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Hsp90 may be referred to as the 'guardian of the proteome,' since it regulates the correct structure and function of many of the important proteins encoded by our DNA.
This figure illustrates some of the many channels through which Hsp90 can team up with co-chaperones to target client proteins that in turn activate hallmarks of cancer. More than 200 potential Hsp90 clients within the cell have been identified. Didier Picard, PhD, a professor in the Department of Cell Biology at the University of Geneva in Switzerland, maintains a database of Hsp90 interactors at www.picard.ch/downloads.
While p53 is often called the “guardian of the genome” for its important role in preventing the accumulation of cancer-causing DNA mutations, Hsp90 might equally be referred to as the “guardian of the proteome” (a cell’s protein complement), since it regulates the correct structure and function of many of the important proteins encoded by our DNA. Like p53, Hsp90 has become recognized as an important anticancer therapeutic target. A number of Hsp90-targeted agents are now in development.
Hsp90 is a member of the heat shock protein (Hsp) family, first described in 1962 as proteins induced during thermal stress. Despite the name, Hsp90 is actually active in most, if not all, cells under normal nonstress conditions; in fact, it makes up as much as 1% to 2% of total cellular protein content. Under conditions of stress (eg, lack of oxygen or nutrients, extreme temperatures), the expression of Hsp90 is further activated beyond normal levels in order to promote cell survival.
Hsps play a very important role in the cell as molecular chaperones. Once genes have been translated into proteins, they need to be folded into the correct three-dimensional structure in order to become biologically active. Hsps “chaperone” these proteins to ensure that they fold correctly and interact appropriately with other proteins. If proteins are damaged, Hsps facilitate protein refolding, or, if the damage is irreversible, they target the protein for degradation by the proteasome (the cell’s protein degradation machinery). Hsps ultimately guard the cell against the dangers of protein misfolding and aggregation.
Hsps form large multiprotein complexes with other chaperones and adaptor molecules, which aid in their function. Each Hsp has a range of different target proteins, known as clients, and exerts its chaperone activity upon these clients through cycles of binding and release, driven by the cellular energy source adenosine triphosphate (ATP).
Studies have identified more than 200 potential Hsp90 clients within the cell. Hsp90 is a particularly important chaperone in relation to cancer because many of its client proteins are cancer hallmark-causing signal transduction proteins. They include HER2, c-KIT, AKT, MET, telomerase, and the matrix metalloproteinase MMP-2.
Hsp90 is predominantly found in the cytoplasm in two different isoforms: Hsp90Î± (the heat shock-induced form) and Hsp90Î² (the constitutively active form). However, three other isoforms of Hsp90 exist in the cell. There are two isoforms localized to the endoplasmic reticulum (ER) and the mitochondria and a third membrane-bound form. Hsp90 also has been reported to be secreted into the extracellular matrix. The secreted and membrane-bound forms are thought to have important roles in angiogenesis and metastasis.
Ganetespib (formerly STA-9090; Synta Pharmaceuticals Corp)
This intravenously administered molecule is currently undergoing phase IIb/III investigation in non-small cell lung cancer (NSCLC). The GALAXY trial (Ganetespib Assessment in Lung CAncer with DocetaXel) is a randomized, international study evaluating docetaxel versus ganetespib plus docetaxel in patients with stage IIIb or IV NSCLC.
The drug also is being tested in patients with metastatic hormone-resistant prostate cancer, solid tumors, myeloproliferative disorders, and esophagogastric cancer, among others. Interim data from clinical trials indicate that ganetespib shows promise in the treatment of lung cancer and solid tumors; in a phase I, open-label, dose-escalation study of twice-weekly ganetespib in 36 patients with metastatic solid tumors, there was one partial response and 10 incidences of stable disease, and it was well tolerated.
Clinicaltrials.gov identifiers: NCT01348126; NCT01270880; NCT01183364; NCT00858572; NCT01167114; NCT00688116
Retaspimycin hydrochloride (IPI-504; Infinity Pharmaceuticals)
Also intravenously administered, retaspimycin hydrochloride is currently in phase II trials in combination with docetaxel in patients with NSCLC, and in a phase II trial of patients with previously treated NSCLC. It is also being studied in combination with everolimus in patients with KRAS-mutant NSCLC.
This agent is undergoing investigation in phase I/II trials in patients with NSCLC, HER2- positive advanced breast cancer, gastric cancer, and gastrointestinal stromal tumor (GIST). It is also being studied alone and in combination with trastuzumab in HER2-positive breast cancer and with the proteasomal inhibitor bortezomib in patients with multiple myeloma. In a phase I dose-escalation study, 14% of patients experienced prolonged disease stabilization. It also is administered intravenously.
NCT01124864; NCT01404650; NCT01402401
KW-2478 (Kyowa Hakko Kirin Pharma, Inc)
Phase I/II trials are underway to evaluate the drug in combination with bortezomib in patients with relapsed or refractory multiple myeloma.
BIIB021 (Biogen Idec)
This agent is an orally administered drug that recently completed phase II testing in patients with GIST, and in combination with exemestane in patients with hormone receptor-positive metastatic breast cancer.
BIIB028 (Biogen Idec)
This intravenously administered version recently completed phase I testing in patients with advanced solid tumors.
Debio 0932 (Debiopharm)
Formerly CUDC305 (Curis), the orally administered, small molecule is in phase I trials in patients with advanced solid tumors or lymphoma.
This orally administered version of the inhibitor is undergoing phase I clinical testing in patients with advanced solid tumors.
MPC-3100 (Myrexis, Inc)
Also an orally administered small molecule, MPC-3100 recently completed phase I testing in patients with relapsed or refractory cancer. MPC-3100 also served as parent molecule in the development of MPC-0767, which has better solubility and is more easily formulated. MPC- 0767 is undergoing preclinical testing.
While there are currently no approved Hsp90-targeted drugs, nearly 20 agents are in clinical development, many of which are now reaching more advanced stages in a variety of different cancers. This list includes small-molecule inhibitors targeting the amino-terminal domain of Hsp90, also called the N-terminal.
The important chaperone function of Hsp90 is hijacked during cancer, so that mutated and overexpressed proteins are protected from misfolding and degradation. This promotes cancer survival in its stressful environment and promotes the ability of cancer cells to tolerate the many genetic alterations associated with cancer.
Increased expression of Hsps is common in both solid tumors and hematologic malignancies. In particular, the overexpression of Hsp90 correlates with poor prognosis in breast cancer patients.
Hsp90 is the only chaperone for which targeted cancer agents have been developed thus far. It is considered an attractive therapeutic target because, unlike targeting individual components of signal transduction pathways, Hsp90 agents have the potential to target multiple oncogenic pathways simultaneously, by enabling the cell to degrade a variety of mutant proteins. Although there are currently no approved Hsp90 agents, there are many in clinical development.
The prototypical Hsp90 inhibitor is a naturally occurring antibiotic called geldanamycin. The first generation of Hsp90 inhibitors to enter the clinic were synthetic analogs of geldanamycin. 17-AAG (tanespimycin) entered clinical trials back in 1999 and has been evaluated in phase I, II, and III trials, the latter in combination with the proteasomal inhibitor bortezomib in patients with multiple myeloma. However, the development of 17-AAG has been plagued by problems with poor solubility and significant hepatotoxicity, and it has demonstrated only moderate clinical activity. A second agent, 17-DMAG (alvespimycin) entered clinical trials in 2004 and improved on the solubility and toxicity issues associated with 17-AAG, but still demonstrated poor clinical response.
A second generation of Hsp90 inhibitors is now in development. These are mostly small-molecule inhibitors targeting the amino-terminal ATPbinding domain of Hsp90. (Sidebar) These inhibitors have demonstrated significantly increased potency and reduced toxicity, so hope for Hsp90 inhibitors remains high.
A significant problem with many of these inhibitors has been the development of resistance. Recent studies have indicated that Hsp90 inhibition may actually drive a heat shock response (rapid induction of Hsps in response to stress), which increases the cellular levels of prosurvival chaperones, and is likely one of the primary causes of resistance. Currently in preclinical development are carboxy-terminal inhibitors, which do not induce this response and may help overcome resistance. These molecules are based on the coumarin antibiotic novobiocin.
Several studies have demonstrated improved effectiveness of combining chemotherapy, radiation therapy, or other targeted agents with Hsp90 inhibitors. For example, Hsp90 inhibitors are undergoing phase I trials in combination with the topoisomerase inhibitor irinotecan and phase II trials with the chemotherapeutic agent gemcitabine.
The expression of co-chaperones and posttranslational modification of Hsp90 can affect the efficacy of Hsp90 and its inhibitors. Targeting co-chaperones or their interaction with Hsp90 might prove to be a therapeutically beneficial strategy, especially when combined with Hsp90 inhibitors. For example, p50 is an important co-chaperone of Hsp90 that helps to recruit many of its protein kinase clients. It may therefore provide a target for the design of kinase-specific Hsp90 inhibitors.
The ATP binding pocket of Hsp90, depicted as a ball-and-stick figure atop the surface of the protein, is situated in the N-terminal domain, which has emerged as a target for small-molecule inhibitors.
Hsp90 is subject to several posttranslational modifications, including phosphorylation and acetylation. Studies have shown that Hsp90 function can be impaired by the inhibition of the enzyme histone deacetylase (HDAC). The HDAC inhibitor LBH589 (panobinostat; Novartis) is currently in phase I/II trials and may be a promising combination therapy with Hsp90 inhibitors, to offer a double hit on Hsp90 function.
Development of cell location-specific or isoform-specific inhibitors may also provide a future avenue of research. For example, the cell surface isoform of Hsp90 could prove to be an effective antimetastatic agent, given the proposed role of this isoform in metastasis and invasion.
Now that we have overcome some of the developmental issues with Hsp90 inhibitors, and have a number of agents showing clinical promise, choosing the appropriate indication and identifying patients who may benefit from their use will become increasingly important. Studies have shown the value in choosing cancers driven by Hsp90 client proteins. For example, both HER2 and bcr-abl are Hsp90 clients, and promising results have been observed in HER2-positive breast cancer, acute myelogenous leukemia, and drug-resistant chronic myelogenous leukemia, which have a dependence on the bcr-abl protein.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.