Heat Shock Protein-Based Cancer Drugs

Heat shock proteins (HSP) are cytoplasmic proteins and they function in various intra-cellular processes. They play an important role in protein-protein interactions, including folding and assisting in establishing of proper protein conformation, and prevention of inappropriate protein aggregation. HSP is so named because these proteins were first found in cells that were exposed to high temperatures. HSPs are classified into a series of families, such as HSP60, 70, and 96, based on their molecular mass in kilodaltons. They act like 'chaperones,' making sure that the cell's proteins are in the right shape and in the right place at the right time. HSPs are also believed to play a role in the presentation of pieces of proteins (or peptides) on the cell surface to help the immune system recognize diseased cells. These peptides are called antigens - a term that describes any substance capable of triggering an immune response. HSP technology works by generating HSP-peptide complexes that have been isolated from individual patient's cancer cells. The HSP-peptide contains unique profile of signals or the antigenic fingerprint of the patent's cancer. These unique signals have the capacity to activate the immune system to elicit a powerful anti-tumor response.

Table 4. Heat Shock Protein-Based Cancer Drugs

Heat shock protein 90 (HSP90) is a protein chaperone that binds to several sets of signaling proteins, known as "client proteins." These client proteins include a list of cancer-relevant targets such as mutated p53, Bcr-Abl, Raf-1, ErbB2 and other kinases, as well as steroid hormone receptors. Disruption of the HSP90-client protein complexes leads to proteosome-mediated degradation of client proteins. The polyketide geldanamycin, such as 17-AAG, and its analog, KOS983, bind to HSP90 and cause its dissociation from, and consequently, degradation of, the client proteins. Because the HSP90 client proteins are so important in signal transduction and in transcription (processes critical to the growth and survival of cancer cells), KOS983 may serve as chemotherapeutic agents in a number of cancers. These compounds are synergistic with certain other inhibitors of the signal transduction client proteins, as well as several conventional anticancer agents.

Oncophage, HSP 96 peptide complexes (HSPPC)-96, is an investigational personalized vaccine designed to treat cancers. Oncophage is a vaccine made from individual patients' tumor. Patients have surgery to remove part or all of the cancerous tissue, and a portion of this tissue is shipped overnight to the manufacturing facilities. The HSP-peptide complexes are extracted and purified from each sample. The vaccine is shipped frozen back to the hospital for use when the patient has recovered from surgery. Oncophages to renal cell carcinoma and melanoma are under phase III development.

AG858 consists of autologous heat shock protein 70 (HSP70)-peptide complexes purified from the peripheral blood mononuclear cells of chronic myelogenic leukemia (CML) patients. Antigen-presenting cells (APCs) take up HSPs together with the peptides they chaperone, the accompanying peptides are delivered into the antigen-processing pathways, leading to peptide presentation by major histocompatibility complex (MHC) molecules. T cells recognize the antigenic peptides and are specifically activated against cancer cells bearing these peptides.