Funzionalità, Meccanismi di Escape, Potenziali Targets di Sinergismo Inibitorio. Federica Recine, MD

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2 Studiando il Pathway di mtor Funzionalità, Meccanismi di Escape, Potenziali Targets di Sinergismo Inibitorio Federica Recine, MD Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy

3 mtor protein kinase (Mammalian Target of Rapamycin Macmillan Publishers Ltd, Nature Reviews Clinical Oncology 2010; 7(4)

mtor: The Central Regulator of Growth and Metabolism Nutrients Normal Cell mtor is a central regulator that senses changes in: Growth Factors Availability of growth factors mtor Availability of

4 mtor: The Central Regulator of Growth and Metabolism Nutrients Normal Cell mtor is a central regulator that senses changes in: Growth Factors Availability of growth factors mtor Availability of nutrients Availability of fuel/energy Protein Synthesis Cell Growth Bioenergetics & Proliferation Angiogenesis mtor regulation can affect: Angiogenesis Cell growth Nutrient uptake Metabolism Wullschleger et al. Cell. 2006;124(3): Humar et al. FASEB J. 2002;16(8): Edinger and Thompson. Mol Biol Cell. 2002;13(7):

5 mtor signaling gpathways mtor activity is linked to PI3K/AKT signaling PTEN regulates negatively PI3K PI3K AKT mtor is a downstream component of several growth factor signaling pathways Upstream signals (ex IGF 1) activate PI3K/AKT pathway Activated mtor phosphorylates p downstream effector molecules S6K1 and 4EBP1 Translation Cyclin D1, c Myc, HIF1α, and others S. Faivre et al. Nature 2006; 16 (9): 674

mtor pathways AKT dipendent mechanisms AKT is a

mtorc1 by phosphorylating and inhibiting TSC2)

inactivation activation of the small GTPase

6 mtor pathways AKT dipendent mechanisms AKT is a substrate of mtorc2 (but indirectly activates mtorc1 by phosphorylating and inhibiting TSC2) The TSC complex (TSC1 /TSC2) are key components in the upstream regulation of mtor AKT phosphorylation of TSC2 leads to TSC inactivation activation of the small GTPase Rheb, which switches mtorc1 signaling Memmott M. et al., Cell Segnal, 2009

7 mtor signaling in cancer Aberrant activation of the PI3K/AKT/mTOR pathway leads to cell cycle progression, tumor angiogenesis, i and proliferation Deregulation of mtor can result in loss of growth control and metabolism Mutations in the mtor pathway have been linked to specific cancers J Zha et al. Clinical Cancer Research 2010; 16 (9): Huang J et al. Science 2007; 318 (5857): Engelman JA et al. Nat Rev Cancer 2009;9 (8):

8 mtor signaling in cancer Upstream aberrant activation: overexpression of RTKs (HER1 4, PDGFR/KIT, IGFR) and Ras activating mutations of PIK3CA p110 subunit of PI3K PTEN inactivation or loss mutation of NF1 Amplifications of AKT inactivation or mutations of TSC1/2 Downstream deregulation: S6K1 and IF4E hyperactivation p53 loss J Zha et al. Clinical Cancer Research 2010; 16 (9): Huang J et al. Science 2007; 318 (5857): Engelman JA et al. Nat Rev Cancer 2009;9 (8):

9 mtor inhibitor classes Rapalogs Direct active site inhibitors Everolimus BEZ235 Temsirolimus Perifosina BKM120 Janes et al, Nat Med 2010

10 Why mtor inhibitors in NET? Comprehensive analyses have definitely shown activation of mtor pathway in both experimental, sporadic and Hereditary NETs Lessons from Lessons from Lessons from clinical Hereditary Syndromes MEN1gene VHL gene preclinical studies PI3K AKT PTEN study RADIANT SAGA Translational medicine TSC complex NF 1 gene DAXX/ATRX TSC2 mir21 mtor (S6K1 4EBP1)

11 Preclinical i lti Trial s messages High expression rates of pmtor have been demonstrated in poorly differentiated NETs, suggesting a potential role of mtor inhibitors in NET treatment Everolimus blocks IGF production and consequence PI3K activation EverolimustreatmentledtoNETcellgrowthinhibitionandhighexpression of the molecular l targets (mtor mrna and phosphorylated h mtor levels) l predicted response to mtor inhibition Zatelli et al., Endocr Related Cancer, 2010 Zitzmann et al., Neuroendocrinology and Cancer Lett, 2007, 2010 Svejda et al., Cancer, 2011 Meric-Bernstam et al., Clin Cancer Res, 2012

12 Clinical Trial s messages Dose and time dependent rise in lactate dehydrogenase with everolimus treatment has been associated with better PFS. This is postulated to be related to tumor hypoxia from mtor inhibition Yao et al., JCO, 2008 Yao et al., JCO, 2010 Yao et al., NEJM, 2011 Duran et al., Br J Cancer, 2006 Yao et al., JCO, 2010

13 Why mtor inhibitor hb in Breast Cancer? Preclinical studies have demonstrated activation of the PI3K/mTOR pathway after long term estrogen deprivation Growing evidence supports a close interaction between the mtor pathway and ER signaling Everolimus synergizes with letrozole in preclinical models mtor activation is a mechanism of escape to long term estrogen deprivation Do Rapalogs reverse resistance to endocrine therapy? Martin LA et al. J Biol Chem 2003 Miller TW et al. J Clin Invest 2010 degraffenried LA Clin Cancer Res 2004) Boulay et al. Clin Canc Res 20004

14 BOLERO 2: Study Design Primary endpoint: PFS (investigator assessment) Secondary endpoints: OS, ORR, clinical i l benefit rate, safety ft Randomized 2:1; stratified by sensitivity to previous hormonal ltherapy, presence of visceral metastases Treatment until disease progression or unacceptable toxicity Postmenopausal women with ER positive advanced breast cancer who progressed on previous nonsteroidal AI therapy* (N = 724) Exemestane 25 mg/day + Everolimus 10 mg/day (n = 485) Exemestane 25 mg/day + Placebo (n = 239) *> 50% of patients in each arm with 3 previous therapies Baselga J et al. N Engl J Med 2012;366:520 9.

15 BOLERO 2: PFS Patien nts (%) Local HR: 0.44 (95% CI: ; Log rank P value: < 1 x ) EVE + EXE: 7.4 mos PBO + EXE: 3.2 mos EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239) Central HR: 0.36 (95% CI: ; Log rank P value: < 1 x ) EVE + EXE: 11.0 mos PBO + EXE: 4.1 mos EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239) 0 Patients at Risk, n Wks Everolimus Wks Everolimus Placebo Placebo Significant PFS benefit with everolimus observed in all patient subgroups including: age, hormone sensitivity, visceral metastasis, ECOG PS, previous chemotherapy, number of previous therapies, and PR status Baselga J et al. N Engl J Med 2012;366:520 9.

16 BOLERO-2 (12-Mo Follow-up): Safety Adverse Events, % Exemestane + Everolimus Exemestane + Placebo (n = 482) (n = 238) All Grades Grade 3/4 All Grades Grade 3/4 Stomatitis Rash Fti Fatigue Diarrhea < 1 Appetite decreased < 1 Nausea Noninfectious pneumonitis Hyperglycemia < 1 Baselga J et al. N Engl J Med 2012;366:520 9.

17 Why mtor inhibitor in Kidney Cancer? PI3K/Akt/mTOR pathway activation is common in RCC* Inhibition of mtor with rapalogs has clinical value in advanced/metastatic RCC: Temsirolimus increases overall survival of pts with multiple poor prognostic factors (compared with IFN) Everolimus increases PFS of pts who progress on VEGFR TKIs (compared with placebo) Consistent toxicity profile of rapamycin analogs *Lin F et al Ann Clin Lab Sci 2006 Lin F, et al, Ann Clin Lab Sci 2006 Pantuck AJ et al, Cancer 2007 Robb V et al, J Urol 2006

18 Late Breaking Abstract # 5026 RECORD 1: RAD001 (Everolimus) + Best Supportive Care (BSC) vs BSC + Placebo in Pts With Metastatic RCC After Progression on VEGFr TKI Therapy R. Motzer, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, R. Figlin, J. Thompson, V. Grünwald, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud, for the RECORD 1 Study Group

19 Study Design Target N = 362 Stratification Prior VEGFr TKI: 1 or 2 MSKCC risk group 1 : favorable, intermediate, or poor R A N D O M I Z A T I O N 2:1 Interim analysis Everolimus + BSC Upon Disease Progression Placebo + BSC Interim analysis Final analysis Interim analyses planned after 30% and 60% of targeted Motzer events et al. J Clin Oncol. 2004;22:

20 Progression-Free Survival by Treatment Central Radiology Review Prob bability, % Hazard ratio = % CI [0.22, 0.40] Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo P value < Everolimus (n = 272) Placebo (n = 138) Months Patients at Risk Everolimus Placebo

inhibition Feedback loop circuits activated

of the PI3K pathway mtorc 2 mediated AKT

(crosstalk) O Reilly K E et al. Cancer Res.

21 Rapalogs and resistance mechanisms Incomplete and substrateselectivemtorc 1 inhibition Feedback loop circuits activated by mtorc1 inhibition: feedback activation of the PI3K pathway mtorc 2 mediated AKT iperactivation feedback activation of MAPK (crosstalk) O Reilly K E et al. Cancer Res February 1; 66(3): Seth A W et al. J Clin Invest 2011; 121(4): q1 Yatscoff RW et al. Ther Drug Monit 1993 ; 15:

22 PI3K/mTOR pathway inhibitors Dual PI3K/mTOR inhibitors Pure PI3K inhibitors AKT inhibitors Dual mtorc1/2 inhibitors XL765 BEZ235 GDC0980 RKT PI3K AKT mtor XL147 GDC0941 BKM120 CAL101 BYL719 Perifosine MK2206 GDC 0068 OSI 027 AZD8055 INK 128

23 Clinical Benefits for Perifosine/Capecitabine Combination Not Realized in Phase III Study for Metastatic Colorectal Cancer X PECT was a phase III study that randomly assigned 468 patients with refractory colorectal cancer (CRC) to receive perifosine/capecitabine (P CAP; 234 patients) or capecitabine (CAP; 234 patients) The median OS was 6.4 months and 6.9 months for patients receiving P CAP and CAP, respectively (p = 0.315). The difference in OS also was not significant when analyzed based on K RAS status. In addition, the difference in PFS was not significant for patients in the P CAP arm of the study (10.9 weeks for P CAP and 11.4 weeks for CAP; p = 0.752). O Reilly K E et al. ASCO 2012

24 BEZ235: Dual lpi3k and mtor Inhibitor BEZ235 is a potent oral inhibitor of PI3K and the downstream effectors, mtorc1/2 Significantly inhibits growth and induces apoptosis in a variety it of tumor cells lines BEZ235 suppresses estrogen independent growth in ER+ breast cancer cells BEZ235 has reversed resistance to other anti cancer therapies in a variety of tumor cell lines In vivo studies have confirmed the anti growth and anti angiogenic potential of BEZ235 BEZ235 exhibited dose and day dependent PI3K inhibition in a Phase I study and is now entering Phase II development Maira SM, et al. Mol Cancer Ther 2008;7: Serra V, et al. Cancer Res 2008;68: Engelman JA, et al. Nat Med 2008;14: Brachmann S, et al. Proc Natl Acad Sci USA 2009;106: Eichhorn PJ, et al. Cancer Res 2008;68: Brünner Kubath C, et al. Breast Cancer Res Treat 2011;129: Bhende PM, et al. Leukemia 2010;24: ;

25 Conclusions Overall, molecular clues are the proof of the concept and have furnished the rationale for the use of mtor inhibitors in the treatment of disregulated mtor cancers Prognostic and predictive biomarkers for mtor targeted therapies are needed Improvements in overcoming drug resistance it are needed dd

10/15/2012. Overcoming Endocrine Therapy Resistance. The Problem in ER+ Tumors is Endocrine Therapy Resistance

10/15/2012. Overcoming Endocrine Therapy Resistance. The Problem in ER+ Tumors is Endocrine Therapy Resistance Overcoming Endocrine Therapy Resistance Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology Slide Credits: Hope Rugo, MD The Problem in ER+ Tumors is Endocrine Therapy Resistance