Targe&ng the mTOR pathway in AML
Sergio Amadori Tor Vergata University Hospital
Rome
SIES 10/2012
DICHIARAZIONE
Relatore: Sergio Amadori
Come da nuova regolamentazione della Commissione Nazionale per la Formazione Con>nua del Ministero della Salute, è richiesta la trasparenza delle fon> di finanziamento e dei rappor> con soggeF portatori di interessi commerciali in campo sanitario.
• Posizione di dipendente in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) • Consulenza ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE)
• Fondi per la ricerca da aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) • Partecipazione ad Advisory Board (Novar&s)
• Titolarietà di breveF in compartecipazione ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE) • Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE)
• Altro
Biologic heterogeneity • Host • Disease
The Achilles Heels of AML
cells
?
Inability to prevent or overcome
drug resistance
Obstacles to curing AML
The PI3K/Akt/mTOR network
Central integrator of mul&ple incoming signals (GF, nutrients,
energy/oxygen state)
Controls cell growth, prolifera&on and survival
Dysfunc&onal in cancer by mul&ple mechanisms
Target for drug development
mTOR: central controller of prolifera&on
Serine-‐threonine kinase
Modulates mRNA transla&on regula&ng cell growth and
prolifera&on
Downstream of PI3K/Akt oUen deregulated in cancer
mTOR deregula&on causes loss of growth control in cancer
mTOR: two complexes
Rapamycin sensi&ve
Rapamycin insensi&ve
Signaling abnormally ac&vated
in AML • PI3K >50% • mTORC1 >90%
Inhibi&ng mTOR enhances response to
cytotoxics and impairs LSC survival
Target for therapy
Role in AML
mTORC1 inhibitors
Rapamycin • Poor solubility and stability
Rapalogs • Improved PK, less immunosupp
Clinical development in AML
Rapamycin and Rapalogs
• Recher et al (Blood 2005) • 9 pts (R/R AML 8, sAML 1) • Rapamycin 6 mg d1, 2 mg d2-‐28
– >50% blast reduc&on (BM or PB): 4 pts; 1 pt SD • Biologic ac>vity
– PD: target inhibi>on (p-‐S6) in responders – Ex vivo: impaired clonogenic proper>es of fresh AML blasts (no effect
on normal progenitors)
• PK: highly variable bioavailability
mTOR inhibi&on in AML
Analogs with be_er PK profile needed
• Perl et al (Clin Cancer Res 2009) • Phase 1: Sirolimus + MEC • 29 pts (R/R AML 26, sAML 3) • Sirolimus (5 dose levels): 3-‐15 mg d1, 1-‐5 mg d2-‐7 • DLT: prolonged aplasia • MTD: 12 mg followed by 4 mg/d on days 2-‐7 • 6/27 (22%) pts responded (4 CR, 2 PR)
mTOR inhibi&on in AML
• Kasner et al (ASH 2011) • Sirolimus (12 mg d1, 4 mg d2-‐9) + MEC • 27 pts (R/R or untreated poor-‐risk AML) • PD monitoring of p-‐S6 (blood or marrow blasts)
– Paired day 1 and 4 samples (flow cytometry)
mTOR inhibi&on in AML
ORR by baseline
p-S6+ blasts
present ORR 53%
>50% reduction ORR 67%
• Wei et al (ASH 2010) • 24 pts (untreated AML, unfit; median age 74y) • LDAC 20x2 d1-‐10 + Everolimus 2,5/5/10 mg d1-‐28
– MTD 5 mg (DLT: mucosi>s and sepsis at 10 mg) • ORR 34% (CR 13%, CRi 4%, PR 17%)
– 30-‐d and 60-‐d mortality: 8% and 25% – Median OS 180 days (1-‐y 29%, 2-‐y 18%)
mTOR inhibi&on in AML
Median OS LDAC+Ev 175 d LDAC 44 d
GIMEMA study
• CLO+Temsirolimus
• Salvage therapy
• Elderly AML
AML-‐1107 (phase II)
Amadori et al, BJH 2012
Pre-‐clinical synergism between
rapalogs and cytotoxics
Modest single agent ac&vity in
AML
Temsirolimus IV deriva&ve of rapamycin that targets mTORC1
Clofarabine 2nd-‐genera&on nucleoside analog with
ac&vity in AML
Ra&onale
Treatment plan
Schedule • Induc&on (1/2 courses)
– Clo 20 mg/m2 iv days 1-‐5 – Tor 25 mg iv day 1, 8, 15
• Maintenance – Tor 25 mg iv day 1, 8 (mo x 12)
CloTor (course#1)
CR/CRi
Tor maint (monthly x12)
PR
CloTor (course #2)
CR/CRi
Tor maint (monthly x12)
< CR/CRi
Off study
Failure
Off study
Primary EP: ORR (CR+CRi)
Enrollment: 54 pts (2 stages)
Demographics (N=53) • M/F 31/22 • Median age yrs (range) 69 (60-‐78) • WHO PS 0-‐1/2 45/8 • Status of disease
– PIF 18 – 1st relapse 35
• CR1< 6 mos 12 • CR1 ≥6 mos 23
• Cytogene>cs (MRC) – Favorable 4 – Intermediate 38 – Adverse 6 – N/A 5
Induc&on outcome (N=53)
No. (%)
CR 4 (8)
CRi 7 (13)
PR 1 (2)
No response 34 (64)
Early death (
• Analysis of p-‐S6 (by flow) • Paired d0 and d2-‐3 or d9-‐10 BM samples available from 25/53 (47%) pts • 12/25 (48%) pts achieved >50% target inhibi>on
In vivo mTORC1 inhibi&on
Median p-‐S6 39% (19-‐47)
Median p-‐S6 101% (59-‐161)
mTORC1 inhib predic&ve of response
p-‐S6 inhib (>50%)
p-‐S6 inhib (
Conclusion
• 21% CR+CRi rate • Median OS 4.0 mos (9.1 resp)
Encouraging clinical ac&vity
• Grade ≥ 3: cytopenia, infec>on, neutropenic fever Manageable toxicity
• Predic>ve of response
In vivo mTORC1 inhibi&on
• More efficient inhibi>on of mTOR signaling needed
Effec&ve mTOR inhibi&on in 50% of pts
mTORC1, but not mTORC2, inhibited by
rapalogs
Enzyma>c inhibitors may overcome
Compensatory/feedback mechanisms oppose inhibi&on of mTOR signaling
Combina>on with other pathway
inhibitors (IGFR, MEK/Erk)
Reasons for limited efficacy of Rapalogs
Op&mizing mTOR inhibi&on
Novel PI3K pathway inhibitors
Potent, specific, oral PI3K and mTORC1/2 inhibitor
Broad an&prolifera&ve effect across different tumors
Pro-‐apopto&c effect in PI3K-‐pathway ac&vated tumor models
Pre-‐clinical evidence of strong ac&vity against AML cells*
Phase I/II trials in oncology
BEZ235 (Novar&s)
*Chapuis et al, Clin Cancer Res 2010
Oral pan-‐class I PI3K inhibitor (α,β,γ,δ isoforms)
Broad an&prolif and pro-‐apopto&c effects across different in vitro/vivo tumors
An&angiogenic ac&vity in vivo
Phase I/II trials in oncology (as single-‐agent and in combo)
BKM120 (Novar&s)
Maira et al, Mol Cancer Ther 2012
BKM120 Day 1 to 14 (induct) Day 1 to 10 (consolid)
Dose escala&on (course 1)
Steps: 50, 75, 100 mg/day
3+3 scheme
Sample size: 18 pts (max)
Ind Cons
Age: 61-‐75 Primary EP: DLT rate (end-‐of-‐cycle 1)
MICE + BKM120
CR/CRi ICE (x2) + BKM120
BKM120: GIMEMA phase I
IGFR-‐1 + mTORC1 PI3K + MEK/Erk
Targe&ng compensatory pathways
PI3K/AKT/mTOR pathway commonly dysregulated in AML: a_rac&ve therapeu&c target
Inhibi>on of mTORC1 with Rapalogs has limited clinical value in AML: combo > monotherapy
Inhibitors of mTORC1/2 and other targets in the pathway: greater an&leukemic efficacy?
Targe>ng mTOR and other compensatory pathways: a poten&ally powerful strategy for AML?
Key Takeaways
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