisce al potenziale invasivo stimolando la produzione di metalloproteinasi della matrice (MMPs)

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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

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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

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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


Protein Synthesis

mTOR

Angiogenesis

Nutrients Growth Factors

Normal Cell

Bioenergetics

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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


Protein Synthesis

Angiogenesis

Bioenergetics

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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


Protein Synthesis

Angiogenesis

Bioenergetics

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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

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


Angiogenesis

Protein Synthesis

Bioenergetics

Akt

PI3K ERAbl

Ras

Ras

EGF

IGF

Nutrients

VEGF

Growth Signaling

Cancer Cell

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mTOR Pathway is Deregulated in Many Cancers

Brain

Oral SCC

Breast

Pancreas

ColonUterus

Prostate

Skin

Ovary

BloodLung

Thyroid

Sarcoma

Kidney

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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

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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

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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

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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

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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

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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

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Production of Transporters

mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Coordinates Cancer Cell Growth

GlucoseTransporter

IncreasedNutrient Uptake



Cancer Cell

Amino AcidTransporter

Mutations in Cancer

Blood Vessel

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mTOR

MG1

G2

S

Cancer Cell Growth

mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways

GlucoseTransporter


Cancer Cell

Amino AcidTransporter

Blood Vessel

DECREASED


DECREASED

The role of programmed cell death in tumor development

Deirdre A. Nelson et al. Genes Dev. 2004; 18: 1223-1226

autophagy

hypoxic

Differenze nella risposta di cellule normali e tumorali allo stress metabolico

In che modo è possibile manipolare il metabolismo delle cellule tumorali in modo da indurre la morte cellulare attraverso una catastrofe

metabolica?

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mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies

mTORInhibition

Antiestrogens

RadiationChemotherapy

Growth Factor Signaling Inhibitors

Antiangiogenics

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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

PI3K/Akt/mTOR. I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Autosufficienza rispetto ai...

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