Winship Cancer Institute

HSP 90 Inhibitors in Lung Cancer:
Shock and Awe
Suresh S. Ramalingam, MD
Associate Professor
Director, Division of Medical Oncology
Emory University
Winship Cancer Institute

Will the Heat be Shocked

Hsp90: Background
• Heat shock proteins
represent 1‐2% of all
cellular proteins
• Facilitate protein‐folding
and stabilization
• Induced under stress,
hypoxia and oxidative
damage
Soti et al, J Biol Chem, 2002.

Hsp90 Client Proteins Influence All Aspects of
Neoplastic Transformation
• > 200 Hsp90 client proteins
have been described
• Many oncoproteins are relevant in
NSCLC
Banerji U. Clin Cancer Res, 2009

Targeting Hsp90: Rationale
• Cancer cells depend on Hsp90 machinery to
preserve mutated and overexpressed
oncoproteins
– ‘Facilitates’ oncogene addiction
• Hsp90 is overexpressed in cancer cells
Trepel et al, Nature Reviews, 2010; Kamal et al, Nature, 2003.

Hsp90 Inhibitors are Selective to
Tumor Cells
‣ 17‐AAG has 100‐fold higher affinity for tumor‐derived Hsp90 than in normal cells
‣ Tumor cells contain Hsp90 complexes in activated, high‐affinity conformation
Kamal et al, Nature, 2003.

Hsp90 Inhibitors‐ The History
1962 1970
2000 2005
2010
Heat shock
proteins
discovered
Geldanamycin
purified for use as
antibiotic
1 st ‐generation
• 17‐AAG, 17‐DMAG
• Formulation issues, toxicity
• Lack of robust efficacy
2 nd ‐generation
• Structurally unrelated to 17‐AAG
• Higher potency, improved safety
7
7

HSP 90 Inhibitors in Clinical Development
Agent Sponsor Administration
17AAG (Tanespimycin) NCI/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.

Hsp90 Inhibition in NSCLC

Lower gene expression of HSP90 correlates with
improved Survival in NSCLC
Gallegos Ruiz et al, PLoS One. 2008 Mar 5;3(3):e0001722.

STA‐9090 in NSCLC: Salient Findings
• Phase II study in advanced NSCLC
• Patients had progressed following 2‐3 prior regimens
• STA‐9090 was tolerated well and there were no undue
safety concerns
• Objective responses seen exclusively in ALK+ positive
patients (all 4 responders were ALK+)
• Disease stabilization noted in EGFR and KRAS mutated
patients
Wong, Shapiro et al, ASCO 2011, Abs # 7500

Significance
• Among the earliest signs of success with Hsp90
inhibition in lung cancer
• Clear signal in a molecularly selected subset of
adenocarcinoma patients
• Improved safety profile over first‐generation
Hsp90 inhibitors

IPI‐504 in Advanced NSCLC
• Eligibility:
– Histologically confirmed NSCLC, stage IIIb (with effusion) or IV.
– Failed prior EGFR TKI therapy.
• No limit to the number of prior therapies.
• Dose and schedule:
– Days 1, 4, 8 and 11 of each 21 day cycle; 225 mg/m 2 iv
Mutant EGFR Cohort
Enroll 10 patients
Wild‐Type EGFR Cohort
Enroll 10 patients
If >1 CR, PR, or SD for at
least 3 months
If >1 CR, PR, or SD for at
least 3 months
Expand to a total of
29 patients
Expand to a total of
29 patients
Sequist et al, J Clin Oncol, 28:4953‐4960, 2010

Salient Results
Number of patients
Median age
76 patients
64 yrs
Never-smokers 45%
No. of prior regimens
4
(median)
Objective responses 5 (7%)
mPFS
2.9 m
• Two out of 3 patients with ALK positive NSCLC had major responses
• Activity noted in patients with mutated EGFR and wild‐type KRAS

Role of Hsp90 Inhibition in ALK+ NSCLC

17‐AAG can Overcome Crizotinib Resistance
Katayama R et al. PNAS 2011;108:7535-7540

17‐DMAG is Effective Against EML4‐ALK–driven NSCLC in Genetically Engineered
Mouse Model.
Though responses were seen, it was not durable with 17‐DMAG
Chen Z et al. Cancer Res 2010;70:9827-9836

Association of EML4‐ALK proteins with the HSP complex.
• EML4‐ALK associated proteins in complex
– Hsp90
– Hsp70
– HSC70
– BIP/Grp78
– Cdc23
– cdc37
Chen Z et al. Cancer Res 2010;70:9827-9836
©2010 by American Association for Cancer Research

IPI‐504 Inhibits ALK Signaling
Normant et al, Oncogene, Jan 2011, Epub ahead of print.

Clinical Results: HSP90 Inhibition in ALK + NSCLC
30
Response(% change from baseline)
20
10
0
-10
-20
-30
-40
-50
-60
Patients
IPI‐504
STA‐9090
*simulated waterfall plot
based on reported results
N=11
*Durability of responses not reported

Hsp90 Inhibtion in ALK + NSCLC
• There is now clear evidence of robust anticancer
effects with Hsp90 inhibitors in ALK +
NSCLC
– Durability of responses is not established yet
(mPFS)
• Next steps
– Combination of Crizotinib with Hsp90 inhibitors
– Hsp90 inhibition in Crizotinib‐resistant ALK +NSCLC

APotential Follow‐up Study
ALK + NSCLC
Resistance to
Crizotinib
Crizotinib
+
Hsp90 Inhibition
Hsp90 Inhibition

Hsp90 Inhibition in NSCLC
• It is likely that other genetic backgrounds
beyond ALK + disease are susceptible to Hsp90
inhibition
• The effects in KRAS mutated tumors provides
the rationale for combining Hsp90 inhibitors
with other novel agents
• Patients with HER‐2 and RAF mutated tumors
are also potential candidates

Other Strategies for Using Hsp90
Inhibitors in NSCLC

Rationale for Combining Hsp90 inhibitors
and Taxanes
• Hsp90 inhibitors are
synergistic with taxanes
– 17-AAG sensitizes tumor
cells to taxane-induced
apoptosis by inhibition Akt
activation
– STA-9090 and docetaxel
have synergistic effects
• Phase I study of 17-AAG
and paclitaxel
– Tolerated well
– No objective response
Solit et al, Cancer Res, 2003; Sawai et al, Cancer Res, 2008; Proia et al, AACR 2010;
Ramalingam et al, Clin Cancer Res, 2008.;

Emory Univ. Docetaxel + STA-9090
Combination Phase I Study
• 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/m 2 ;
Ganetespib 150 mg/m 2
• DLTs- myelosuppression and diarrhea (with 200 mg/m 2 )
• Promising anti-cancer activity
PI: Drs. Harvey and Ramalingam

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.

Hsp90 Inhibition: Some Gaps in
Current Knowledge
• Optimal biomarker to assess target modulation
– Changes in Hsp70 do not have a consistent
correlation with anti‐cancer or target effects
• Use of imaging methods to detect target
modulation
– Recent study of HER2 PET in breast cancer
• Targeting the C‐terminal of Hsp90

Conclusions
• Hsp90 inhibitors have entered the therapeutic
algorithm for ALK + NSCLC
• Newer Hsp90 inhibitors have an improved
safety profile and lend themselves for
combination approaches
• In the historically disappointing development of
Hsp90 inhibitors, we have reached an
important and exciting turning point

We are Beginning to Connect the Dots!