Contributed equally
Heat shock protein (Hsp)90 serves as a chaperone protein that promotes the proper folding of proteins involved in a variety of signal transduction processes involved in cell growth. Hsp90 inhibitors, which inhibit the activity of critical client proteins, have emerged as the accessory therapeutic agents for multiple human cancer types. To better understand the effects of Hsp90 inhibitors in cancer treatment, the present study reviewed 15 published phase II clinical trials to investigate whether Hsp90 inhibitors will benefit patients with cancer. Information of complete response, partial response, stable disease, objective response and objective response rate was collected to evaluate clinical outcomes. Overall, Hsp90 inhibitors are effective against a variety of oncogene-addicted cancers, including those that have developed resistance to specific receptors.
Tumors are one of the most common lethal diseases worldwide, with 14 million new cases diagnosed annually. They are also the leading cause of mortality worldwide, causing 8.2 million mortalities annually, as reported in the World Health Organization World Cancer Report 2014. Although cytotoxic chemotherapy has revolutionized the prognosis for patients with most tumor types, survival remains dismal as a whole and exploring the novel therapeutic approaches is required. Considering that oncoproteins serve a pivotal role in tumorigenesis, molecular target therapies in different types of tumor have been more and more crucial and promising.
The molecular chaperone, heat shock protein (Hsp)90, serves an important role in the formation, stability and function of the proteins involved in cell growth and survival signaling pathways (
PubMed (
All human-associated studies, regardless of tumor types, were included once they met the following criteria: Malignant tumor, monotherapy with Hsp90 inhibitor or Hsp90 inhibitor combined with other antitumor drugs, histological confirmation, relatively stable administration dosage of Hsp90 inhibitor and sufficient data of clinical outcomes.
Two investigators extracted data independently and reached a consensus on all items. For each study, the following information was collected: First author, year of publication, country of the first author, the number of total and evaluable patients, median age, gender, cancer type, stage, prior treatment, name of Hsp90 inhibitor or other combined drugs, dose regimen, median cycle of treatment, clinical outcomes, including the number of patients who achieved stable disease (SD), partial response (PR), complete response (CR), objective response (OR) or progressive disease (PD). Other evaluation data, including the median overall survival (OS), progression-free survival (PFS), time to progression (TTP) and response of duration (DR) were also collected. For studies including different tumor types, data were extracted separately by tumor types if there was enough information in the text. Additionally, the studies mentioning genomic alteration were extracted separately to investigate if Hsp90 inhibitors have the ability to overcome resistance to receptor-specific targeted treatments.
A total of 1,261 published articles were identified from PubMed and 1,110 duplicated and unrelated articles were excluded. Within the remaining 50 publications related to clinical trials, articles were excluded if administration dosage of Hsp90 inhibitor was not stable; all Phase I studies were excluded for this reason. Therefore, a total of 15 articles were eligible for assessment in the present study. Of these 15 articles, 9 mentioned that genomic alteration were extracted separately, as discussed later.
Due to the heterogeneity of patients, Hsp90 inhibitor types, regimens, clinical settings and a large variety of outcome measurement used in these trials and pooling of data for meta-analysis was inappropriate. The results were, therefore, summarized qualitatively.
Details from 15 eligible trials published between 2006 and 2014 were analyzed in
Details of eligible trials with an Hsp90 inhibitor were noted in
The majority of Hsp90 inhibitors were administered by intravenous infusion. For 17-AAG, the dosage was 50/175/220/340 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle; or 300/450 mg/m2 on days 1, 8 and 15 of a 28-day cycle; 154 mg/m2 on days 1, 8 (
In trials combining an Hsp90 inhibitor with other drugs, three added the molecularly targeted agent trastuzumab/bortezomib to 17-AGG or IPI-504, and one added the cytotoxic drug gemcitabine to 17-AGG (
Response criteria were used, as defined by the Response Evaluation Criteria in Solid Tumors (
Of the 15 trials that used Hsp90 inhibitors, OR was observed in 7 studies, with ORR ranging between 0.04 and 0.22, demonstrating that in tumors driven by client proteins are hypersensitive to Hsp90 inhibition at the currently deliverable doses and schedules (
Additionally, trials that failed to achieve OR are also summarized in
Hsp90 is a chaperone for a wide variety of signaling proteins, many of which serve an important role in tumorigenesis, including HER2, EGFR, Akt, c-RAF, BRAF and re-arranged ALK (
The present review summarized 15 phase II clinical trials of different types of tumor and found that the Hsp90 inhibitor may be a potential agent against tumors via the inhibition of intended client proteins. Modi
Tillotson
The lack of efficacy of Hsp90 inhibitors in these initial phase II studies may be due to the treatment-associated toxicity limitation accounting for insufficient dose of drug or infrequent schedule of administration, which leads to the lack of adequate inhibition of target proteins. Although overexpression of Hsp72 and low expression of Hsp90 were detected, the client proteins, including HER2 and cyclin-dependent kinase (CDK)4 depletion were not consistently detected in patients with metastatic melanoma (
In conclusion, only tumor types driven by client proteins that are hypersensitive to Hsp90 inhibition will be susceptible to the effects of Hsp90 inhibitors at the currently doses and schedules. The present review summarized 15 phase II clinical trials using Hsp90 inhibitors and found that Hsp90 inhibitors may be a potential cancer therapy against a variety of oncogene-addicted cancer types, including those developing resistance to specific receptors.
The present study was funded by the continuous financial support from the National Natural Science Foundation of China Youth Found (no. 81501980).
Characteristics of trials using an Hsp90 inhibitor.
Patient characteristics | ||||||||
---|---|---|---|---|---|---|---|---|
Trial | Authors, year | Total number | Median age (years) | Gender (male/female) | Cancer type | Status | Prior treatment (no. patients) | Refs. |
1 | Gartner |
11 (7 |
54 | 0/11 | Breast | Locally advanced or metastatic | Chemotherapy (all) Hormonal therapy (all) | ( |
2 | Modi |
31 (27 |
53 | 1/30 | Breast | Metastatic | Chemotherapy (n=25) Trastuzumab therapy (all) | ( |
3 | Jhaveri |
22 (6/13/3) |
51 | 0/22 | Breast | Metastatic | Chemotherapy (all) Trastuzumab therapy (n=12) | ( |
4 | Modi |
26 | 53 | 1/25 | Breast | Locally advanced or metastatic | Chemotherapy (all) trastuzumab therapy (all) | ( |
5 | Hendrickson |
29 (11/14 |
68/65.5 | 0/25 | Ovarian Peritoneal | Relapsed or persistent | Chemotherapy (n=25) | ( |
6 | Richardson |
22 (8/8/6) |
62.5 | 14/8 | Multiple myeloma | Relapsed or refractory | Prior-SCT (n=18) Chemotherapy (all) | ( |
7 | Ronnen |
20 (12/8) |
68 | 14/6 | Renal | Metastatic | Nephrectomy (n=8/7) Radiation (n=4/2) Immunotherapy (n=11/2) Chemotherapy or hormonal (n=2/0) | ( |
8 | Heath |
17 (15 |
68 | 15/0 | Prostate | Metastatic | Prostatectomy (n=5) Chemotherapy (n=13) Radiation therapy (n=12) Androgen ablation (n=14) | ( |
9 | Oh |
19 (4/15) |
68.5/60 | 0/19 | Prostate | Castration-resistant | Chemotherapy (n=15) hormonal therapy (majority of patients) | ( |
10 | Solit |
15 (6/9) |
66/55 | 12/3 | Melanoma | Stage III/IV | Chemotherapy (n=5/9) | ( |
11 | Pacey |
14 (11 |
60 | 8/6 | Melanoma | Metastatic | Surgery (n=14) Chemotherapy (n=13) Radiotherapy (n=2) Immunotherapy (n=5) Molecularly targeted agent (n=5) Isolated limb perfusion (n=2) | ( |
12 | Cercek |
17 | 58 | 11/6 | Colorectal | Metastatic | Chemotherapy (all) Anti-EGFR (patients with KRAS wild-type: 6) | ( |
13 | Socinski |
99 (15/17/66) |
61 | 47/52 | Lung (NSCLC) | Stage IIIB/IV | Systemic therapy (all) | ( |
14 | Sequist |
76 | 64 | 28/48 | Lung (NSCLC) | Stage IIIB/IV | Systemic therapy (all) EGFR TKIs (all) | ( |
15 | Dickson |
23 | 59 | 14/9 | GIST | Refractory | Imatinib (all) sunitinib (all) sorafenib (n=14) nilotinib (n=2) | ( |
The number of patients eligible for the assessment of clinical outcomes.
Patients enrolled in two groups, eotjer exposure to gemcitabine or not, which also apply to the following data.
Patients were divided into three groups of dosage with 340, 175 or 50 mg/m2.
Patients enrolled in clear-cell RCC cohort or papillary RCC, which also apply to the following data.
Patients with wild-type or mutant BRAF.
Subtype of ER(+)/HER-2(−), HER-2(+) and triple negative breast cancer.
Subtype of mutant EGFR, mutant KRAS and wild-type EGFR or KRAS.
Patients of chemotherapy-naïve or docetaxel-treated. SCT, stem cell transplant; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; EGFR, epidermal growth factor receptor: ER, estrogen receptor; HER, human epidermal growth factor receptor; GIST, gastrointestinal stromal tumors; TKIs, tyrosine kinase inhibitors; IVD, intravenous dose; NA, not available.
Treatment administration and clinical outcomes of the studies that used Hsp90 inhibitor.
Treatment administration | Clinical outcomes | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Trial | Cancer type | Drug | Dose regime | Median cycles | PR | CR | OR | ORR | SD | PD | Others (median) | |
1 | Breast | 17-AAG | 220 mg/m2 IVD on days 1, 4, 8 and 11 of a 21-day cycle | 2 | 0 | 0 | 0 | 0 | 3 | 4 | PFS: 1 month OS: 10 months | |
2 | Breast | 17-AAG + Trastuzumab | 450 mg/m2 iv. + 2 mg/kg iv. weekly (intial dose of 4 mg/kg was >21 days prior to the present study | NA | 6 | 0 | 6 | 0.22 | 10 | 11 | PFS: 6 months OS: 17 months DR: 147 days | |
3 | Breast | Ganetespib | 200 mg/m2 IVD days 1, 8 and 15 of a 28-day cycle | NA | 0/2/0 |
0/0/0 | 0/2/0 | 0.09 | 0/6/1 | NA | PFS: 7 weeks OS: 46 week | |
4 | Breast | IPI-504 Trastuzumab | 300 mg/m2 iv. weekly plus trastuzumab 6 mg/kg iv. every 3 weeks (intial dose of 8 mg/kg for patients whose last trastuzumab therapy was >4 weeks prior to study entry) | 3 |
0 | 0 | 0 | 0 | 16 | NA | NA | |
5 | Ovarian Peritoneal | 17-AAG + Gemcitabine | 154 mg/m2 iv. on days 1 and 8, days 1 and 9 of subsequent cycles + 750 mg/m2 iv. gemcitabine on day 7 (days 1 and 8 of subsequent cycles) of a 21-day cycle | 4/3.5 |
0/1 | 0/0 | 0/1 | 0.04 | 4/2 | 7/11 | OS: 11.5/18.3 months TTP: 2.7/1.6 months | |
6 | Multiple myeloma | 17-AAG + Bortezomib | 340/175/50 mg/m2 iv. plus bortezomib + 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle | NA | 2 | 0 | 3 |
0.14 | 10 | NA | NA | |
7 | Renal | 17-AAG | 220 mg/m2 IVD days 1, 4, 8 and 11 of a 21-day cycle | NA | 0 | 0 | 0 | 0 | 9/5 |
NA | TTP: 3.3/1.6 months | |
8 | Prostate | 17-AAG | 300 mg/m2 IVD days 1, 8 and 15 of a 28-day cycle | 2 | 0 | 0 | 0 | 0 | 1 | 13 | TTP: 1.8 months 6-month OS: 71% | |
9 | Prostate | IPI-504 | 400 mg/m2 IVD days 1, 4, 8 and 11 of a 21-day cycle |
2 | 0 | 0 | 0 | 0 | 1 | NA | NA | |
10 | Melanoma | 17-AAG | 450 mg/m2 IVD weekly (6/8-week cycle) | 5 dose | 0 | 0 | 0 | 0 | 1 | 14 | NA | |
11 | Melanoma | 17-AAG | 450 mg/m2 IVD weekly | 10 | 0 | 0 | 0 | 0 | 3 | 8 | OS: 232 days | |
12 | Colorectal | Ganetespib | 200 mg/m2 IVD days 1, 8 and 15 of a 28-day cycle | NA | 0 | 0 | 0 | 0 | 2 |
NA | PFS: 1.6 months OS: 5.1 months 6-month OS: 71% | |
13 | Lung (NSCLC) | Ganetespib | 200 mg/m2 IVD days 1, 8 and 15 of a 28-day cycle | NA | 0/0/4 |
0/0/0 | 0/0/4 | 0.04 | 6/6/26 | 7/7/26 | PFS: 1.9/1.9/1.8 months OS: 7.1/11.0/8.8 months PFS rate at 16 weeks: 13.3/5.9/19.7% | |
14 | Lung (NSCLC) | IPI-504 | 400 mg/m2 IVD days 1, 4, 8 and 11 of a 21-day cycle |
2 | 5 |
0 | 5 | 0.07 | 18 | NA | PFS: 2.86 months DR: 120 days | |
15 | GIST | BIIB021 | 12 patients: 600 mg p.o. twice a week of a 28-day cycle 11 patients: 400 mg p.o. three times a week of a 28-day cycle | NA | 3 |
0 | 5 | 0.12 | 4/2 |
NA | DR:25-138 days |
Patients enrolled in two groups whether exposure to gemcitabine or not, which also apply to the following data.
One patient of minimal response in the 340 mg/m2 dose group and two patients of PR in the 175 mg/m2 dose group.
Nine patients from the clear-cell RCC cohort and five patients from the papillary RCC cohort, which also apply to the following data.
Patients with KRAS G12V mutations.
Subtype of ER(+)/HER-2(−), HER-2(+) and TNBC, which also apply to the following data.
Subtype of mutant EGFR, mutant KRAS and no EGFR or KRAS mutations, which also apply to the following data.
Cycle 1 was defined receiving at least two doses of IPI-504.
A reduced dose of 300 mg/m2 due to two mortalities were assessed by the investigator.
Due to hepatotoxicities observed at the 400 mg/m2 dose in a separate trial of IPI-504 in patients with GI stromal tumors, the last enrolled patient started at a dose of 225 mg/m2.
For EGFR status, four patients had EGFR wild-type and one patient had EGFR mutations; for KRAS status, three patients had KRAS wild-type; for ALK status, two patients had ALK rearrangement and one patient had ALK wild-type
evaluated by FDG-PET criteria
evaluated by RECIST and Choi criteria. PFS, progression-free survival; OS, overall survival; TTP, time to progress; NA, not available; DR, response of duration; NSCLC, non-small cell lung cancer; GIST, gastrointestinal stromal tumors; IVD, intravenous dose; RCC, renal cell carcinoma; ER, estrogen receptor; HER, human epidermal growth factor receptor; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; OR, objective response; ORR, objective response rate; 17-AAG, 17-allylamino-17-demthoxygeldanamycin; IPL-504, retaspimycin HCl; ALK, anaplastic lymphoma kinase.
HSP90 inhibitor used in tumors harboring genomic alteration.
Response |
||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Trial | Drug | Cancer status | Genotype | Prior therapy |
Total | CR | PR | SD | PD | Others ( |
1 | 17-AGG | Locally advanced or metastatic breast cancer | TNBC (n=6); HER2(+) (n=0) | Chemotherapy (all); hormonal (all); bevacizumab (n=1); lapatinib (n=1) | 11(7 |
0 | 0 | 3 | 4 | PFS: 1 month OS: 10 months |
2 | 17-AGG + Trastuzumab | Advanced trastuz-umab-refractory breast cancer | HER2(+) (all) | Chemotherapy (n=25); trastuzumab (all) | 31(27 |
0 | 6 | 10 | 11 | PFS: 6 months OS: 17 months DR: 147 days |
5 | 17-AGG | Metastatic melanoma | Wild-type BRAF (n=6); V600E BRAF (n=9) | Chemotherapy (n=5/9) | 15 | 0 | 0 | 1 | 14 | NA |
6 | Ganetespib | Stage IIIB/IV NSCLC | Mutant EGFR (n=15); mutant KRAS (n=17); no EGFR or KRAS mutations (n=66) | Systemic therapy (all); TKI (mutant EGFR, n=14) | 98 | 0/0/0 | 0/0/4 |
6/6/26 | 7/7/26 | PFS: 1.9/1.9/1.8 months PFS rate at 16 weeks: 13.3/5.9/19.7% |
7 | Ganetespib | Metastatic breast cancer | ER(+)/HER2(−) (n=6); HER2(+) (n=13); TNBC (n=3) | Chemotherapy (all); trastuzumab (HER2(+), n=12) | 22 | 0/0/0 | 0/2/0 | 0/6/1 | NA | PFS: 7 weeks OS: 46 weeks |
8 | Ganetespib | Metastatic colorectal cancer | KRAS wild (n=6); KRAS mutant (n=10) | Chemotherapy (all); anti-EGFR therapy (KRAS wild-type) | 17 | 0/0 | 0/0 | 0/2 | NA | PFS: 1.6 months 6-month OS: 41% OS: 5.1 months |
10 | IPI-504 | Advanced or metastatic breast cancer | HER2(+) (all) | Chemotherapy (all); trastuzumab (all) | 26 | 0 | 0 | 16 | NA | NA |
11 | IPI-504 | Stage IIIB/IV NSCLC | EGFR (wild/mutant) (n=40/28); KRAS (wild/mutant) (n=26/12); ALK (wild/rearranged) (n=12/3) | Systemic therapy (all); TKI (all) | 76 | 0/00/00/0 | 4/13/01/2 | 10/64/53/3 | NA NA | PFS: 2.86/2.76 months 2.86/3.91 months 2.86 months/NA |
12 | BIIB021 | GIST refractory to imatinib and sunit-inib | KIT exon 11 mutation (n=7); KIT exon 9 mutation (n=1); no detected PDGFRA or KIT mutation (n=1); unknown mutation status (n=14) | Imatinib (all); sunitinib sorafenib (n=14); nilotinib (n=2) | 23 | 0 | 5 | 10 | NA |
The data separated by separator according to genotype sequence.
Median: data are median values.
Patients with ALK rearrangement. PFS, progression-free survival; OS, overall survival; TTP, time to progress; NA, not available; DR, response of duration; NSCLC, non-small cell lung cancer; GIST, gastrointestinal stromal tumors; ER, estrogen receptor; HER, human epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; OR, objective response; ORR, objective response rate; 17-AAG, 17-allylamino-17-demthoxygeldanamycin; IPL-504, retaspimycin HCl; PDGFRA, Platelet-derived growth factor receptor α; ALK, Anaplastic lymphoma kinase.