Heat Shock Protein 90: An Emerging Target for Anticancer Therapy

Lecia V. Sequist, MD, MPH
Massachusetts General Hospital Cancer Center, Boston, Massachusetts

A popular strategy for preventing or treating resistance to targeted agents is simultaneous inhibition of multiple targets or blocking a downstream process affected by multiple pathways so that redundancy in signaling can be overcome. The heat shock proteins represent one promising class of targets for such a strategy.

Heat shock proteins (HSPs) are a family of cytoplasmic house keeping proteins that are frequently overexpressed in a variety of cancers and upregulated by cells in response to stress.^97,98 HSPs function as molecular chaperones, clustering together to form complexes that protect and usher other proteins, termed "client proteins," that are unfolded or otherwise damaged back into their normal conformation.^99,100 HSP-90 is one of the most abundant members of the HSP family and has been the leading candidate for HSP-targeted drug development. It is an ATP-dependent enzyme that binds, chaperones, and releases its client proteins in a cyclic manner.¹⁰¹

In cancer cells, HSP-90 stabilizes and protects client proteins, many of which are oncoproteins or key components of oncogene-addicted cellular signaling pathways, including EGFR, HER2, Bcr-Abl, c-Kit, c-Raf, c-MET, p53, HIF-1·, PDGF·, IGF R1, Akt, CDK4, and Src.^100,102 The frequently mutated state of these client proteins and resulting protein instability, coupled with the central role these proteins play in tumor cell biology, highlights the greater role HSP-mediated stabilization may play in malignant cells compared with normal cells.^103,104 When HSP-90 function is impaired, the client proteins are ubiquitinated and degraded via the proteasome pathway.¹⁰⁵ HSP-90 is thus vital for ensuring the integrity of signaling pathways. It also regulates cancer cell proliferation, angiogenesis, metastasis, and the acquisition of the malignant phenotype.¹⁰¹ Blocking HSP-90 function and enhancing degradation of its client proteins is therefore a rational strategy for anticancer therapy. In preclinical models, HSP-90 inhibition has been effective against many tumors defined by a dominant molecular change such as Bcr-Abl CML with an acquired T315I mutation, EGFR-mutated NSCLC with an acquired T790M mutation, and acute myelogenous leukemia (AML) with FLT3 tandem duplications.^102,106,107

17-AAG

Geldanamycin is a naturally occurring benzoquinoid ansamycin antibiotic that binds HSP-90 and prevents its ATPase activity, interrupting its functional cycle.¹⁰⁸ In the presence of gel danamycin, unstable client proteins are dissociated from HSP-90 and shunted towards the proteosome for degradation, leading to cell death.⁹⁸ Geldanamycin in its natural form caused significant hepatotoxicity in dogs and therefore has not been studied in man; however, a modified form, 17-allylamino-17-demethoxygel-danamycin (17-AAG), has been developed.¹⁰⁹ Several phase I studies have been performed in patients with advanced solid tumors, utilizing 17-AAG as a single agent or in combination with various chemotherapeutics.^110-114 17-AAG was typically administered intravenously once or twice a week in these studies. Toxicity has been reasonable, consisting of dehydration, nausea, and mild to moderate liver function abnormalities. Significant hepatotoxicity was not observed, except in one study that utilized continuous twice-weekly administration.¹¹³ Hence, subsequent studies have mandated a break in therapy for each cycle.

Some of the extrahepatic toxicity of 17-AAG may be due to the fact that it is a water-insoluble molecule and requires delivery in dimethyl sulfoxide or Cremophor. In order to circumvent the need for Cremophor and reduce its associated toxicities, several pharmaceutical companies are developing HSP-90 inhibitors that are chemically related to 17-AAG but do not require delivery in Cremophor. Examples include 17-DMAG (Kosan) and IPI-504 (Infinity).^116,117 In addition, synthetic HSP-90 inhibitors not derived from the natural ansamycins are also in the pipelines of many biotech companies.

Results from phase I dose-finding trials with 17-AAG did not demonstrate significant tumor shrinkage in heavily pretreated patients with solid tumors, although stable disease was seen. This, along with the molecular rationale for HSP-90 inhibition, has shifted many of the ongoing studies utilizing this class of drugs towards cancers that are highly dependent on client protein signaling.¹¹⁸ Using this approach, responses or indications of possible clinical benefit have been observed in trastuzumab-resistant, HER2-overexpressing breast cancer using 17-AAG plus trastuzumab, and in imatinib-resistant GIST using IPI-504.^114,119 Results from further studies in cancer-specific populations are expected within the next 1 to 2 years.

< < PREV

NEXT > >