Ganetespib, an investigational drug, is a small molecule inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone required for the proper maturation and activation of numerous client proteins. Many of these Hsp90 client proteins play critical roles in cell growth, differentiation, and survival. Relative to normal cells, cancer cells are more reliant on elevated levels of the active form of Hsp90 and, as such, appear to be selectively sensitive to Hsp90 inhibitors, including ganetespib.
In contrast with therapies that target a single oncogene driver, such as ALK or HER2, inhibition of Hsp90 results in the simultaneous disruption of numerous signaling pathways that are critical for tumor cell proliferation and survival. These can be broadly divided into three categories, with distinct anti-cancer applications:
- “Oncogene-addiction”: Certain genetically-defined cancers, such as ALK-positive lung cancer or HER2-positive breast cancer, show a strong dependence on a single mutated or overexpressed Hsp90 client protein. Hsp90 inhibition, by leading to the destabilization of these client proteins, offers a potential approach to treating these cancers that is distinct from kinase inhibitors or antibodies, which bind to the oncogene driver directly. Strong Hsp90 clients that drive oncogene-addicted cancers include ALK, HER2, mutant BRAF and EGFR, androgen receptor (AR), estrogen receptor (ER), and JAK2.
- Resistance: Cancer cells often develop resistance to commonly used anti-cancer treatments such as chemotherapy and radiation therapy. Many of these resistance mechanisms involve cell-cycle checkpoint, DNA repair, and anti-apoptosis pathways, which rely on Hsp90 client proteins including ATR, BCL2, BRCA1/2, CDK1/4, CHK1, survivin, and WEE1. Inhibition of these client proteins supports combining ganetespib with chemotherapy or radiation therapy in order to investigate whether the combination reduces resistance and improves potential clinical activity. In preclinical models of cancer, ganetespib has shown synergistic activity with chemotherapies including docetaxel, paclitaxel, pemetrexed, gemcitabine, cytarabine, irinotecan, etoposide, doxorubicin, carboplatin, cisplatin, and vincristine as well as with radiation therapy.
- Aggressive tumor biology properties, including angiogenesis and metastasis: In advanced stage disease, tumors develop properties that allow them to spread throughout the body. These include the activation of pathways that regulate new blood vessel formation (angiogenesis) and those that enable cancer cell separation from primary tumors and establishment of new tumor lesions (metastasis). Many Hsp90 client proteins play key roles in these processes. These include HIF-1alpha, VEGFR, PDFGR, and VEGF in angiogenesis; and MET, RAF, AKT, MMPs, HIF-1alpha, and IGF-1R in metastasis. In preclinical models, ganetespib has shown an ability to inhibit these proteins and suppress these aggressive properties.
Ganetespib is being evaluated in over 25 clinical trials including trials in lung, breast, colorectal, and hematologic malignancies. To date, approximately 1000 patients have been treated with ganetespib.