Heat Shock Protein 90 (HSP90) was originally proposed as a cancer drug target in the 1990s, though no drug in this class have ever successfully completed a randomized clinical trial, let alone achieve regulatory approval. Despite repeated setbacks, HSP90 inhibitors are poised to find a significant niche in the evolving cancer treatment landscape.
We will provide an overview of the drug class in this free Chimera Blog post, and you can find additional, freely available, archived information such as clinical trial listings, medical conference abstracts and presentations at www.HSP90central.com. Interested in learning more? Consider becoming a Chimera Research Group subscriber to gain access to my complete series of forthcoming articles that will review the history of these drug candidates, assess the competitive landscape, and evaluate investment opportunities levered to the commercial and clinical potential of HSP90 inhibition.
The HSP90 protein is a molecular chaperone, and as such is responsible for the folding, activation, and/or stability of scores of “client” proteins in the cell. While active in normal cells, HSP90 is over-expressed in cancer cells and plays a critical role in maintaining the activation of oncogenic proteins, managing cell stress, and promoting malignant transformation and tumor progression.
The critical involvement of HSP90 in a diverse group of cellular functions allows these drugs to hold promise in cancer therapy via a variety of mechanisms. Virtually all of these applications for HSP90 inhibition have been validated in preclinical studies, but few clinical results are available to date. HSP90 inhibitors may be able to:
- Sensitize cancer cells to treatment with traditional cytotoxic chemotherapy agents
- Overcome resistance to targeted kinase inhibitors (TKIs) that occurs via either mutations or activation of bypass pathways
- Exhibit single agent anti-tumor activity in cancers driven by a predominant, HSP90-addicted oncoprotein such as HER2, ALK, or BRAF.
- Block the accumulation of multiple mutated forms of signaling and regulatory proteins
- Resist resistance – no mutation has ever been described that conferred resistance to an HSP90 inhibitor
Initial clinical studies failed to deliver on the rationale for targeting HSP90. First-generation inhibitors derived from the natural product geldanamycin (**see note below) displayed insufficient potency and unacceptable toxicity. Then, a number of potent second-generation HSP90 inhibitors with “improvements” in medicinal chemistry properties such as solubility and oral bioavailability were found to cause significant ocular toxicity. The HSP90 inhibitor field has survived these major setbacks and stands ready for its next (perhaps last) chance at success. The timing is fortuitous, as these drugs offer the promise of an important role in the evolving cancer therapy landscape that is increasing focused on rational, biology-driven combinations and detailed molecular profiling of patient tumors.
By the time the American Society for Clinical Oncology (ASCO) Annual Meeting draws to a close in June 2012, we will have a class of drugs that are potent HSP90 inhibitors, feature manageable side effect profiles, and have reported single-agent or combination therapy objective responses in a variety of advanced cancers (most notably non-small cell lung cancer, NSCLC). If we don’t make our criteria for inclusion too stringent, we are left with the following list:
- Ganetespib (STA-9090) from Synta Pharma $SNTA
- AUY922 from Novartis $NVS and Vernalis
- Retaspimycin HCl (IPI-504) from Infinity Pharma $INFI
- AT13387 from Astex Pharma $ASTX
- Debio0932 from Debiopharm and Curis $CRIS
As we continue through 2012 and 2013, these drugs will continue to have meaningful clinical trial readouts that seek to confirm the utility of HSP90 inhibitors in oncology drug development. Stay tuned to the Chimera Research Group blog and premium subscriber content for continuous in-depth analysis of this drug class and related investment opportunities.
**The literature in the field designates all molecules derived from geldanamycin as “first-generation” HSP90 inhibitors, such as 17-AAG, 17-DMAG, and other variations. At this point, all other fully or semi-synthetic drugs in the class are referred to as “second-generation” inhibitors. IPI-504 is the only first-generation HSP90 inhibitor still under active development.