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1
Emerging Role for Targeting
Hsp90
Mark A. Socinski, MD,
Director, Lung Cancer Section, Division of Hematology/Oncology
University of Pittsburgh Cancer Institute
University of Pittsburgh
2
Hsp90: Background
• Hsp90 is an ATP-dependent
chaperone regulating late
stage maturation, activation
and stability of client proteins
• Maintains protein homeostasis
in normal cells
• Induced under stress, hypoxia
and oxidative damage
• Exploited by cancer cells for at
least 2 purposes:- support oncoproteins including many
kinases and transcription factors that are
mutated, translocated or overexpressed
- buffer cellular stresses induced by the
malignant lifestyleSoti et al, J Biol Chem, 2002.Neckers et al, CCR 2012.
3
Hsp90 serves as a buffer against the many environmental
stresses that cancer cells must endure and overcome
Neckers L , Workman P Clin Cancer Res 2012;18:64-76
©2012 by American Association for Cancer Research
4
Activated client; cell
survival, proliferationHsp90 binds to client
Hsp90 inhibitorsprevent Hsp90 binding to
client
Inactive client, degraded
through proteasome
HSP90 client
proteins: ALK, AKT,
BCR-ABL, BRAF,
CDK4, CHK1,
EGFR, FLT3, HER2,
HIF1a, KIT, MET,
PDGFRa, CRAF,
SRC, VEGFR, AR,
ER …
Hsp90 chaperone inhibition leads to
client protein degradation
5
Inhibition of distinct drivers distinct applications
HSP90
X
Ganetespib
X
X
Monotherapy
ALK, RAF,
HER2, …
Oncogene drivers,
targeted cancer
indications
Combination therapy
Tumor recovery/repair
mechanisms
DNA repair,
cell cycle
clients
HIF-1Tumor aggressiveness
Angiogenesis
EMT, metastasis
Immune evasion
Chemo-resistance
6
Hsp90 inhibition: single target, simultaneous
inhibition of multiple oncogenic pathways
HSP90
X
ALK
AKT
BCR-ABL
FLT3
RAF
c-KIT
c-MET
EGFR
HER2
VEGFR
PDGFR
HIF-1
Others
X
X
XXXX
X
X
XX
X
X
Hsp90 Inhibitor
X
H3122 ALK+ NSCLC cells
Hsp90 clients: many
key cancer drivers
7
Where are Hsp90 inhibitors likely to have most
pronounced activity as monotherapy?
X X
X √
Oncogene addicted tumor?
No Yes
Weak Hsp90
client
Strong Hsp90
client
ALK, HER2,
RAF, others
8
ALK rearranged cancer cell lines are
sensitive to heat-shock protein 90 (Hsp90)
inhibitors.
Sequist L V et al. JCO 2010;28:4953-4960
©2010 by American Society of Clinical Oncology
9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ganetespib (30
nM)
AZD6244 (24 nM) CombinationAZD6244
(24 nM)
… and synergy with other targeted agents
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ganetespib (13
nM)
PLX4032 (59 nM) Combination
A375 melanoma
Fra
cti
on
Aff
ec
ted
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ganetespib (7.5
nM)
everolimus (3.4
nM)
Combination
GIST882A375 melanoma
Ganetespib
(30 nM)
Combo PLX4032
(59 nM)
Ganetespib
(13 nM)
Combo Everolimus
(3.4 nM)
Ganetespib
(7.5 nM)
Combo
MEK Inhibitor mTOR InhibitorBRAF InhibitorALK Inhibitor
H3122 NSCLC
Ganetespib
10
How do Hsp90 inhibitors lead to changes
in gene expression and tumor biology ?
11
Ganetespib selective in-vivo accumulation
in tumor vs normal tissue
12
Changing the biology of tumors
Foley et al., AACR April 2010 #2638; Ying et al., Mol Canc
Therap Jan 2012; Mahaseth et al, AACR 2012 Abst #2326
HT-29 CRC cells
__ +
Ganetespib
Ganetespib inhibits hypoxia-induced-factor, HIF-1
Preclinical Patients treated with G
HIF-1α
VEGF
ACTIN
RT-PCR, patient tumor samples
First 3 pts, Emory university G rectal ca trial
Control – before treatment
*** p<0.005
Ganji, Diaz, El-Rayes et al, “Antiangiogenic Effects of
Ganetespib in Colorectal Cancer Mediated Through
Inhibition of HIF-1α and STAT-3,” submitted
13
Hypoxia, HIF drive tumor aggressiveness
HIF-1Genomic instability,
tumor progression
Adapted from R. Jain, ASCO 2012 plenary session; G. Semenza “HIFs: mediators of cancer
progression and targets for cancer therapy” (2012). Not an exhaustive list of genes
Switch to anaerobic
metabolismEMT Invasion,
metastasis
Angiogenesis
Resistance to radio-,
chemo-, immuno-therapy
Inflammation,
immunosuppressionVEGF, ANGPT, SDF, PGF
GLUT, LDH-A
ID2, SNAI,
VIM
TGFA, IGF2, EDN1, ADM
AMF, MET, CXCR4,
MMP, LOX, L1CAM,
Stem cell
immortalizationTERT, NANOG, GPI, PGM
MDR1, BCL2, …
CCL28, T-Reg
HYPOXIA
14
Changing the biology of tumors: angiogenesis
Methods of angiogenesis inhibition
1. Block ligand bevacizumab
2. Block receptor TKI
3. Inhibit transcription ganetespib
HT-29
HCT-116
Control Ganetespib
Egg cam assay
HT-29
HCT-116
Matrigel plug assay
Ganji, Diaz, El-Rayes et al, “Antiangiogenic Effects of Ganetespib in Colorectal Cancer Mediated
Through Inhibition of HIF-1α and STAT-3,” submitted; Mahaseth et al., AACR 2012 Abstr 2326
Ganetespib inhibits
production of VEGFControl Ganetespib
15
Implications to combination therapy?
….Ganetespib synergy w/ anti-angiogenic therapy
1
10
100
1000
10000
10 13 16 19 22 25 28 31 34 37 40
Days After Tumor Implantation
i.v. / i.p. Dosing (1X/Week):
Vehicle
Bevacizumab (10 mg/kg)
Ganetespib (150 mg/kg)
Bevacizumab (10 mg/kg) + Ganetespib (150 mg/kg)
17
3
-90
Avera
ge T
um
or
Volu
me (
mm
3)
H1975 NSCLC
16
…. tumor sensitization to chemo- / radiotherapy
0
100
200
300
400
500
600
700
800
18 21 24 27 30 33 36 39 42 45 48 51
Days After Tumor Implantation i.v. Compound #1:
Radiation:
Ave
rag
e T
um
or
Vo
lum
e (
mm
3)
Vehicle
Ganetespib (150 mg/kg)
Radiation (2 Gy)
Ganetespib (150 mg/kg) + Radiation (2 Gy)
100
-36
32
28
Cervical Cancer Xenograft Model
Cervical cancer xenograft
17
Isobologram
analysis, H522
NSCLC cells
Synergy in
H1975 NSCLC
xenografts
Synergistic mechanisms
– Complementary cell cycle effects
– G suppresses anti-apoptotic factors
– G Inhibits tumor invasiveness and
angiogenesis
Synergy in preclinical models
Phase 2 NSCLC monotherapy
– G single-agent clinical activity
– G toxicity profile non-overlapping with
taxanes
Phase I combination trial
– Established RP2D, schedule
– Combination well tolerated
– No PK interaction
G inhibits VEGF production, angiogenesis
Rationale for ganetespib+docetaxel in NSCLC
18
Ganetespib effects on cell cycle and DNA repair
HEL92.1.7 cells treated for 24 hrs
Cell-cycle genes inhibited
by ganetespib
Gene Fold Change
CDC2 -21.0
E2F-7 -15.2
Cyclin E2 -12.0
Cyclin F -10.2
CDC25A -6.1
CDC25C -5.3
Cyclin E1 -5.1
DHFR -4.6
E2F-1 -3.7
Cyclin A2 -3.6
Ganetespib
Ganetespib
W. Ying et al. Molec Canc Therap Dec 2011;
D. Proia et al PLoS One 2011;6:e18552
19
19
Hsp90 Inhibitors- The History
1962 2000 20051970
Heat shock
proteins
discovered
Geldanamycin
purified for use as
antibiotic
1st-generation
2010
• 17-AAG derivatives
• Formulation issues, limited clinical activity, toxicity (hepatic, ocular)
2nd-generation
• Structurally unrelated to 17-AAG
• Higher potency, improved safety
19
21
Development of Hsp90i: 1st-gen vs. 2nd-gen
W. Ying et al Molec Canc Therap 2012; 11 p. 475
17-AAGHydroquinone salt form 17-AAG
17-DMAG IPI-504
Ganetespib
1st-gengeldanamycinderivatives
Synthetic
Low molecular weight
Absence benzoquinone moiety, liver DLTs
10-100x more potent than 1st-gen
Benzoquinone moiety implicated in liver toxicity and 17-DMAG
22
Accumulation of Hsp90 inhibitors in eye:
ocular toxicity
17-DMAG, AUY-922, SNX-5422, AT-13387, …
Hsp90 inhibitor
Clinical
observationCommon ocular tox
Retina – in vivo
Properties
17-AAG, ganetespib
Little/no ocular tox
Hydrophilic, greater accumulation in retina
ONL
INL
ONL
INL
ONL
INL
INL
ONL
AUY-922
17-DMAG
17-AAG
Ganetespib
Rodent model
ONL: outer nuclear layer, elevated Hsp90
Hydrophobic; reduced accumulation in retina
Zhou et al, “Associating retinal drug exposure and retention with the ocular toxicity profiles of Hsp90 inhibitors”
ASCO June 2012 Abst. #3086
24
HSP 90 Inhibitors in Clinical Development
Agent Sponsor Administration
17AAG NCI/Kosan iv
KOS-953 (tanespimycin) Kosan iv
17DMAG Kosan Iv & oral
IPI-504 (Retaspimycin) Infinity iv
STA-9090 (Ganetespib) Synta iv
AUY-922 Novartis iv
DS-2248 Daiichi Oral
XL-888 Exelixis Oral
IPI-493 Infinity Oral
MPC-3100 Myrexis Oral
SNX-5422 Serenex Oral
CNF-2024 Biogen Idec Oral
Source: Clinicaltrials.gov, accessed 3/29/2011.
25
HSP 90 Inhibitors in Clinical Development
Agent Sponsor Administration
17AAG NCI/Kosan iv
KOS-953 (tanespimycin) Kosan iv
17DMAG Kosan Iv & oral
IPI-504 (Retaspimycin) Infinity iv
STA-9090 (Ganetespib) Synta iv
AUY-922 Novartis iv
DS-2248 Daiichi Oral
XL-888 Exelixis Oral
IPI-493 Infinity Oral
MPC-3100 Myrexis Oral
SNX-5422 Serenex Oral
CNF-2024 Biogen Idec Oral
Source: Clinicaltrials.gov, accessed 3/29/2011.
26
Dose and Schedule of Hsp90 inhibitors
Agent Dose (mg/m2) Schedule
IPI-5041 400 ↓ to 225* d1, 4, 8, 11 q21d
AUY9222 70 Weekly
Ganetespib3 200 d1, 8, 15 q28d
*Dose decreased from 400 to 225 mg/m2 due to hepatotoxicities seen in a separate trial of
IPI-504 in GI stromal tumors. 75 of 76 patients started at 400 mg/m2 and 19 were still on therapy
when the dose reduction was implemented
1. Sequist LV et al J Clin Oncol 28:4953-4960, 2010
2. Garon EB et al J Clin Oncol 30: ASCO 2012, abstr # 7543
3. Wong K et al. J Clin Oncol 29:ASCO 2011, abstr # 7500 (Socinski MA et al, manuscript submitted)
27
Most Common Grade 3/4 Toxicities in Phase II
Trials of Hsp90 Inhibitors in NSCLC
IPI-5041 AUY9222 Ganetespib3
Diarrhea 11 7 8
Nausea 8 0 0
Vomiting 8 2 0
Anorexia 5 3 0
Fatigue 8 4 14
Myal/Arthral 3 1 0
Visual 0 7* 0
Dyspnea 8 8 12
ALT 7 - 4
AST 9 - 0
*70% had grade 1-2 eye disorders – most commonly photopsia, visual impairment, blurred vision, night blindness
and reduced visual acuity
1. Sequist LV et al J Clin Oncol 28:4953-4960, 2010
2. Garon EB et al. J Clin Oncol 30: ASCO 2012, abstr# 7543
3. Wong K et al. J Clin Oncol 29: ASCO 2011, abstr# 7500 (Socinski MA et al. manuscript submitted)
28
Clinical Activity of Hsp90 Agents in
Advanced NSCLC
# pts ORR (%) ORR/DCR (%) by genotype
EGFR mt KRAS mt ALK +
IPI-5041 76 7 4/21 0/42 67/100
AUY9222 120 14 20/57 0/39 29/57
Ganetespib3 99 4 0/13 0/6 50/87
1. Sequist LV et al. J Clin Oncol 28:4953-4960, 2010
2. Garon EB et al. J Clin Oncol 30: ASCO 2012, abstr # 7543
3. Wong K et al. J Clin Oncol 29: ASCO 2011, abstr # 7500 (Socinski MA et al. Manuscript submitted)
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Enrolled N=96
Evaluable N=76
• Previously treated
stage IIIB/IV
NSCLC
• ECOG - PS 0, 1
• Disease
progression at
study entry
• Genotyping*
Study Design
F/U
Until
PD
Stra
tifica
tion
*1 patient with unknown genotype
First Patient First Visit, Dec, 2009;
Last Patient first visit, May, 2011
A: mEGFR (n=16)
B: mK-Ras (n=17)
C: wild-type EGFR/wild-type K-Ras (n=25)
D: Adenocarcinoma only (n=37)
Simon two stage design
Ganetespib 200 mg/m2 q wk for 3 out of 4 weeks
Primary endpoint: PFS rate at 16 weeks
E: addition of qw docetaxel on PD if clinical benefit
Wong K….Shapiro G, Socinski MA. J Clin Oncol 29:2011, abstr# 7500
30
Adverse Events Occurring in ≥ 10% Patients
0
10
20
30
40
50
60
70
80
90
100
Dia
rrhea
Fatig
ue
Nause
a
Decr
eased
Appet
ite
Dysp
nea
Constip
ation
Back
Pain
Vom
iting
Cough
Dehyd
ratio
n
Diz
zines
s
Inso
mnia
Anxie
ty
Head
ache
Hypona
trae
mia
Incr
eased
ALT
Incr
eased
ALK
PHOS
Hyper
glyca
emia
Musc
ular W
eakn
ess
UTI
G5
G4
G3
G2
G1
Drug-related SAEs, one patient each: asthenia, atrial fibrillation,
cardiac arrest, diarrhea, lipase elevation, renal failure, vomiting
31
Best Response in Target Lesions
31
*
■ Cohort A (mEGFR)
■ Cohort B (mKRas)
■ Cohort C+D (WT)
*
* * ** * * *
** **** **
* SD ≥ 16 wks
* Partial Responses
32
Genetic Profiling
For crizotinib-naïve patients:
7 out of 8 (88%) patients with ALK-positive tumors had disease control lasting at least 16 weeks.
6 out of 8 (75%) patients with ALK-positive tumors had tumor shrinkage in target lesions.
4 out of 8 (50%) patients with ALK-positive tumors had objective response.
*
*
* = presumed ALK+; prior crizotinib
ALK Rearrangement Cohorts C/D
• no mutations detected beyond EGFR and KRAS (Sequenom)
• 4 patients had EGFR polysomy
*
33
Proof of principle: ganetespib monotherapy
clinical activity, ALK+ NSCLC
24 year old male
• Chemotherapy, progressed; crizotinib 1 year (PR), progressed
• Enrolled ganetespib monotherapy (single-agent)
Baseline
After three weeks
(3 doses) ganetespib
34
Responses in EGFR-mutant and ALK+ NSCLC in
AUY922 trial
Baseline Cycle 3, Day 1
Baseline Cycle 7, Day 1
3rd line EGFRm+ patient
5th line ALK+ patient
35
Rationale for Combining Hsp90
inhibitors and Taxanes
• Both drugs have single agent activity in NSCLC
• STA-9090 and docetaxel have synergistic effects on
– Cell cycle
– Both drugs affect microtubuli
– Hsp90 inhibitors interfere with taxane resistance mechanisms (eg, AKT expression, anti-apoptotic signaling through VEGF)
– Effects of Hsp 90 inhibition on microenvironment sensitize tumors to docetaxel (vasculature, blood flow, metabolic state)
36
Emory Univ. Phase 1 Docetaxel + Ganetespib Combination
• Phase I study in patients with advanced solid organ malignancies (ongoing)
• Docetaxel – day 1
• Ganetespib- days 1 & 15
• N=20 patients to date
• Recommended phase II dose: Docetaxel 75 mg/m2; Ganetespib 150 mg/m2
• DLTs- myelosuppression and diarrhea (with 200 mg/m2)
• 8 patients are still on study therapyPI: Drs. Harvey and Ramalingam
37
Phase Ib Study of Docetaxel + IPI-504 in Advanced
NSCLC
• Partial Response
seen in 6 patients
(ORR = 26%)
• Stable Disease
seen in 7 patients
Riely et al, Abstract # 7516, ASCO 2011.
38
Preliminary results from a randomized 2b/3
study of ganetespib and docetaxel combination
versus docetaxel in advanced NSCLC (the
GALAXY Trial, NCT01348126)
Suresh S. Ramalingam1, Bojan Zaric2, Glenwood D. Goss3, Christian
Manegold Sr.4, Rafael Rosell5, Vojo Vukovic6, Iman El-Hariry6, Florentina
Teofilovici6, Sarah Mulcahey6, Wei Guo6, Dean Anthony Fennell7
1Emory University, Atlanta, GA; 2Institute for Pulmonary Diseases of Vojvodina, Serbia; 3The
Ottawa Hospital Cancer Centre, Ottawa, ON; 4University Medical Center, Mannheim, Germany; 5Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain; 6Synta
Pharmaceuticals, Lexington, MA; 7University of Leicester, Leicester, United Kingdom
ESMO 2012, Vienna, Austria
Abstract #1248P_PR
39
Study design
Stratification
• ECOG PS
• Time since diagnosis of
advanced disease
• Baseline serum LDH
• Smoking history
Eligibility criteria
• Stage IIIB/IV NSCLC
• ECOG 0,1
• 1 prior Rx advanced setting
• Measurable disease
• Documented PD
• Clinically stable CNS metastases
• Available tumor tissues
• Adequate organ function
Statistical assumptions
Co-primary: 90% power PFS 6 12
wks (elevated LDH pts); 5 10 wks
(mKRAS pts)
Key secondary: all adenocarcinoma
pts – 88% power PFS 3 4.5 mo,
73% power OS 6 8.5 mo
1-sided alpha of 0.05
40
All adenocarcinoma patients (N=172)D (N=88)
n (%)
G+D (N=84)
n (%)
Median Age (Range) 58 (34, 86) 60 (41, 79)
Sex Male
Female
54 (61)
34 (39)
46 (55)
38 (45)
ECOG Status 0 1
39 (44)
49 (56)
41 (49)
43 (51)
Stage at Study Entry IIIB
IV
4 (5)
83 (94)
5 (6)
79 (94)
Smoking History Current
Past
Never
25 (28)
43 (49)
20 (23)
17 (20)
44 (52)
23 (27)
Interval since dx advanced ≤ 6 mo
disease > 6 mo
25 (28)
54 (61)
26 (31)
54 (64)
LDH Normal
Elevated
63 (72)
25 (28)
60 (71)
24 (29)
Prior Therapy Plat-Based chemo
Bevacizumab
Maintenance
81 (92)
8 (9)
7 (8)
78 (93)
5 (6)
8 (10)
Geographic Region North America
Eastern Europe
Western Europe
16 (18)
58 (66)
14 (16)
18 (21)
52 (62)
14 (17)
Baseline characteristics
41
* Neutropenia and Anemia from both reported AEs and laboratory results of ANC and RBC, respectively
All grades Grade 3 or 4
D (N=86)
n (%)
G + D (N=81)
n (%)
D (N=86)
n (%)
G + D (N=81)
n (%)
Neutropenia * 43 (50) 40 (49) 29 (34) 28 (35)
Diarrhea 10 (12) 34 (42) 0 3 (4)
Fatigue 17 (20) 25 (31) 2 (2) 4 (5)
Anemia* 9 (11) 17 (21) 1 (1) 4 (5)
Nausea 13 (15) 15 (19) 2 (2) 2 (3)
Decreased appetite 8 (9) 12 (15) 1 (1) 0
Dyspnea 9 (11) 11 (14) 2 (2) 1 (1)
Alopecia 8 (9) 11 (14) 0 0
Rash 5 (6) 11 (14) 0 2 (3)
Vomiting 8 (9) 9 (11) 1 (1) 0
Asthenia 8 (9) 8 (10) 2 (2) 1 (1)
Pyrexia 6 (7) 8 (10) 0 0
Febrile neutropenia 2 (2) 8 (10) 2 (2) 8 (10)
Cough 9 (11) 7 (9) 0 0
Adverse events in >10% patients
42
D
(N=88)
G + D (N=84)
p-Value*
PFS 2.8 mo 4.2 mo 0.076HR=0.782
(90% CI: 0.55, 1.11)
ORR 8% 16% 0.078
PFS, ORR
* All p-values are calculated using 1-sided stratified log-rank test for survival endpoints and using Fisher’s Exact
test for response rate.
43
OS, ITT (Sep cutoff, N=172)
ganetespib + docetaxel
docetaxel
D G+D
N 88 84
Deaths 26 (30%) 19 (23%)
Median OS 7.38 mo NR
p-Value 0.183 (stratified log-rank,1-sided)
HR 0.688 (90% CI: 0.417, 1.135)
Median follow-up: 3.26 mo
44
Hsp90 Inhibition in NSCLC - Conclusions
• Hsp90 inhibitors are active agents in NSCLC
• Design of 2nd generation agents have overcome toxicities
seen with the 1st generation inhibitors
• As single agents mostly likely to be active in oncogene
addicted tumors that are also strong hsp90 clients
- ALK+ disease best example to date
- Best as single agents vs combinations? Best schedule?
• Preclinical models suggest synergism with chemotherapy
and HIF-1α inhibition
• Future directions
- combinations with other targeted agents, chemo, RT
- biomarker development