Spotlight on 17-AAG as an Hsp90 Inhibitor for Molecular Targeted Cancer Treatment
Running title: 17-AAG as an Hsp90 Inhibitor for Cancer Treatment
Sona Talaei1,2, Hassan Mellatyar1,2, Asadollah Asadi3, Abolfazl Akbarzadeh4, Roghayeh Sheervalilou1, Nosratollah Zarghami1,2,5*
1Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
3Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
4Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
5Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cbdd.13486
This article is protected by copyright. All rights reserved.
Corresponding author: Nosratollah Zarghami, PhD,
Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. Postal code: 13191-45156.
E-mail: [email protected], Tel: +984133355788, Fax: +984133355789.
Abstract
Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17-allylamino- 17-demethoxy-geldanamycin (17-AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90’s client proteins. There have been several preclinical studies of 17-AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases clinical trials show that 17-AAG can be given safely at biologically active dosages with mild toxicity. Even though 17-AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials-based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17-AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17-AAG.
Key words: Hsp90, 17-AAG, Hsp90 client proteins, cancer therapy
Abbreviations
17-AAG 17-Allylamino-17-demethoxygeldanamycin
Ad-mda7 Melanoma differentiation-associated gene-7
ALL Acute lymphoblastic leukemia
AML Acute myeloid leukemia
APL Acute promyelocytic leukemia
AR Androgen receptor
BBB Blood brain barrier
CCA Cholangiocarcinoma
CDK Cyclin-dependent kinases
CHIP C-terminus of HSP70-interacting protein
cHL classical Hodgkin lymphoma
CLL Chronic lymphocytic leukemia
CML Chronic myeloid leukemia
CSC Cancer stem cells
DLT Dose-limiting toxicity
DMSO Dimethyl sulfoxide
EGFR Epidermal growth factor receptor
EOC Epithelial ovarian cancer
ErbB2 Erythroblastic leukemia viral oncogene homolog 2
ERK Extracellular signal regulated kinase
ESCC Esophageal squamous cell carcinoma
FA Folic acid
FLT-3 FMS-like tyrosine kinase-3
GBC Gallbladder cancer
GBM Glioblastoma multiforme
GISTs Gastrointestinal stromal tumors
GRP94 Glucose regulated protein 94
GSK3β Glycogen synthase kinase 3β
HIF1a Hypoxia-inducible transcription factor 1-alpha
HOP Hsp70/Hsp90 organizing protein
HR Homologous recombination
HSF-1 Heat shock factor-1
Hsp90 Heat shock protein 90
IP Immunophilins
Jaks Janus kinases
KSHV Kaposi’s sarcoma-associated herpesvirus
LBH589 Histone deacetylase inhibitor
LCSCs Liver cancer stem-like cells
LET Linear energy transfer
MCL Mantle cell lymphoma
MM Multiple myeloma
MMP Matrix metalloproteinases
mTORC1 Mammalian target of rapamycin complex 1
NF-κB Nuclear factor-kappa B
NPs Nanoparticles
NSCLC Non-small cell lung cancer
PARP Poly-ADP ribose polymerase
PBMCs Peripheral-blood mononuclear cells
PDGF Platelet-derived growth factor
PDT Photodynamic therapy
PFL Primary effusion lymphoma
PI3K Phosphatidylinositol-3 kinase
PKCε Protein Kinase C epsilon
PLA Poly (D, L lactic acid)
RES Reticuloendothelial system
rHG recombinant Human Gelatin
SCC Cutaneous squamous cell carcinoma
Snai2 Transcription factor Slug
STAT Signal transducer and activator of transcription
TRAIL Tumor necrosis factor-related apoptosis-inducing ligand
TRAP-1 Tumor necrosis receptor-associated protein 1
Trast-NG Trastuzumab-conjugated nanogels
UCN-01 Chk1 inhibitor
VEGF Vascular endothelial growth factor
VIP Vasoactive intestinal peptide
XIAP Akt/X-linked inhibitor of apoptosis protein
ZAP70 Zeta-associated protein of 70kDa
1.Introduction
Hsp90, as a member of heat shock protein family, is an evolutionarily conserved and highly abundant molecular chaperone that comprise 1–2% of the total cytosolic protein and is overexpressed in response to cellular stress conditions such as heavy metal exposure, high temperature, and oxidative stress (1, 2). Hsp90 proteins contain three different domains: a 24 to 28 kDa N-terminal domain (ATP and drug-binding site) that is critical for ATP-dependent chaperone functions, a 33 to 44 kDa middle domain (client protein and co-chaperone binding site), and a 11 to 15 kDa C-terminal homodimerization domain (second drug and other co- chaperone binding site) (3, 4).
Hsp90 has key roles in cellular processes including the organization and maturation of a set of substrate proteins known as client proteins, Hsp90 is involved in signal transduction, protein degradation, and protein transportation among sub-cellular compartments (5, 6). It acts in a multiprotein complex comprised of co-chaperone proteins, such as Hsp70, Hsp40,
cdc37, p23, Hop, and IPs. There is a complex cycle regulated through binding and hydrolysis of ATP (7, 8) (Fig. 1).
The client proteins of Hsp90 fall into three general groups including steroid hormone receptors, serine-threonine or tyrosine kinases, and proteins with unrelated functions (9, 10) which are involve in signaling pathways related to tumor progression including Bcr-abl, FLT- 3, PI3K/AKT, Ras/Raf/MEK/ERK, and NF-κB pathways (11) (Table 1).
The chaperone Hsp90 is not only required to achieve a hormone-activatable state of steroid receptors, it is also required to maintain that state (12, 13). These receptors by their ligand- binding domains are bound to Hsp90 that are dissociated from the Hsp90 (14). In addition, nuclear localization of steroid receptors is key to their function and Hsp90 has a main role in the regulating this translocation (15).
The client proteins are necessary to regulate cell transformation, progression, and survival of special types of cancers (16, 17). The expression of some client proteins, such as signaling pathways proteins and growth factor receptors are enhanced in cancer cells (18).
Hsp90 stabilizes and protects mutated proteins arising during the process of transformation from proteasomal degradation, enabling malignant transformation (19). Hsp90 also considerably contributes to providing the necessary conditions for cell malignancy (20). On the other hand, expression of Hsp90 and its ATPase activity increase in tumor cells and normal chaperoning functions of Hsp90 can be used at the time of tumorigenesis to promote malignant progression. These findings suggest a key function for Hsp90 in maintaining a transformed cellular phenotype that makes it as a potent target for cancer prevention and treatment (21, 22).
Generally, the inhibition of Hsp90 affects processes involved during the cancer initiation that are known as the “Hallmarks of Cancer” (23, 24) (Fig. 2). As mentioned in this section, client
proteins are involved in various stages of carcinogenesis. Therefore, Hsp90 inhibition by inhibitors and degradation of these proteins might be efficient in cancer treatment.
Geldanamycin, a natural benzoquinone ansamycin antibiotic, is the first established inhibitor of Hsp90. It inhibits Hsp90’s ATPase function through binding to its amino-terminal domain (25-29). Geldanamycin is not useful clinical however because of its excessive liver toxicity, poor solubility, and metabolic instability (30).
17-AAG is an analogue of geldanamycin, which retains its potent anticancer activity with reduced hepatotoxicity and improved bioavailability (31). It is the first derivative of geldanamycin that has entered clinical trials for a broad range of human cancers (32).
17-AAG through binding to ATP–binding region of Hsp90 and blocking ATP binding, inhibits formation of Hsp90 multi-chaperone complex and induces degradation of client proteins through the ubiquitin–proteasome pathway (33) (Fig 1). Despite Hsp90 expression in normal and cancer cells, 17-AAG inhibits it in a multichaperone complex formed within cancer cells with greater binding affinity than geldanamycin. 17-AAG displays selectivity for cancer cells and inhibits tumor growth preferentially (5).
17-AAG has been widely investigated in the preclinical and clinical research as a single agent or in combination/nanocombination with other anticancer agents for diverse types of cancers. In these cancers, 17-AAG exerts anticancer effects through interactions with the proteins located in signaling pathways that are Hsp90 client proteins. The preclinical research on 17- AAG as single agent has been summarized in Table 2.
Even though 17-AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use (34, 35). Nanomaterials-based drug delivery carriers may overcome these drawbacks. These carriers can: 1) increase the stability of loaded anticancer drugs and conserve their chemotheruptic effects, 2) provide encapsulation and discharge of poorly soluble chemotherapeutics within the depot, 3)
targeted delivery to the tumor site, causing reduced chemical waste, 4) single-dose drug delivery, and 5) minimized systemic toxicity and side effect to normal tissues because of the escaping systemic circulation of anticancer agents (36).
In this paper, we provide an overall review of preclinical and clinical research data on 17- AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential use of nanocarriers to improve therapeutic effects of 17-AAG.
2.17-AAG in Preclinical Research: Focus on Combination Therapy
Pre-clinical data confirm that 17-AAG combined with anticancer agents inhibits cancer progression and promotes apoptosis in a synergistic manner. The combination of 17-AAG with targeted antibodies, signaling pathway inhibitors, proteasome inhibitors, and conventional cytotoxic drugs pave the way for novel dual mode platforms for cancer therapy (37). The outcome of such combinations may enhance therapeutic effects as a result of either their additive drug action or as a result of their synergistic interaction (38-40).
A combination of trastuzumab (a humanized anti-ErbB2 monoclonal antibody) and 17-AAG induces ubiquitin dependent lysosomal degradation of ErbB2 and cytotoxicity in ErbB2- overexpressing breast cancer cells. Also, trastuzumab in this combination gives better results due to decreased proliferation of these cells (41).
Rapamycin (mTOR inhibitor) combined with 17-AAG inhibits Akt phosphorylation and augments mTORC1 inhibition in MCF-7 and MDA-MB-231 breast cancer cells. The phosphorylation of Akt client protein is enhanced in breast cancer cells and tumor tissues of patients treated with Rapamycin treatment (42). This combination also results in a strong synergistic effect on multiple myeloma cell growth. Both 17-AAG and rapamycin trigger apoptosis and cell cycle arrest, induce cleavage of PARP caspase-8/9, and dysregulate
signaling in the PI3K/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, both agents can inhibit angiogenesis and osteoclast formation (43).
Additive interaction of oxaliplatin and 17-AAG in colon cancer cells inhibits NF-κB signaling. 17-AAG in this combination increased oxaliplatin cytotoxicity by down-regulation of NF-κB transactivation (44).
The combination of 17-AAG with TRAIL inhibits AKT and NF-κB signaling pathways and induces apoptosis in both resistant and sensitive cell lines to TRAIL. Although, TRAIL is a powerful inducer of cancer cell death, in vitro resistance in some cancer cell lines has restricted its value as a single agent. AKT and NF-κB signaling pathways have inhibitory
effects on TRAIL-mediated apoptosis in colon cancer cell lines. (45). The is 17-AAG and
TRAIL combination also induces apoptosis in TRAIL-resistant glioma cells by downregulating survivin (inhibitor of apoptosis) which is mediated through proteasome (46). The 17-AAG potentiates the activity of enzastaurin, an oral inhibitor of PKCβ, against glioma cells. Enzastaurin partially down-regulates Akt and GSK3β phosphorylation in glioma cells. The combination of enzastaurin with 17-AAG considerably increases its cytotoxic antiproliferative effects (47).
Since Hsp90 is a cytoprotective against cellular stressors such as DNA damage, inhibition of Hsp90 by 17-AAG probably potentiates the cytotoxicity of DNA-damaging agents (cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and temozolomide) in glioma cells. 17-AAG potentiated the cytotoxicity of the DNA-crosslinking agents, cisplatin and 1,3-bis(2-chloroethyl)-1- nitrosourea, but not that of the DNA-methylating agent, temozolomide (48).
Fenretinide, a vitamin A analogue, induces apoptosis by the induction of ROS in neuroblastoma. A synergistic effect of fenretinide combined with17-AAG had been observed in neuroblastoma. The synergistic effect of this combination might depend on the cells’ ability to inhibit induction of Hsp70, which protect cancer cells from apoptosis (49).
Platinum-based drugs (such as carboplatin) and taxanes (such as paclitaxel) are a part of standard chemotherapy for patients with ovarian cancer. Carboplatin induces apoptosis by cell cycle arrest at the G2/M checkpoint in ovarian cancer cells. In addition to cell cycle arrest, paclitaxel can induce apoptosis through activation of caspase proteins in these cells. Combining 17-AAG with carboplatin/paclitaxel can be beneficial in treating ovarian cancer. 17-AAG inhibits signaling through the RAS/RAF/MEK/ERK and PI3K pathways. Inhibition of these pathways resulted in sensitization of selected cancer cells to carboplatin (50).
Another combination therapy for ovarian cancer is 17-AAG paired with olaparib (inhibitor of PARP). Epithelial ovarian cancer (EOC) has epigenetic abnormalities in genes involved in HR DNA repair pathway. The BRCA1/2, a client protein of Hsp90, is one of the proteins involved in this pathway. PARP inhibitors exhibit synthetic lethality in HR deficient tumors. Therefore, inhibition of HR pathway is essential to enhance their activity in HR-proficient EOC cells. Combining 17-AAG and olaparib inhibits HR pathway through downregulation of BRCA1 and RAD51 levels, and induces γH2AX activation (51).
Combination of rapamycin, CI-1040, and 17-AAG, inhibit mTOR/Erk/Hsp90, which in turn blocks the metastatic capacity of prostate cancer via Slug inhibition. Snai2, a member of the Snail family, is crucial in regulating metastases in prostate cancer through PTEN/Akt, mTOR, Erk, and AR/Hsp90 signaling pathways. It is now well established that the inhibition of Hsp90 via 17-AAG reduces Slug expression levels through degradation of AR (52).
17-AAG increases paclitaxel-induced cytotoxicity and downregulates VEGF expression in NSCLC. Co-treating with 17-AAG and paclitaxel results in superadditive growth inhibition effects in these cells (53).
Another effective combination for lung cancer is 17-AAG and Ad-mda7. This combination induces cell death by inhibiting p-AKT in lung cancer cells in a highly synergistic manner (54).
The combined treatment of 17-AAG and carbon ion irradiation has more efficient tumor growth delay for lung tumor cells than radiation alone. 17-AAG through checkpoint arrest at G2/M phase and inhibition of the HR pathway sensitizes cancer cells to the radiation and enhances the effect of high LET heavy ions on tumor cells (55).
High expression of Hsp90 and PI3K/AKT/mTOR pathway proteins have been found in melanoma patients. Therefore, a combination of 17-AAG and NVP-BEZ235 (PI3K/mTOR inhibitor) could indicate synergistic activity in melanoma patients. This combination retards melanoma cell growth and induced apoptosis through targeting MAPK and PI3K/AKT/mTOR pathways simultaneously (56).
A synergistic inhibitory effect of 17-AAG combined with cisplatin (a C-terminal inhibitor) has been shown on ESCCs. This synergistic effect was mediated through induction of apoptosis by downregulation of the Akt/XIAP pathway (57).
Combining 17-AAG with ritonavir reduces the expression of HSF-1, an HSP transcription factor, and induces cell cycle arrest and apoptosis by downregulating cyclin D1 and cyclin- dependent kinase 4 in renal cancer cells (58). The MEK inhibitor U0126 in combination with 17-AAG, through abolition of the transient ERK activation induced by 17-AAG, potentiates the growth inhibitory effect of 17-AAG on pancreatic cancer cells (43).
Co-treatment of 17-AAG with FLT-3 kinase inhibitor, PKC412, is effective against AML cells with mutant FLT-3. The 17-AAG directed FLT-3, a receptor tyrosine kinase, to proteasomal degradation by disruption of corporation between FLT-3 and Hsp90 (59).
Some human leukemia cells are resistant to antileukemic drug-induced apoptosis, although 17-AAG, induces apoptosis in these cells (60), by reducing Bcr-Abl levels. Confirming this effect, Hawkins et al. combined 17-AAG with imatinib (a tyrosine kinase inhibitor) and showed that this combination can inhibit resistance to imatinib in Bcr-Abl cells of ALL (61). 17-AAG and cisplatin was another effective combined inhibitor of Hsp90 chaperone function
in Bcr-Abl-positive human leukemia cells that contained imatinib-resistant CML cells. The combination can act synergistically, but not antagonistically, on those cells (62).
17-AAG plus the histone deacetylase inhibitor LBH589 is highly active on CML-BC and AML cells with activating mutation of FLT-3. Treatment with LBH589 results in acetylation of histone H3 and H4 of Hsp90, enhancing p21 levels, and inducting apoptosis in leukemia cells. This combination exerted synergistic apoptotic effects through down-regulation of the levels of Bcr-Abl and FLT-3 in CML-BC and AML cells (63).
17-AAG potentiates UCN-01 (an inhibitor of CDK) cytotoxicity in leukemia cells. These agents interact in a highly synergistic manner to induce mitochondrial damage and apoptosis in leukemia cells. The increased cytotoxicity of this combination interrupts the Akt and the Raf-1/MEK/ERK cytoprotective signaling pathways (64).
Also, it has been found that 17-AAG enhances the cytotoxicity of flavopiridol, a CDK inhibitor (CDKI), in MCL via autophagy suppression. Flavopiridol inhibits the interaction between Cyclin D1 and CDKs and can be used for MCL therapy. Recently, it has been revealed that flavopiridol may confer drug resistance to CDKI-targeted therapies via induction of protective autophagy in MCL cells. 17-AAG suppresses flavopiridol-induced autophagy through inhibition of Beclin1 (one of the autophagy-related proteins) stability and ERK activation (65).
3.17-AAG in Clinical Research
Several phase I trials have investigated the inhibitory effects of 17-AAG as a single agent and in combination with other anticancer agents on hematological malignancies and solid tumors (Table 3).
3.1.Pharmacokinetics
17-AAG is metabolized by cytochrome P450 3A4/5 and NQ01 into 17-amino-geldanamycin (17-AG). 17-AG, as an active metabolite of 17-AAG, may provide its activity (66). The maximum plasma concentration (Cmax ) and area under the curve (AUC) of 17-AAG and 17- AG were enhanced linearly with 17-AAG dosage. The 17-AAG clearance averaged 30 l/h/m2. The terminal half-life of 17-AAG is 3 to 6 h. 17-AG is also detected in plasma with terminal half-life of 6.2 – 7.6 h. Urinary excretion of 17-AAG estimated for almost less than 10% of a dose and quickly cleared by the hepatobiliary system (67, 68).
3.2.Toxicity
The main DLT of 17-AAG administration was hepatotoxicity with elevated hepatic transaminases and serum bilirubin (69) (Table 3). Nausea, diarrhea, and vomiting were side effects for patients treated with 17-AAG dissolved in DMSO (70). Hypersensitivity reactions observed with cremophor-based formulations were pacified through pre-medicating patients with steroids and antihistamines (71).
3.3.Pharmacodynamics
To evaluate Hsp90 inhibition, PBMCs were collected pretreatment and also following 17- AAG administration. Intracellular Hsp70 levels rose considerably at 6 and 25 h after 17-AAG administration. Also, phosphorylated Akt, Raf-1, and cdk4 (client proteins of Hsp90) levels were reduced by the drug treatment. Since drug-induced changes in client protein levels were more variable in phase I trials, these proteins could not be considered as an alternative for assessing adequacy of Hsp90 inhibition (24, 67).
3.4.Clinical Efficacy
The phase I and II research did not demonstrate considerable clinical efficacy for treatment with 17-AAG as a single agent, except in a small number of patients, who experienced some prolonged disease stabilization (Tables 3 and 4). Gartner et al. reported on a Phase II trial of patients with metastatic and locally advanced breast cancer, who received 220 mg/m2 of 17- AAG on days 1, 4, 8, and 11 every 21 days (72). There was no response and three patients had stable disease. Five patients experienced advanced grade 3 or 4 hepatic and pulmonary toxicities. Pacey et al. performed a phase II trial with patients diagnosed with metastatic melanoma. 17-AAG was administered weekly. No significant efficacy was noted (73). Combining 17-AAG with other anti-cancer drugs is well tolerated and has displayed some clinical benefit for cancer patients. A Phase I trial of 17-AAG combined with trastuzumab has been performed in patients with trastuzumab-refractory HER-2–overexpressing breast cancer. The patients received weekly trastuzumab followed by intravenous 17-AAG. Responses observed were one partial response, four minor responses, and four stable diseases. Results showed that 17-AAG combined with trastuzumab has superior anticancer function in these patients (71). Phase II research of 17-AAG in combination with trastuzumab was built upon phase I results. The results showed an overall response rate of 22% and clinical benefit rate of 59%. The median progression-free survival was 6 months, and the median overall survival was 17 months for patients with trastuzumab-refractory HER-2– overexpressing breast cancer (74).
Hubbard et al. studied clinical activity of 17-AAG combined with gemcitabine and/or cisplatin in patients with refractory solid tumors. In this phase I research, six patients showed partial responses (75). Exposure of cancer cells to 17-AAG resulted in degradation of Chk1 (an Hsp90 client protein) and annulling a G1/S arrest induced through Gemcitabine. Therefore, cytotoxicity of gemcitabine was enhanced when 17-AAG exposure was followed
by gemcitabine treatment (76). Cisplatin could inhibit HSF1 mediated heat shock response that 17-AAG induced through blocking HSF binding to the promoter region for this transcription factor (77).
In a phase I trial of docetaxel and 17-AAG co-treatment for patients with solid tumors, one patient with lung cancer experienced a partial response, and minor responses were observed in patients with prostate, lung, bladder, and melanoma cancers (67). Preclinical results suggested that simultaneous administration of 17-AAG only on days when the taxane was administered would synergistically amplify the affect between the two drugs (78). A phase I trial of 17-AAG and paclitaxel was performed with patients diagnosed with advanced solid malignancies. In six patients, disease stabilization was noted, but there was no partial or complete response (79). Exposure of breast cancer cells to 17-AAG sensitizes these cells to the apoptotic effects of paclitaxel through the activation of caspase-3 and caspase-9 (80). Vaishampayan et al. reported on a phase I trial of 17-AAG with sorafenib (a Raf-kinase inhibitor) in patients with renal cancer, melanoma, and colorectal cancer. They found that Hsp90 inhibition by 17-AAG influences the Raf-kinase signaling pathway and would increase antitumor effects of sorafenib. Moreover, 9% of patients showed a partial remission and 61% had stable disease (81). Richardson et al. investigated in a Phase I/II study 17-AAG combined with bortezomib (a proteasome inhibitor) in patients with relapsed and refractory multiple myeloma. Three of the patients showed complete responses and eight patients had partial responses (82). In vitro studies showed that 17-AAG synergizes with bortezomib to inhibit the proteasome and induce apoptosis in primary MM cells (83, 84).
NIH-funded phase I, II, and III clinical trials of 17-AAG are summarize in Table 5. In summary, the role of 17-AAG in cancer treatment at the present time is evolving. 17-AAG needs to be assessed in the more phase II and III trials in combination/nanocombination with other anticancer agents for more types of solid tumors and hematological malignancies.
4.17-AAG Loaded Nanocarriers
Although 17-AAG has potent and suitable therapeutic pharmacological effects, it has low water solubility and needs DMSO and Cremophor EL for systemic administration (32, 34). These drug solubilizers have their own adverse effects including peripheral neurotoxicity, hypersensitivity, and can disturb gastrointestinal function . In addition 17-AAG delivered via DMSO or Cremophor EL has a short half-life, limited ability to reach target cells, induction of drug resistance, poor specificity, and high hepatotoxicity that restrict its clinical use (85).
In recent years, advances in nanomaterials-based drug delivery carriers has paved the way for overcoming these obstacles (86-88). The main advantages of nanocarriers for anticancer drugs include improved therapeutic effect, extended half-life in the bloodstream, increased water solubility, improved stability, selective delivery to specific site, and decreased hepatotoxicity (89-92). Despite these benefits, each nanocarriers has some drawbacks, which are discussed below.
The nanocarriers can reach tumor site through either passive or active drug targeting (93, 94). In passive targeting, nanocarriers accumulate preferentially in the tumor by enhanced permeability and retention (EPR) effects (95). In order to penetrate nanocarriers into tumors through EPR effect, these carriers must circulate in the blood stream for as long as possible. This can be achieved by coating the surface of nanocarriers with a hydrophilic polymer, such as polyethylene glycol (PEG) with the process known as “PEGylation” (96, 97).
In active targeting, targeting ligands are attached on the nanocarrier surface which bind to receptors on the tumor cell surfaces. With this mechanism, the encapsulated drug can be internalized by nanocarriers into tumor cells (98).
Selective accumulation of hsp90 inhibitors within malignant tissues has been reported (99). To further accentuate this effect on malignant cells, the use of nano-scaled delivery systems appears to be an ideal strategy because of their more specifically accumulation within tumors via passive and active targeting.
4.1.Encapsulated 17-AAG in Micelle
Among the most frequently used nanomaterial drug carriers are biodegradable and biocompatible polymeric micelles that can enhance solubility of poor water soluble drugs such as 17-AAG (100). This type of micelles are formed via self-assembly of amphiphilic block copolymers. They have a hydrophobic core as a storage site for hydrophobic drugs and a hydrophilic shell that enhances circulation time and stability of the micelles within the bloodstream (100, 101). Such polymeric micelles are in principle ideal hydrophobic drug carriers. Their small size, high structural stability, high water solubility, and low toxicity are advantages of these materials. Despite these advantages, lack of stability in blood, premature drug leakage, limited polymers for use, insufficient tissue distribution, and lack of suitable methods for large-scale production are major limitations of polymeric micelles (102, 103). Polymeric micelles can be accumulated in tumor tissues with an EPR effect, raising their value as a chemotherapeutic agent (104). The use of micelles as carriers for 17-AAG has increased in preclinical and clinical research over the last few years.
One particular micelle is an amphiphilic diblock composed of poly (ethylene oxide)-b- poly(D,L-lactide) (PEO-b-PDLLA). This results in higher water solubility for 17-AAG compared with free 17-AAG (150-fold higher), while retaining pharmacokinetic properties of free 17-AAG in MCF-7 breast cancer cells (105).
17-AAG can cross the BBB due to its lipophilic nature, but poor water solubility limits its clinical use for GBM treatment. In order to solve this limitation, Saxena et al. encapsulated
17- AAG in Pluronic ®P-123 / F-127 mixed micelles. These mixed micelles showed good cellular uptake in U87MG cell line possibly due to enhanced internalization via endocytosis. As such, Pluronic ®P-123 / F-127 mixed micelles may increase the cytotoxicity of 17-AAG and sustain release inside the cells (104).
In another study, Chandran et al. constructed poly (ethylene glycol)-block-distearoylphos phatidylethanolamine (PEG-b-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as nanocarriers for 17-AAG. They reported that these micelles have an ability to deliver 17-AAG at clinically relevant dosages and exhibited higher cytotoxicity compared to free 17-AAG on human ovarian cancer cells (SKOV-3) (34).
Also, Katragadda et al. used these mixed micelles for co-delivery of 17-AAG and Paclitaxel. They demonstrated that 17-AAG/paclitaxel-loaded PEG-DSPE/TPGS mixed micelles were more efficient in the inhibition of SKOV-3 cells growth than the combined free drugs (106). Larson et al. applied poly (styrene-co-maleic acid) (SMA) to make micelles containing 17- AAG by a hydrophobic interaction between the styrene moiety of SMA and 17-AAG. SMA- 17-AAG micelles showed inhibitory effect against DU145 human prostate cancer cells in vitro and in vivo in nude mice bearing DU145 human prostate cancer xenografts. Moreover, it was found that the therapeutic index of 17-AAG is enhanced in SMA-17-AAG micelles compared to pure 17-AAG (100).
As previously mentioned, the combination of 17-AAG and other anti-cancer drugs increases cytotoxicity of these drugs in cancer treatment. Therefore, Shin et al. prepared and characterized PEG-b-PLA micelles to deliver combinations of paclitaxel, etoposide, docetaxel, and 17-AAG at clinically related dosages. They found that the stability of different hydrophobic drugs in PEG-b-PLA micelles was due to the presence of 17-AAG (101). Triolimus (PEG-b-PLA micelles) is a multidrug-loaded micelle containing paclitaxel, rapamycin, and 17-AAG. Its antitumor properties have been examined both in vitro and in
vivo. Results of studies on lung and breast cell lines showed that the three drug combination in Triolimus exerted potent synergistic cytotoxicity in both cell lines. In xenograft models, tumor growth and cancer cell proliferation were delayed through enhanced apoptosis induction (107). Also Triolimus was found to exhibit potent radiosensitization effects in vitro and in vivo (108).
In other research designed to enhance the water solubility of epothilone B, rapamycin, and 17-AAG, Shin and Kwon loaded all three drugs into PEG-b-PLA micelles and reported high efficiency of these micelles against A549 cancer cells in vitro and in vivo (85).
Furthermore, Le et al. delivered a combination of docetaxel, rapamycin, and 17-AAG into the micelle system (DR17) and tested its antitumor efficacy in prostate cancer. Results of in vitro studies showed that packaging the drugs into DR17 increases the cytotoxic effects. DR17 simultaneously targeted several main signaling pathways in prostate cancer such as mTOR, AR, and PI3K/AKT. DR17 also reduced prostate weight in a mouse model of prostate cancer. Le et al. showed that this weight reduction was due to increased apoptosis and decreased cell proliferation (109).
Phospholipid nanomicelles are one important type of polymeric micelles in which the hydrophobic core is a lipid instead of a hydrophobic polymer block. As such, they can facilitate the loading of high concentrations of drug per micelle (110). Önyüksel et al. developed long-circulating sterically stabilized phospholipid nanomicelles (SSM) in which VIP was grafted as an active targeting moiety to the tip of PEG. This confirmed that 17-AAG can be formulated in these nanomicelles. Furthermore the cytotoxicity of 17-AAG-loaded nanomicelles in MCF-7 breast cancer cells was similar to that of 17-AAG dissolved in DMSO (35).
4.2.Encapsulated 17-AAG in Nanogels
Biodegradable polypeptide-based nanogels (NGs) are another type of nanomaterials that can be used to encapsulate 17-AAG. Nanogels have several potential advantages that make them attractive for drug delivery. These include high hydrophilicity, high loading capacity for drugs, high biocompatiblity, softness, and swelling. But the main advantage of nanogels is their fast response to environmental changes, which can help control their response at the target site (111-113). Despite these benefits, high cost requiring to remove the solvents and surfactants at the end of preparation, and toxicity resulting from remained surfactant or monomer traces are drawbacks (114).
Desale et al. explored nanogels comprised of PEG-b-PGA containing both 17-AAG and doxorubicin. They demonstrated that NGs-based co-delivery of 17-AAG and doxorubicin had efficiency in treating both human breast cancer lines and an ErbB2- driven xenograft model relative to combined free drugs (115). Recently, Raje et al. prepared Trast-NG containing doxorubicin targeting ErbB2 receptor. They showed that pretreatment with 17-AAG, facilitates the intracellular delivery of Trast-NGs/dox both in vitro and in vivo. Trast- NGs/dox follow intracellular trafficking of ErbB2 and are degraded in the lysosomes (116).
4.3.Encapsulated 17-AAG in Nanoparticle
Recently, polymeric NPs have been used for the delivery of 17-AAG. The advantages of NPs as drug carriers are high stability, high bioavailability, low toxicity, feasibility of incorporation of both hydrophilic and hydrophobic substances, and high encapsulation efficacy for the drugs. These NPs also possess useful controlled release properties,(117, 118). The relatively slow biodegradability of polymeric NPs is their main disadvantage that could lead to systemic toxicity (119).
Hyaluronic acid-decorated poly lactic-co-glycolic acid nanoparticles (HA-PLGA NPs) were developed to co-deliver 17-AAG and docetaxel by Pardhan et al. They used an oil-in-water emulsification/solvent evaporation technique to load these two drugs into HA-PLGA NPs. HA present on the surface of PLGA NPs specifically facilitated binding to receptors, such as CD44 and RHAMM (CD168). Moreover, the cellular uptake of HA-PLGA NPs was mainly from CD44 receptor-mediated endocytosis (120).
Using self-assembled biodegradable NPs is one way to improve the bioavailability of 17- AAG. The extended circulation time for drugs in the bloodstream, decreased side effects, and avoidance of the RES are advantages of self-assembled NPs (121).
Won et al. prepared self-assembled NPs based on rHG modified via alphatocopheryl succinate (TOS) for delivery of 17-AAG. They found that the therapeutic efficiency and biocompatibility of 17-AAG was enhanced in rHG-TOS NPs (122).
NPs decorated with surface-bound folic acid have achieved considerable success (123). Saxena et al. prepared folate targeted PLGA–PEG–FA NPs containing 17-AAG as a targeted delivery system for breast cancer. They showed that 17-AAG loaded PLGA–PEG–FA NPs have much higher intracellular uptake compared to non-targeted PLGA NPs in MCF-7 cells. Folate-receptor mediated endocytosis is responsible for the increased cellular uptake and cytotoxicity of 17-AAG (124) in this construct. These receptors are highly expressed by breast cancer cells. This type of delivery system improves intracellular delivery and avoids collateral toxicity (125).
Doxorubicin combined with 17-AAG can sensitize the breast cancer cells to the cytotoxic effects of doxorubicin via inhibitory effect of 17-AAG on Hsp90 function. With that in mind, Gupta et al. developed folate-receptor targeted hybrid lipid-core nanocapsules including a hybrid lipid core lodging 17-AAG and a polymeric corona lodging doxorubicin (F-DTN). These NPs inhibited MCF-7 cells growth with increased cellular uptake and notable
apoptosis. Also, an in vivo pharmacokinetic study showed that the bioavailability and plasma circulation time for the drugs increased once they were encapsulated into F-DTNs (126). PDT is a promising non-invasive therapeutic modality that might be developed to treat prostate cancer. PDT induces the expression of several client proteins of Hsp90. Therefore, combining 17-AAG with PDT may improve the efficiency of PDT. To achieve this goal, Lin et al. developed a multifunctional nano-platform (Nanoporphyrin) for targeted delivery of heat, reactive oxygen species, and 17-AAG simultaneously to the tumor sites in transgenic and xenograft murine tumor models (127).
Magnetic nanoparticles are a group of smart nanomagnetic materials with small particle size, high specific surface area, magnetic response, and superparamagnetism (128, 129). It is well known that magnetic nanoparticles can be used to deliver drugs in cancer diagnosis and treatment. Magnetic NPs can be used in some chemotherapy protocols, magnetic hyperthermia, photothermal therapy, and photodynamic therapy. Common ways they are used is in combined therapy to enhanced a therapeutic effect. Since magnetic hyperthermia combined with 17-AAG has promising effects against pancreatic cancer, Rochani et al. prepared 17-AAG and Fe3O4 loaded magnetic NPs coated with PLGA to increase the efficacy of 17-AAG. They indicated that combination of 17-AAG and magnetic hyperthermia serve as a potential alternative treatment for pancreatic cancer (130).
Although magnetic hyperthermia has an ability to eliminate LCSCs, thermoresistance in these cells upon subsequent heating can inhibit apoptosis. Inhibition of Hsp90 via 17-AAG can overcome thermoresistance and increase the apoptosis of LCSCs. Yang et al. reported that CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17- AAG/TMs) inhibited Hsp90 and enhanced the sensitivity of CD90+ LCSCs to magnetic hyperthermia (131).
Cyclodextrin NPs are commonly used to improve the solubility and stability of drugs (132, 133). β-cyclodextrin is a semi-natural compound that can increase bioavailability of drugs. Gandomkar et al. used β-cyclodextrin NPs to encapsulate 17-AAG thus increasing the water- solubility of 17-AAG. They demonstrated antiproliferative effects of the β-cyclodextrin-17- AAG-complex against T47D breast cancer cells (134).
4.4.Encapsulated 17-AAG in Liposome
Recently, liposomes have been used to increase water solubility of 17-AAG. Liposomes are nanocarriers composed of lipid bilayers surrounding aqueous compartments (135, 136); they are able to carry both hydrophilic and hydrophobic molecules (137). The unique advantages of liposomes including biodegradability, biocompatibility, protection of drug from degradation, and targeting of the drug to the site of action. These features make them attractive as drug carrier (138, 139). However, liposomes has been limited use clinically due to low water solubility of active compounds, low encapsulation efficiency, and a slow drug release rate (140). To overcome these limitations, several researchers have proposed to using liposomes containing hydroxypropyl-β-cyclodextrin (HPβCD) (141). Petersen et al. prepared liposomes-containing 17-AAG: HPβCD to improve solubility of 17-AAG. They established that encapsulating 17-AAG:HPbCD inside liposomes resulted in a 33-fold-enhancement of the drug’s water solubility (140).
In sum, there are efforts underway to incorporate 17-AAG into the different nanocarriers. Recently, our group reported the successful loading of 17-AAG and 17-DMAG (a hydrophilic derivative of 17-AAG) into electrospun polymeric nanofibers (142, 143). These nanofibers are biocompatible, biodegradable, highly porous, and possess high surface-to- volume ratio. They can as well be implanted into tumors for local drug delivery (144). Our finding indicated that 17-AAG and 17-DMAG-loaded PCL/PEG nanofibers are more
effective than the free drugs against lung and breast cancer cells. Our data suggest that drug- loaded nanofibrous scaffolds might be a way to improve clinical efficacy and reduce hepatotoxicity of anticancer drugs (142).
5.Conclusion and Future Prospects
In this review, inhibitory effect of 17-AAG on several signaling pathways and the proteins involved in these pathways are summarized. Both preclinical and clinical results show that 17-AAG provides better anti-tumor activity and clinical efficiency when is combined with cytotoxins, radiation, biologics, and antiangiogenics agents compared to when those agents are used alone. Also, combining 17-AAG with antitumor agents can prevent the development of drug resistance in cancer treatment. In addition, based on the recent studies, there are attempts to gain novel formulations of 17-AAG with improved clinical pharmacokinetics and pharmacodynamics effects, so that novel nanomaterials-based drug delivery systems are in progress to decrease the side effects, facilitate intracellular administration, and improve the clinical efficiency of 17-AAG. Novel therapeutic platforms using nanotechnology provide a promising future for the effective delivery of drug to treat various types of cancers.
Acknowledgements
This study was financially supported by grant No: 951204 of the Biotechnology Development Council of the Islamic Republic of Iran (which was a part of a PhD thesis written by Sona Talaei in Tabriz University of Medical Sciences). The authors would like to thank Prof. Richard Joel Wassersug (University of British Columbia, Vancouver, BC, Canada) for his editorial assistance on this manuscript.
Conflict of Interest
The authors declare no conflict of interest.
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Figure Legends
Fig. 1: Hsp90-client protein cycle. Initially, an early complex is composed by binding client protein to Hsp70, Hsp40, and HIP which interacts with the Hsp90 homodimer through HOP to compose an intermediate complex. Binding of ATP to the N-terminal domain of Hsp90 and its subsequent hydrolysis releases the co-chaperones from the intermediate complex and Hsp90 composes a mature complex, containing co-chaperones p23, cdc37, and IPs that is necessary for chaperone activity of Hsp90 and catalyzes the structural maturation of the client protein. 17-AAG binds to the ATP-binding region of Hsp90, inhibits formation of mature
complex and resulting in ubiquitination and degradation of the client proteins through the CHIP ligase.
Fig. 2: Hsp90 and the hallmarks of cancer.
Table 1: A list of Hsp90 client proteins and their roles in various cancer types
Client protein Function of client protein Cancer type
Steroid hormone receptors
ER Ligand mediated gene transcription(145, 146) Breast
AR Ligand mediated gene transcription(147, 148) Prostate
PR Ligand mediated gene transcription(149) Breast
Ser/Thr and Tyr kinases
EGFR Signal transduction(150, 151) Breast, Lung, Colorectal and Head and neck
HER-2 PI3 kinase signalling(152) Ovarian, Breast
Chk1 Cell cycle regulation(76) AML
B-Raf MAPK signalling(153) Melanoma
Raf-1 MAPK signalling(153, 154) Melanoma
FAK Actin-based cell motility(155) Colon, Breast
IGF1-R Signal transduction(156) Multiple Myeloma
PLK Cell cycle regulation(157, 158) Colorectal
Wee1 Cell cycle regulation(159, 160) Lung
Bcr-Abl Pathogenesis of myeloid leukaemia(60, 161) CML
CDK-4 Cell cycle regulation(162) NHL
AKT PI3 kinase signalling(163, 164) Lung
FLT-3 PI3K/AKT signalling(165) AML
c-MET HGF/SF-MET motility signalling(166) Prostate, Lung, Head and neck
Proteins with various other functions
hTERT Cell mortality and senescence(167, 168) Prostate
HIF-1α Hypoxia-induced angiogenesis(169-171) Breast
Mutant p53 Mutant form of cell cycle checkpoint protein(172) Colorectal, Lung
ZAP-70 Signal transduction(158) CLL
Survivin Inhibitor of apoptosis(173) GBM
ER: Estrogen receptor; PR: Progesterone receptor; HER-2: Human epidermal growth factor receptor 2; IGF1-R: Insulin-like growth factor 1 receptor; Chk1: Check point kinase 1; PLK: Polo-1 kinase; FAK: Focal adhesion kinase; CDK-4: Cyclin-dependent kinase-4; NHL: Non- Hodgkin Lymphoma; hTERT: Catalytic subunit of telomerase.
Table 2: Preclinical studies summary
Cancer Incorporated pharmaceutical Target protein Function
Breast 17-AAG HER2 Retinoblastoma (RB)-dependent G1 block, induction of differentiation and apoptosis (174), inhibition of HER2 kinase and degradation of HER2 protein, inhibition of signaling by HER3/PI3K/AKT pathway (152), inhibition of Akt activation, and cyclin D expression (175)
Ovarian cancer 17-AAG Raf1 and Cdk4 Inhibition of growth and expression of CDK4, c-RAF-1, and HSP70 (176)
Prostate cancer 17-AAG AR, Akt, and HER2 Proteosomal degradation of AR, Akt, and HER2 (147, 177)
Prostate cancer 17-AAG Akt Tumor growth inhibition, local induction of apoptosis and minimal clinical toxicity (178)
Prostate cancer 71-AAG AR Blocking nuclear localization of AR (15)
Glioblastoma 17-AAG Cdc2 and Cdc25 Downregulation of cycle 2 and cdc25 level and inhibition of cdc2 kinase activity (179)
GBM 17-AAG Akt/EGFR Inhibition of PI3K/AKT/mTOR survival pathway and PDGF signaling pathway GBM (26)
Glioma 17-AAG NF-κB Blocking the FAK/IKK/IκBα/NF-κB signaling pathways and inhibiting the NF-κB –mediated MMP-9 secretion induced by hyaluronic acid (180)
Colon cancer 17-AAG N-ras, Ki-ras, c-Raf-1, ERK1/2, and c-Akt Depletion of N-ras, Ki-ras, c-Raf-1, ERK1/2, and c-Akt, inhibition of c-Akt phosphorylation (30, 181, 182)
GIST 17-AAG KIT Degradation of KIT oncoprotein (183)
Lung cancer 17-AAG NF-κB,
Cdc2, and cdc25 Degradation of IKKβ and RIP, inhibition of TNF-induced NF-κB
activation and antiapoptotic gene expression (184), and induction of G2- M arrest via degradation of Cdc25 and Cdc2 (185)
Lung cancer 17-AAG HIF-1α Repression of the Hsp90/HIF-1α interaction and expression of HIF-1α in radioresistant cancer cells (186)
Melanoma 17-AAG c-Raf-1 Modulation of Hsp90 and down- regulation of c-Raf-1 (187)
Melanoma 17-AAG hTERT Inhibition of telomerase catalytic activity and induction of apoptosis (168)
GBC 17-AAG phospho-ERK, AKT,
phospho-AKT, EGFR, cyclin D1, and cyclin B1 Decrease of client proteins level (188)
Osteosarcoma 17-AAG p-Akt, cyclin D1, cdc2, and ERK Induction of apoptosis by
depolarization of mitochondrial membrane, activation of caspase-8 and caspase-9, and release of AIF from mitochondria into cytosol (189)
Urinary bladder cancer 17-AAG NF-κB Downregulation of multiple signaling molecules and caspase-mediated cell death (190)
Thyroid cancer 17-AAG Akt and Raf Disruption of Hsp90 binding to Akt and Raf (191)
Multiple Myeloma 17-AAG HSF-1 Upregulation of MICA and MICB (192)
SCC 17-AAG PKCε Inhibition of Hsp90-PKCε interaction and reduction in the expression levels of MMP-2 and MMP-9 (29)
CCA 17-AAG Bcl-2 and survivin Enhancement of caspase-3 activation, reduction in anti-apoptotic Bcl-2 and survivin expressions, and induction of G2/M cell cycle arrest via reduction in Cyclin B1 expression (193)
CML 17-AAG Bcr-Abl Degradation of Bcr-Abl by shift binding it from Hsp90 to Hsp70, reduction of Bcr-Abl levels, and induction of apoptosis (60)
AML 17-AAG Akt, c-Raf-1, c-kit, and c- Src Reduction of survival-signaling protein kinases level (194, 195)
AML 17-AAG FLT-3 Degradation of downstream JAK/STAT, MAPK, and PI3K/AKT signaling pathways (196)
MCL 17-AAG Cyclin D1, cdk4, and Akt Activation of mitochondrial caspase pathway, depletion of Bid and downregulation of cyclin D1, cdk4 and Akt (197)
ALCL 17-AAG NPM-ALK Reduction of NPM-ALK expression and phosphorylation and destruction its association via phospholipase C- gamma, Shc, Grb2, and IRS-1 (198)
CLL 17-AAG ZAP-70 Degradation of ZAP-70 and subsequently apoptosis induction (158)
APL 17-AAG ? Induction of apoptosis (199)
cHL 17-AAG STAT Inhibition of permanent Jak-STAT signaling by abrogating STAT phosphorylation and reducing protein expression of Jaks (200)
CSC 17-AAG HIF1a Disturbing the transcriptional function of HIF1a (201)
PEL 17-AAG NF-κB Inhibition of NF-κB transcriptional activity (202)
CML-BC: chronic myeloid leukemia blast crisis, ALCL: Anaplastic large cell lymphomas, Shc: Src homology 2 domain-containing protein, FLIP : cellular FLICE-like inhibitory protein levels , IRS-1 : insulin receptor substrate-1, cdc2: cell division cycle 2, cdc25c: kinase and cell division cycle 25c, RIP: receptor-interaction proteins, IKKβ: IκB kinase β, Grb2 : growth factor receptor-bound protein 2.
Table 3: 17-AAG in Phase I Research
Number of
Patients Cancer Recommended Phase II Dose Schedule DLTs Response
30 Melanoma (11), Sarcoma (4), Breast (3), Colon (2), Ovarian (2), Renal (1), Lung (1), Pancreas (1),
Others (5) 450 mg/m2 Weekly (no rest) Diarrhea, elevated AST/ALT Two patients with stable disease (203)
17 Atypical teratoid/rhabdoid tumor (1), Ependymoma (4), Ewing sarcoma (1), Juvenile granulosa cell tumor (1), Hepatoblastoma (1), Wilms’ tumor (2), Neuroblastoma (1), Peripheral nerve sheath tumor (1), Osteosarcoma (1), Primitive neuroectodermal tumor (CNS) (1), Renal cell carcinoma (1), Synovial sarcoma (2) 360 mg/m2 Weekly (2 out of
3 weeks) NO DLT No objective response, three patients with stable disease (204)
21 Colorectal (12), Lung (3),
Thyroid (1), Anal (1), Small bowel (1), Ovary (1), Liver (1), 308 mg/m2 Weekly (3 out of
4 weeks) Elevated bilirubin, myalgias, Nausea/vomiting, anemia No tumor response (205)
Others (1)
44 Colorectal (17), Lung (8), Head and neck (4), Prostate (3),
Pancreas (3),
Sarcoma (3), Esophageal (2), Others (4) 175 mg/m2
200 mg/m2 2x weekly (3 out
of 4 weeks) 2x weekly (3
out
of 4 weeks) Nausea/vomiting, headache, abdominal pain, elevated AST/ALT No objective tumor response (206)
45 Colorectal (14), Lung (8), GU (7), Head and neck (7), Others (9) 295 mg/m2 Weekly (3 out of
4 weeks) Pancreatitis, fatigue, anorexia, diarrha No objective response (207)
13 GI (7), Sarcoma (2), Melanoma (2), Skin (1), Renal (1) 220 mg/m2 Weekly (2 out of
3 weeks) Elevated AST/ALT, dehydration, hyperglycemia, diarrhea No tumor response (208)
15 Osteosarcoma (6), Neuroblastoma (6), Ewing’s sarcoma (2), Desmoplastic small round cell tumor (1) 270 mg/m2 2x weekly (3out
of 4 weeks) Grade 3 transaminitis, hypoxia No objective response (209)
54 Prostate (18), Breast (8), Renal (7), Lung (6),
Bladder (5), Melanoma (4), Head and neck (3), Others (3) 80 mg/m2
112 mg/m2 5x daily (3 out of
4 weeks) 3x daily (3
out of
4 weeks) Nausea/vomiting, abdominal, elevated AST/ALT, pain, seizure
(210) -
29 Relapsed multiple myeloma 150-525 mg/m2 Weekly (2 out of
3 weeks) Up to 8
cycle Diarrhea, back pain, fatigue, nausea, anaemia, thrombocytopenia One patient with minimal response (68)
25 Trastuzumab-refractory Her-2 overexpressing breast cancer 450 mg/m2 (Trastuzumab
4 mg/kg first wk then 2
mg/kg) Weekly Thrombocytopenia, fatigue One patient with partial response, four patients with minor response, and four patients with stable disease (71)
39 Ovarian (7), Lung (5), Other (27) 154 mg/m2 gemcitabine 750 mg/m2 3+3 design 3 weeks Neutropenia, leukopenia, thrombocytopenia Six patients with partial response (75)
25 Prostate (5), Esophagus (4), Lung (4), Ovary (2),
Colon (2), Others (8) 175 mg/m2 Paclitaxel
80 mg/m2 17-AAG Days 1, 4, 8,
11,
15, 18. Paclitaxel Days 1, 8,15 Fatigue, chest, myalgia pain (musculoskeletal) Six patients with stable diseases, no partial or complete response (79)
49 Prostate (16), Melanoma (12), Head/Neck (7), Renal (4), Lung (3), Bladder (3), Breast (2), Other (2) 500 mg/m2 Docetaxel 70 mg/m2 21-days cycle Leukopenia, lymphopenia, neutropenia Partial response (67)
72 Relapsed multiple myeloma 100-340 mg/m2 Bortezomib
0.7- 1.3 mg/m2 Weekly (2 out of
3 weeks) Neutropenia, constipation, anorexia Three patients with complete response (82)
27 Kidney (12), Melanoma (6), Adrenal (1), Colorectal (4), Thyroid (1), Cervix (1), Pancreas (1), Tongue (1) 400 mg/m2 Sorafenib 400 mg/m2 1, 8, 15 in a 28-day cycle
3x daily (14 day
before 17- AAG) Transaminitis, hand-foot syndrome, fatigue Partial remission, stable disease (81)
11
Relapsed AML
150 mg/m2 Bortezomib 0.7 mg/m2
17-AAG Weekly (2
out of
3 weeks) Bortezomib Day 1, 4, 8,
11
Neutropenia, AST/ALT,hypeglxcemia
No objective response (211)
Table 4: Phase II Research with 17-AAG
Number of Patients Disease Dose Drugs Schedule Response
15 Hormone-Refractory Metastatic Prostate cancer 300 mg/m2 17-AAG Weekly
(3 out of 4 week) No response(212)
15 Metastatic Melanoma 450 mg/m2 17-AAG Weekly
(6 weeks ) No response(213)
20 Papillary and clear cell renal cell carcinoma 220 mg/m2 17-AAG 2x weekly
(2 out of 3 week) No response(214)
66 Metastatic pancreatic cancer 154 mg/m2 17-AAG with 17-AAG No response(33)
750 mg/m2 Gemcitabine
of
Gemcitabine
days 2 and 9 Gemcitabine days 1 and 8
Table 5: NIH Funded Terminated and Completed Research
Disease Identifier Number Phase Drugs Status Results
Refractory Locally Advanced or Metastatic Breast Cancer NCT00096109 II Tanespimycin (17- AAG) Terminated (Closed to accrual before all 12 planned patients were enrolled) Response Rate 0 of 7 patients
Progression Free Survival 2 of 11 patients
Months (1 to 11) Serious adverse events
Gastrointestinal disorders Blood and lymphatic system
disorders
General disorders Immune system disorders
Infections and infestations
Metastatic Prostate NCT00118092 II 17-AAG Completed Overall response 0 of 15 patients
Percentage of response (0 to 22)
Overall survival 9.4 of 15 patients
Months (2.7 to 17.7) Disease-free survival 1.8 of 15 patients Months (1.3 to 3.4) Serious adverse events
Neutrophil count decreased Thrombosis(212)
Solid Tumors and Her2 Positive Metastatic Breast Cancer NCT00773344 I/II Tanespimycin and Trastuzumab (Herceptin) Completed No Results Posted
Kidney Tumors in Von Hippel-Lindau Disease NCT00088374 II 17-AAG Completed Renal Tumor Response 0 of 8 patients
Non-renal Tumor Response
0 of 2 patients Adverse Events 9 of 9 patients
Serious adverse events Dizziness
Metastatic or Unresectable Solid Tumors NCT00087217 I 17-AAG and Paclitaxel Completed No Results Posted
Advanced Malignancies NCT00779428 II Tanespimycin Completed No Results Posted
Advanced Cancer NCT00003969 I Tanespimycin Completed (203)
Recurrent Advanced Ovarian Epithelial or Peritoneal Cavity Cancer NCT00093496 II Tanespimycin and Gemcitabine hydrochloride Completed Overall response Confirmed Partial Response: 0.071 of 14 patients [Cohort
1 (No Prior Gemcitabine Exposure)]
0 of 11 patients [Cohort 2
(Prior Gemcitabine Exposure)]
Times to Progression
1.6 of 12 patients in Cohort 1
Months (1.2 to 3.5)
2.7 of 11 patients in Cohort 2
Months (1.3 to 5.1) Overall Survival
18.3 of 12 patients in Cohort 1
Months (6.2 to N/A)
11 of 11.5 patients in Cohort 2
Months (4.0 to 13.7) Toxicity
9 of 14 patients in Cohort 1 7 of 11 patients in Cohort 2
Serious adverse events Blood and lymphatic system
disorders
Gastrointestinal disorders General disorders
Infections and infestations,…
Unresectable/Metastatic Solid Tumors NCT00121264 I 17-AAG and Sorafenib Completed No Results Posted
Advanced Solid Tumor NCT00047047 I Tanespimycin, Gemcitabine hydrochloride, and Cisplatin Completed No Results Posted
Solid Tumor and Lymphoma NCT00004075 I 17-AAG Completed No Results Posted
Refractory Advanced Solid Tumors or Hematologic Cancer NCT00004065 I 17-AAG Completed No Results Posted
Recurrent or Refractory Leukemia or Solid Tumors NCT00093821 I 17-AAG Completed No Results Posted
Relapsed or Refractory Solid Tumors or Leukemia NCT00079404 I 17-AAG Completed No Results Posted
Multiple Myeloma in First Relapse NCT00546780 III Tanespimycin and Completed No Results Posted
Bortezomib
Relapsed or Refractory Hematologic Cancer NCT00103272 I 17-AAG and Bortezomib Terminated Overall response 0 of 11 patients Adverse events Diarrhea
Nausea Vomiting
Reversible hepatotoxicity Neutropenia (211)
Advanced Solid Tumors or Lymphomas NCT00096005 I Tanespimycin and Bortezomib Terminated No Results Posted
Advanced Solid Tumors or Non- Hodgkin’s Lymphoma NCT00019708 I 17-AAG Terminated No Results Posted
Advanced Epithelial Cancer, Malignant Lymphoma, or Sarcoma NCT00004241 I 17-AAG Completed No Results Posted
Relapsed-refractory Multiple Myeloma NCT00514371 II/III Tanespimycin and Bortezomib Completed No Results Posted
Chronic Myelogenous Leukemia NCT00100997 I 17-AAG Completed No Results Posted
Stage III-IV Melanoma NCT00087386 II Tanespimycin Terminated No Results Posted
Systemic Mastocytosis NCT00132015 II 17-AAG Completed No Results Posted
Metastatic Malignant Melanoma NCT00104897 II 17-AAG Completed (73)
Relapsed B-cell Chronic Lymphocytic Leukemia (CLL) NCT00098488 I 17-AAG Terminated No Results Posted
Metastatic or Unresectable Solid Tumors NCT00058253 I Tanespimycin and Docetaxel Completed No Results Posted
Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Hodgkin’s Lymphoma NCT00117988 II 17-AAG Completed Overall Response Complete Response: 0 of 18
patients
Partial Response: 2 of 18 patients
Serious adverse events Death
Locally Advanced of Metastatic Solid Tumors NCT00119236 I Tanespimycin and Irinotecan
hydrochloride Completed No Results Posted
Inoperable Locoregionally Advanced or Metastatic Thyroid Cancer
NCT00118248 II
Tanespimycin
Completed
Overall Response Complete Response: 0 of 17
patients (Advanced Medullary Thyroid Carcinoma Group)
Partial Response: 1 of 24 patients (Differentiated Thyroid Carcinoma)
Progression-Free Survival 6.4 of 17 patients (Advanced
Medullary Thyroid Carcinoma Group)
Months (2.7 to 17.2) 4.1 of 24 patients
(Differentiated Thyroid Carcinoma)
Months (2.2 to 8.7) Overall Survival
2.1of 17 patients (Advanced Medullary Thyroid Carcinoma Group)
Years (0.67 to 3.1) 1.5 of 24 patients
(Differentiated Thyroid Carcinoma)
Years (0.73 to 3.5) Toxicity
8 of 17 patients (Advanced Medullary Thyroid Carcinoma Group)
9 of 24 patients (Differentiated Thyroid Carcinoma)
Serious adverse events Cardiac disorders
Ear and labyrinth disorders Gastrointestinal disorders General disorders,.
Metastatic or Unresectable Solid Tumors or Lymphoma NCT00354185 I Tanespimycin and Belinostat Terminated No Results Posted
Stage IV Pancreatic Cancer
NCT00577889 II
Tanespimycin, and Gemcitabine hydrochloride
Completed
Six Month Survival Rate Percentage of patients
25 (7.5 to 83) in Arm I (Combination Chemotherapy)
67 (38 to 100) in Arm II (Combination Chemotherapy)
33 (11 to 100) in Arm III (Combination Chemotherapy)
Overall Survival Time Months
4.8 (2.8 to 6.6) in Arm I 6.9 (2.4 to 10.7) in Arm II 4.3 (1.9 to 15.3) in Arm III Time to Disease
Progression Months
2.2(1.4 to 4) in Arm I
4.1 (1.4 to 7.9) in Arm II 2.3 (1.4 to 4.0) in Arm III Confirmed Response Rate Participants
0 in Arm I, Arm II and Arm III
Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes NCT00098423 I Tanespimycin and Cytarabine Completed Overall Response Complete Response: 2 of 21
patients
Partial Response: 4 of 21 patients
Adverse events Disseminated intravascular
coagulation (grades 3 and 5) Acute respiratory distress
syndrome (grade 4) Myocardial infarction (215)
Chronic Lymphocytic Leukemia NCT00319930 I CNF1010 (17- AAG) Terminated (Discontinuation of program) No Results Posted
Chronic Myelogenous Leukemia
NCT00066326 I
Tanespimycin and Imatinib mesylate
Completed
No Results Posted