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PI3K/Akt/mTOR. I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Autosufficienza rispetto ai segnali di crescita e insensibilità ai segnali.

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Presentation on theme: "PI3K/Akt/mTOR. I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Autosufficienza rispetto ai segnali di crescita e insensibilità ai segnali."— Presentation transcript:

1 PI3K/Akt/mTOR

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6 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 nellambiente extracellulare Akt promuove la localizzazione nucleare di Mdm2, favorendone lazione 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

7 I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT 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 NF κB Akt inattiva i fattori di trascrizione Forkhead, inibendo la sintesi di FasL

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9 I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Potenziale replicativo illimitato: Akt aumenta lattività telomerasica fosforilando hTERT

10 I SEGNI CARDINALI DEL CANCRO E I MOLTEPLICI RUOLI DI AKT Angiogenesi: Akt attiva la nitrossido sintetasi endoteliale (eNOS), promuovendo il processo angiogenico

11 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)

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13 13 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 Nutrients Growth Factors mTOR Cell Growth & Proliferation

14 14 mTOR M G1 G2 S Cell Cycle Activation mTOR Coordinates Growth and Nutrient Signaling Increased Nutrient Uptake Secretion of Angiogenic Growth Factors Blood Vessel Growth Factors Nutrients Nutrient Availability

15 15 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 factors 1,2 –Availability of nutrients 1,2 –Availability of fuel/energy 3 mTOR regulation can affect –Angiogenesis 4 –Cell growth 3 –Nutrient uptake, utilization 5 –Metabolism 3 Cell Growth & Proliferation Protein Synthesis mTOR Angiogenesis Nutrients Growth Factors Normal Cell Bioenergetics

16 16 mTOR Integrates Growth Factor Signaling mTOR pathway, PI3K-AKT- mTOR, is a downstream component of several growth factor signaling pathways 1 mTOR activation turns on the synthesis of proteins involved in cell growth 2 mTOR is a critical integrator of signaling that coordinates cell growth control 3 mTOR Growth Signaling PI3K Akt TSC2 Glucose TSC1 AMPK Amino Acids ATP Glucose ATP Cell Growth & Proliferation Protein Synthesis Angiogenesis Bioenergetics

17 17 mTOR Integrates Nutrient Signaling mTOR senses availability of amino acids, metabolic fuel, and energy 1 Nutrients and energy stores are essential for protein synthesis, cell growth, proliferation, and survival 1,2,3 mTOR activation supports growth and survival by increasing cell access to nutrients and metabolic fuels 4 mTOR Growth Signaling PI3K Akt TSC2 Glucose TSC1 AMPK Amino Acids ATP Glucose ATP Cell Growth & Proliferation Protein Synthesis Angiogenesis Bioenergetics

18 18 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

19 19 mTOR Pathway is Deregulated by Mutations in Cancer Normal cell growth, proliferation, and metabolism are maintained by a number of mTOR regulators 1,2 Regulators of mTOR activity mTOR activating mTOR deactivating Deregulation of mTOR can result in loss of growth control and metabolism 1,3 Mutations in the mTOR pathway have been linked to specific cancers 4 PTEN TSC2 TSC1 mTOR Cell Growth & Proliferation Angiogenesis Protein Synthesis Bioenergetics Akt PI3K ER Abl Ras EGF IGF Nutrients VEGF Growth Signaling Cancer Cell

20 20 mTOR Pathway is Deregulated in Many Cancers Brain Oral SCC Breast Pancreas Colon Uterus Prostate Skin Ovary Blood Lung Thyroid Sarcoma Kidney

21 21 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/TSC2 31,32 IGF-1/IGF-1R 33 VHL 34 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/TSC2 40 p-Akt, 38% 38 PTEN, 31% 39 TGF /TGF 1, 60%–100% 35 VHL, 30%–50% 36,37 IGF-1/IGF-IR, 39%-69% 9 % Incidence of mutation in select cancer

22 22 mTOR Activation Supports Cancer Cell Growth Cancer cells have deregulated growth Key proteins are regulated by mTOR activation: –Cell cycle regulators 1 –Proangiogenic factors 2 –Amino acid and glucose transporters 3,4 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 1 LAT1 Cell Growth mTOR Protein Synthesis Growth Signaling 4E-BP1 S6 S6K1 elF-4E HIF-1 Cyclin D

23 23 mTOR mTOR Activates Cell Cycle Progression Israels and Israels. Oncologist. 2000;5:510-513, with permission. Restriction point G2G2 M S G1G1 Cyclin D1 Protein Synthesis

24 24 mTOR Pathway Activation Promotes Angiogenesis Secretion of Angiogenic Growth Factors Angiogenesis enables cancer cells access to growth factors, nutrient and energy resources 1 mTOR activation elevates protein synthesis of HIF-1 and HIF-2 2 HIF turns on several hypoxic stress genes including VEGF and PDGF- 3 Cancer cells secrete the proangiogenic factors that promote the formation of new vessels 1,4,5 HIF- 1/2 mTOR Hypoxic Stress Genes Protein Synthesis Angiogenic Factors Secretion VHL

25 25 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 Angiogenic Growth Factors Tumor Cancer Cell Vascular Pericyte Endothelial Cell

26 26 mTOR Activation Increases Nutrient Uptake mTOR Protein Synthesis Amino Acids 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

27 27 Production of Transporters mTOR M G1 G2 S Cancer Cell Growth mTOR Coordinates Cancer Cell Growth Glucose Transporter Increased Nutrient Uptake Nutrient Availability Secretion of Angiogenic Growth Factors Cancer Cell Amino Acid Transporter Mutations in Cancer Blood Vessel

28 28 mTOR M G1 G2 S Cancer Cell Growth mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways Glucose Transporter Secretion of Angiogenic Growth Factors Cancer Cell Amino Acid Transporter Blood Vessel DECREASED Nutrient Availability DECREASED

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39 The role of programmed cell death in tumor development Deirdre A. Nelson et al. Genes Dev. 2004; 18: 1223-1226

40 autophagy hypoxic

41 Differenze nella risposta di cellule normali e tumorali allo stress metabolico

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

43 Figure 16.43a The Biology of Cancer (© Garland Science 2007)

44 Figure 16.43b The Biology of Cancer (© Garland Science 2007)

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47 47 mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies mTOR Inhibition Antiestrogens Radiation Chemotherapy Growth Factor Signaling Inhibitors Antiangiogenics

48 48 AgentRationale EGFR inhibitorsDefects in the mTOR signaling pathway may counter the effects of EGFR inhibitors on cell growth and proliferation. Combined treatment has been beneficial in preclinical studies 1 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 inhibitors 2-4 Antiangiogenic agents mTOR inhibition affects angiogenesis through mechanisms that enhance and complement those of anti-VEGF/anti-VEGFR signaling inhibitors 5 AntiestrogensDefects in the mTOR signaling pathway may render estrogen- dependent tumor cells resistant to antiestrogens and aromatase inhibitors. Combinations effective preclinically 6-8 RadiationIn preclinical studies, mTOR inhibition enhances cell killing induced by radiation, possibly by interfering with repair of damage to DNA 9 Combination Therapy Rationale mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies


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