Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies
Abstract
:1. Introduction
1.1. Rational for Combining HDACIs with Other Anticancer Agents
1.2. Structural Requirements of Hb-HDACIs
Hb-HDACIs | Structure | Chemical name | Formula | Molecular mass |
---|---|---|---|---|
Vorinostat | | N-hydroxy-N'-phenyl-octanediamide | C14H20N2O3 | 264.32 g/mol |
Belinostat (PXD101) | | (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl) phenyl]prop-2-enamide | C15H14N2O4S | 318.35 g/mol |
Panobinostat (LBH589) | | (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3l)ethyl]amino}methyl) phenyl]acrylamide | C21H23N3O2 | 349.42 g/mol |
Pracinostat (SB939) | | (E)-3-(2-butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide | C20H30N4O2 | 358.48 g/mol |
Abexinostat (PCI-24781 /CRA-024781) | | 3-[(Dimethylamino) methyl]-N-{2-[4-(hydroxycarbamoyl) phenoxy]ethyl}-1-benzofuran-2-carboxamide | C21H23N3O5 | 397.42 g/mol |
JNJ-26481585 | | N-hydroxy-2-(4-(((1-methyl-1H-indol-3-yl)methylamino) methyl)piperidin-1-yl) pyrimidine-5-carboxamide | C21H26N6O2 | 394.47 g/mol |
Dacinostat (LAQ824) | | (E)-3-(4-(((2-(1H-indol-3-yl) ethyl)(2-hydroxyethyl)amino) methyl)phenyl)-N-hydroxyacrylamide | C22H25N3O3 | 379.45 g/mol |
Resminostat (RAS2410/4SC-201) | | (E)-3-(1-((4-((dimethyl amino) methyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-hydroxyacrylamide | C16H19N3O4S | 349.10 g/mol |
CHR-3996 | | 2-(6-(((6-fluoroquinolin-2-yl) methyl)amino) bicycle [3,1,0]hexan-3-yl)-N-hydroxypy rimidine-5-carboxamide | C21H20FN5O2 | 393.16 g/mol |
HDACIs | Routes of administration | Side effects | FDA approval |
---|---|---|---|
Vorinostat | Oral | Anorexia, fatigue, dehydration, diarrhea, and myelosuppression | Cutaneous T-cell lymphoma |
Belinostat (PXD101) | Oral, i.v. | Lethargy/fatigue, nausea and vomiting | Granted orphan drug and fast track designations for relapsed or refractory peripheral T-cell lymphoma |
Panobinostat (LBH589) | Oral, i.v | Fatigue, nausea, diarrhea and myelosuppression | Not approved |
Pracinostat (SB939) | Oral | Fatigue, nausea, vomiting, anorexia and diarrhoea | Not approved |
Abexinostat (PCI-24781/ CRA-024781) | Oral, i.v. | Under evaluation in clinical trials | Not approved |
JNJ-26481585 | Oral | Under evaluation in clinical trials | Not approved |
Dacinostat (LAQ824) | i.v. | Nausea, vomiting and fatigue | Not approved |
Resminostat (RAS2410/4SC-201) | Oral | Under evaluation in clinical trials | Granted orphan drug designation in relapsed/refractory Hodgkin’s lymphoma and hepatocellular carcinoma |
CHR-3996 | Oral | Thrombocytopenia, fatigue, increase of plasma creatinine and atrial fibrillation | Not approved |
2. Vorinostat in Solid Tumors
2.1. Vorinostat as a Single Agent
Disease | Regimen | No. pts. | PFS | Efficacy | Ref. |
---|---|---|---|---|---|
Metastatic head and neck cancer | Vorinostat: 400 mg orally daily | 13 | SD 2 pts. OR 0% | [51] | |
Metastatic breast cancer | Vorinostat: 400 mg orally daily | 14 | SD 4 pts | [52] | |
Relapsed NSCLC | Vorinostat: 400 mg or 300 mg once daily on days 1–14 of the 21 day cycle | 16 | Median: 2.3 m. | SD 57% | [53] |
Metastatic prostate cancer | Vorinostat: 400 mg orally daily | 27 | Median: 2.8 m. | SD 2 pts. | [54] |
Ovarian or primary peritoneal carcinoma | Vorinostat: 400 mg orally daily | 27 | PR 1 pt. | [55] | |
Recurrent GBM | Vorinostat: 200 mg p.o.twice a day for 14 days, followed by a 7-day rest period | 66 | 6-m.-PFS: 9 of the first 52 patients | OR 2 pts. | [56] |
Metastatic colorectal cancer | Vorinostat: 800 or 1,400 mg/day once a day × 3 days, every 2 weeks +5-FU: preceded by leucovorin, at 400 mg/m2 followed by a 46 h infusion at 2.400 mg/m2 on days 2–3 | 58 | PFS rate did not reach the threshold of 27 out of 43 patients | PR 1 pt. | [57] |
Untreated stage IIIB or IV NSCLC | Vorinostat: 400 mg or Placebo on days 1 through 14 of each 3-week cycle +Carboplatin: AUC 6 + Paclitaxel: 200 mg/m2, both on day 3 of each 21-day cycle | 94 | Median: Vorinostat: 6.0 m. Placebo: 4.1 m. P = ns | RR Vorinostat: 34% Placebo: 12.5% P = 02 | [58] |
Advanced thyroid cancer | Vorinostat: 400 mg orally daily | 19 | SD 56% OR 0 | [59] | |
Recurrent GBM | Vorinostat: 400 mg daily for 14 days of a 21-day cycle + Bortezomib: 1.3 mg/m2 intravenously on days 1,4, 8, and 11 of a 21-day cycle | 37 | Median: 1.5 m. | PR 1 pt. | [60] |
2.2. Vorinostat in Combination Therapy
3. Belinostat in Solid Tumors
Disease | Regimen | No. pts. | PFS | Efficacy | Ref. |
---|---|---|---|---|---|
Recurrent or refractory malignant pleural mesothelioma | Belinostat: 1 g/m2 IV on days 1 to 5 of a 21-day cycle | 13 | Median: 1 m. | SD 2 pts. | [81] |
Recurrent or refractory advanced thymic epithelial tumors | Belinostat: 1 g/m2 IV on days 1 to 5 of a 21-day cycle | 41 | 6-m.- PFS: 46% | RR 8% CB 68% | [82] |
Unresectable hepatocellular carcinoma | Belinostat: 1,400 mg/m2 per day, on days 1–5 every 3 weeks | 54 | Median: 2.64 m. | PR 2.4% SD 45.2% | [83] |
Platinum resistant EOC and LMP ovarian tumors | Belinostat: 1 g/m2 IV on days 1 to 5 of a 21-day cycle | 32 | EOC: Median: 2.3 m. LMP: Median: 13.4 m. | EOC: SD 9/15 pts LMP: PR 2/12 pts | [84] |
Previously treated ovarian, fallopian tube, or primary peritoneal carcinoma | Belinostat: 1g/m² IV daily for 5 days of a 21-day cycle +Carboplatin: AUC 5 on day three of 21-day cycles | 29 | Median: 3.3 m. | RR 7.4% CR 3.7% PR 3.7% SD 44.4% | [85] |
Previously treated ovarian cancer | Belinostat: 1g/m² IV daily for 5 days of a 21-day cycle +Carboplatin: AUC 5 +Paclitaxel: 175 mg/m² both on day 3 of each 21-day cycle | 35 | 6-m. PFS: 48% | RR 43% | [86] |
3.1. Belinostat as a Single Agent
3.2. Belinostat in Combination Therapy
4. Panobinostat in Solid Tumors
Efficacy of Panobinostat in Solid Tumor
Disease | Regimen | No. pts. | PFS | Efficacy | Ref. |
---|---|---|---|---|---|
Refractory metastatic renal cell carcinoma. | Panobinostat: 45 mg orally twice a week | 20 | OR 0 | [99] | |
Previously treated advanced pancreatic cancer | Panobinostat: 20 mg orally three times weekly +Bortezomib: 1.3 mg/m2 IV twice weekly, both during the first two weeks, followed by a 9-day rest period. | Median: 2.1 m. | OR 0 | [100] |
5. Other Hb-HDACIs in Solid Tumors
5.1. Pracinostat
5.2. Abexinostat
5.3. JNJ-26481585
5.4. Dacinostat
5.5. Resminostat
5.6. CHR-3996
6. Conclusions
Disease | Compound | Regimen | No. Pts. | End-Point | ClinicalTrials. gov Identifier |
---|---|---|---|---|---|
Relapsed/refractorysarcomas-age 4–21 years | Vorinostat | Vorinostat: orally on a daily × 4 schedule +Etoposide: at a fixed dose i.v. daily × 3 days | 50 | DLT MTD RR | NCT01294670 |
HER2-positive locally recurrent or metastatic breast cancer | Vorinostat | Vorinostat: 300 mg × 4 days on, then 3 days off +Lapatinib: 1,250 mg daily | 47 | CB | NCT01118975 |
Metastatic RCC | Vorinostat | Vorinostat: escalating doses PO BID on days 1–14 +Bevacizumab: IV on day 1 of a 21-day cycle | 42 | MTD PFS | NCT00324870 |
Advanced soft tissue sarcomas | Vorinostat | Vorinostat: orally once daily for 14 days + Bortezomib: IV on days 1, 4, 8, 11 of a 21-day cycle | 45 | RR | NCT00937495 |
Metastatic NSCLC | Belinostat | Belinostat: dose escalation with starting dose 1 g/m2 i.v. on days 1-5 of a 21-day cycle +Carboplatin AUC 6 +Paclitaxel 200 mg/m2 | 35 | MTD | NCT01310244 |
Recurrent GBM | Panobinostat | Panobinostat: orally three times per week every other week +Bevacizumab: i.v. on days 1 and 15 of a 28-day cycle | 67 | MTD PFS | NCT00859222 |
Advanced sarcomas | Abexinostat | Abexinostat: orally on days 1–5 +Doxorubicin on day 4 of a 21-day cycle | 47 | MTD RR | NCT01027910 |
K-Ras mutated advanced CRC | Resminostat | Resminostat: orally +OLFIRI i.v. | 80 | MTD PFS | NCT01277406 |
HCC pretreated with sorafenib | Resminostat | orally | 60 | PFS | NCT00943449 |
Conflict of Interest
References
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Grassadonia, A.; Cioffi, P.; Simiele, F.; Iezzi, L.; Zilli, M.; Natoli, C. Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies. Cancers 2013, 5, 919-942. https://doi.org/10.3390/cancers5030919
Grassadonia A, Cioffi P, Simiele F, Iezzi L, Zilli M, Natoli C. Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies. Cancers. 2013; 5(3):919-942. https://doi.org/10.3390/cancers5030919
Chicago/Turabian StyleGrassadonia, Antonino, Pasquale Cioffi, Felice Simiele, Laura Iezzi, Marinella Zilli, and Clara Natoli. 2013. "Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies" Cancers 5, no. 3: 919-942. https://doi.org/10.3390/cancers5030919