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HSP-90 Inhibition as an Emerging Target

Luis Paz-Ares

Hospital UniversitarioHospital Universitario

Virgen del Rocio

Sevilla

The Central Dogma (Crick 1958)

DNA

RNA

Protein

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Heat shock protein 90 (HSP – 90)

Hsp90

83 KDa166 KDa dimer

N N

M M

C C

166 KDa dimerATPase in N-terminal domainSubstrate binding site unknown

it is believed that Hsp90 never functions in isolation in eukaryotes; it always appears to be associated with a variety of cofactors

15-7

Hsp90-associated proteins

Cofactor Notes

Hsp70 Hsp90 activity dependent on Hsp70 system (incl. Hsp40)

HOP HOP, Heat-shock Organizing Protein, brings Hsp70 and Hsp90 together via TPR interaction domains

p23 modulates ATPase activity of Hsp90

HIP co-chaperone of Hsp70

PPIases cyclophilin-40, FKBP51, FKBP52

others kinase-targeting co-chaperone Cdc37/p50

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Hsp90 not only assists the folding of proteins, but can also modulate the conformation/function of proteins

binding of steroid to Hsp90-bound steroid receptor releases the receptor in a form that can bind DNA and activate transcription

15-8

Hsp90 functional cycle

targetprotein(non-native/non-functional)

Hsp40

Hsp70

HIP HIP

HOP

Hsp70

HIP

HOP

Hsp70

Hsp90p23FKBP

Hsp90p23

FKBP

p23 FKBPtargetprotein(native/functional)

Hsp90 is also involved in quality control: binding of denatured protein can lead either to its folding or its degradation

• Highly abundant cytoplasmic molecular « chaperone »

• Involved in the folding, stability, and activity of a large number ofclient proteins implicated in the oncogenic process

Heat shock protein 90 (HSP – 90)

client proteins implicated in the oncogenic process

– Involved in cancer cell proliferation, survival, invasion, metastasis, and angiogenesis

– Oestrogen receptor, Androgen receptor, HER2, ERBB1, MEK,c-MET, AKT, MAPK (ERK), CDK, RAF, BCR/ABL, HIF1-α,hTERT

• Inhibition of HSP90:• Inhibition of HSP90:

– Increased degradation of misfolded client proteins, inparticular oncogenic proteins

– Tumour growth inhibition

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HSP90 InhibitionSimultaneous inhibition of multiple molecular pathways

HSP-90 Inhibitor

Hsp90 Client Proteins Influence All Aspects of Neoplastic Transformation

• > 200 Hsp90 client proteins

have been described

• Many oncoproteins are relevant in NSCLC

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Normal vs Cancer Cells

Hsp90 Inhibitors‐ The History1962 2000 20051970

Heat shock proteinsdi d

Geldanamycinpurified for use as

ibi i

2010

discovered antibiotic

1st-generation

• 17-AAG derivatives• Weak potency, modest clinical activity, liver toxicities

10

2nd-generation

• Structurally unrelated to 17-AAG• Higher potency, improved safety

10

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HSP 90 Inhibitors in Clinical Development

Agent Sponsor Administration

17AAG NCI/Kosan iv

KOS‐953 (tanespimycin) Kosan iv

17DMAG Kosan Iv & oral

IPI‐504 Infinity Iv

STA‐9090 (Ganetespib) Synta iv

AUY‐922 Novartis iv

DS‐2248 Daiichi Oral

XL‐888 Exelexis Oral

IPI‐493 Infinity Oral

MPC‐3100 Myrexis Oral

SNX‐5422 Serenex Oral

CNF‐2024 Biogen Idec Oral

S Ramalingam, Asco 2011.

Debio 0932

• Synthetic small molecule• Imidazopyridine derivativeImidazopyridine derivative

• Oral biovailability • Crosses BBB • Accumulates in tumours

Debio 0932 concentration (mean ±SEM) in plasma, normal tissue, and

subcutaneous xenograft tumour tissue following a single oral administration

(30 mg/kg) in mice

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HSP 90 Inhibition: Potential Treatment Strategies

High

Hsp90-Addiction

Single-Agent

“Oncogene addicted tumors”

Hsp90 Client 

Proteins

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“Driven by multiple pathways”

Low Combination

Retaspimycin (IPI‐504)

IPI‐504

Cl• IPI‐504 is a novel, potent, water‐soluble inhibitor 

of Hsp90.

• Pre‐clinical models suggested mutant EGFR may be a stronger client of Hsp90 than wild‐type EGFR; hence, we designed a phase 2 trial to examine   IPI‐504 as salvage therapy after EGFR TKIs in NSCLC.

OH

NH

N

OH

OOH

O

O

OO

NH2

HH

Cl

14

1. Ge GD, et al. J Med Chem. 2006;49:4606-4615. 2. Demetri GD, et al. J Clin Oncol 2007 ASCO Annual Meeting Proc. 2007;25:10024.

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Lower gene expression of HSP90 correlates with improved Survival in NSCLC

Gallegos Ruiz et al, PLoS One. 2008 Mar 5;3(3):e0001722. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target.

IPI‐504 in Advanced NSCLC

• Eligibility:– Histologically confirmed NSCLC, stage IIIb (with effusion) or IV.

Failed prior EGFR TKI therapy– Failed prior EGFR TKI therapy.• No limit to the number of prior therapies.

Enroll 10 patients

If >1 CR, PR, or SD for at least 3 months

Expand to a total of 29 patients

Mutant EGFR Cohort

Wild-Type EGFR Cohort

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Enroll 10 patients

If >1 CR, PR, or SD for at least 3 months

Expand to a total of 29 patients

Sequist et al, ASCO 2010.

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Efficacy

Total

EGFR Status(n=68)

KRAS Status(n=38)

ALK Status(n=15)

Wild Type Mutant Wild Type Mutant No Rearr. + Rearr.

Patients(n [%])

76 40 (53) 28 (37) 26 (34) 12 (16) 12 (16) 3 (4)

Objective Response Rate(All PRs) (n [%])

5 (7) 4 (10) 1 (4) 3 (12) 0 (0) 1 (8) 2 (67)

RECIST SD or better ≥3 months (n [%])

18 (24) 10 (25) 6 (21) 4 (15) 5 (42) 3 (25) 3 (100)months (n [%])

Median PFS (95% CI)

2.9 (2.4-4.2)

2.9 (1.2-5.3)

2.8(2.4-3.9)

2.9(1.2-10.2)

3.9(1.1-4.2)

2.4 (1.1-5.3)

Unable to determine

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Response by EGFR Mutation Status 

70 %

60 %

50 %

40 %

Color by

EGFR Status

mutant

wild type

30 %

20 %

10 %

0 %

‐10 %

‐20 %

‐30 %

‐40 %

‐50 %

*

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Each Bar is an Individual Patient

‐60 %

‐70 %

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Response by ALK FISH Status

70 %

60 %

50 %

40 %

Color by

ALK FISH Status

ALK rearrangement detected

No ALK rearrangement detected

40 %

30 %

20 %

10 %

0 %

‐10 %

‐20 %

‐30 %

‐40 %

19

Each Bar is an Individual Patient

‐50 %

‐60 %

‐70 %

Ganetespib (STA‐9090)

• Potent Hsp90 inhibitor, structurally unrelated to first‐generation ansamycin class of Hsp90 inhibitors 

– Superior activity to these agents in preclinical studies

– Potent activity multiple NSCLC models, single agent/combo

• Promising single‐agent antitumor activity seen in early clinical trials, multiple cancers

• Well‐tolerated to date, >350 patients treated, 15 trialsd h ll d d bl– Most common AE: diarrhea; generally Grade 1 and 2, manageable 

with supportive care

• Absence of serious liver or common ocular toxicities seen with other Hsp90i

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STA-9090 has better potency compared to 17AAG in Hsp90 binding and lung ll h i hibi i

Comparison of Ganetespib with 17-AAG

cancer cell growth inhibition.

0

60

120

% o

f Con

trol

17AAGIC50: 21.0 nM

STA-9090IC50: 3.9 nM

Hsp90 binding FP assay(A)

40

80

120

% o

f Con

trol

17AAGIC50: 88.0 nM

STA-9090IC50: 13.3 nM

1536-well viability assay (A549 cells)(B)

1 10 100 1000 10000-60

Compound (nM)

50

10 100 1000 100000

Compound (nM)

S Ramalingam, Malta 2011

Goldman et al, Targeted Therapies Meeting, Santa Monica, 2011

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Anti-Tumor Activity

20% ↑ (PD)

30% ↓(PR)

* * *

22 pts target lesion stabilization (<20%) 10 pts target lesion shrinkage 3 confirmed PRs – durable: 1 at 14 months, 2 at 6 months

17‐AAG Activity in EGFR mutant and ALK + NSCLC Cells

Sequist L, J Clin Oncol 2011

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17‐AAG Overcomes Crizotinib Resistance

Katayama R et al. PNAS 2011;108:7535-7540

17‐AAG Overcomes Crizotinib Resistance

Chen Z et al. Cancer Res 2010;70:9827-9836

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IP-504 Inhibits ALK Signalling

Normant et al. Oncogene 2011

Rationale for combining Hsp90 inhibitors and taxanes

• Both drugs have single agent activity in NSCLC

• Ganetespib and docetaxel have synergistic MOAs– 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 t t d t l ( l t bl d fl t b li t t )tumors to docetaxel (vasculature, blood flow, metabolic state)

• Non‐overlapping toxicity profile– Docetaxel DLT is bone marrow toxicity– Ganetespib DLT is diarrhea 

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750

Interaction between Ganetespib + Docetaxel

0

150

300

450

600

11 14 17 20 23 26 29 32 35 38

Av

era

ge

Tu

mo

r V

olu

me

(m

m3

)

VehicleGanetespib (50 mg/kg)Docetaxel (4 mg/kg)Ganetespib (50 mg/kg) + Docetaxel (4 mg/kg)

12

33

77

100

11 14 17 20 23 26 29 32 35 38

Days After Tumor Implantation i.v. Dosing (1X/W eek):

NCI-H1437 NSCLC Xenografts

Proia et al, AACR 2010.

In vitroH522

HSP-90 Inhibitors in ALK+ NSCLC

S Ramalinghan, ASCO 2011

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Phase I-II Study in NSCLC

A Phase I-II evaluation of the safety and efficacy of the oral H 90 i hibit D bi 0932 i bi ti ith t d d fHsp90 inhibitor Debio 0932 in combination with standard of care in first- and second-line therapy of patients with Stage IIIb or IV NSCLC

Disease ProgressionDiagnosis of IIIb/IV NSCLC

(EGFR WT)

3131 CONFIDENTIAL26/03/2012

1st-line chemotherapy:Cisplatin / gemcitabine (squamous)

Cisplatin / pemetrexed (non-squamous)

2nd-line chemotherapy:Docetaxel

Debio-0932 Debio-0932

HSP-90 Inhibitors in NSCLC Summary

- Strong rationale for this class of agents in NSCLC.

- Newer Hsp90 inhibitors have an improved safety profile and lend themselves for combination approaches.

- Hsp90 inhibitors have the most promising activity in ALK+ NSCLC.

- Need for a biomarker strategy