Potential barriers to the development of HSP-90 inhibitors as treatments for cancer.

According to the NCI, 211,000 new cases of breast cancer will be diagnosed in 2005 in the US alone and the disease will claim around 40,000 deaths. The majority of these deaths occur subsequent to the development of metastasis, the treatment of which represents an unmet need (see Breast Cancer - Complex Combinations of Old and New). The geldanamycin derivative, 17 allylamino-17-demethoxygeldanamycin (17-AAG) is a natural polyketide and inhibitor of HSP90 with anticancer activity reducing tumor size and the migration of cancer cells in preclinical studies. Kosan Biosciences is currently evaluating 17-AAG in multiple Phase I and Phase Ib clinical trials in collaboration with the NCI. The present study reveals that 17-AAG has osteopenic effects and that against this background activity osteolytic bone metastases, the major metastatic complication of breast cancer, may be exacerbated. This study therefore urges caution in the development of HSP-90 inhibitors and prompts the adjuvant use of bone resorptive agents along side this class.

Breast cancer is one of the most prevalent tumor types, largely affecting women, but also a sm all number of men. According to the NCI, 211,000 new cases of breast cancer will be diagnosed in 2005 in the US alone and the disease will claim around 40,000 deaths. Although the disease is relatively well understood in comparison to other tumor types, significant unmet needs exist (see Breast Cancer - Complex Combinations of Old and New). In particular metastasis represents a significant problem. Indeed the dissemination of tumor cells from their primary site of growth to distant organs is the major cause of morbidity and death among cancer patients

Different cancer types display tend to metastasize to signature organs and in the case of breast cancer, the great majority of patients with advanced disease develop osteolytic metastases. Indeed bone metastases are present in 60% to 80% of patients with metastatic breast cancer. Once tumors have spread to the bone, they frequently do not respond to therapy, with only 20% of breast cancer patients surviving for 5 years after the discovery of bone metastasis. Not only does bone metastasis signal a decline in prognosis it also significantly decreases quality of life as a result of heightened risk of fracture and consequent pain and loss of mobility.

The osteolytic nature of breast cancer metastases results from the recruitment of osteoclasts which are responsible for bone resorption (contrasting with osteoblasts which lay down new bone). Bone destruction can release factors that encourage tumor growth and consequently the process is self-perpetuating. Despite the poor prognosis of metastatic disease clinical options are improving with the current wave of targeted therapies (see Innovative Cancer Therapies). In particular, preliminary data presented at ASCO 2005 reported that the angiogenesis inhibitor Avastin can extend progression-free survival of patients with metastatic breast cancer from 6 to 11 months when added to a standard paclitaxel based regimen.

The heat shock protein family represents one group of molecular targets currently being extensively investigated in relation to a number of diseases including cancer. The heat shock proteins are a group of molecules that have been well preserved through evolution and are thought to serve as a primitive defense against cellular stress. The family can be grouped into 3 major classes based on their approximate molecular weights and degrees of homology. One class comprises several relatively small proteins with molecular weights between 15,000 and 30,000. The most highly conserved class has molecular weights of approximately 70,000. The third class comprises heat shock proteins with molecular weights ranging between 80,000 and 90,000. This latter class, referred to as the HSP90 family, exists in multiple forms in mammalian cells and serves as a molecular chaperone that plays a key role in the conformational maturation of various signaling proteins. This includes oncogenic proteins and since the expression of Hsp90 is increased in cancer Hsp90 inhibitors have been sought as cancer therapeutics. Hsp90 expression correlates with bone metastasis in an in vivo mouse model and inhibitors may therefore block both tumor growth and metastasis.

The geldanamycin derivative, 17 allylamino-17-demethoxygeldanamycin (17-AAG) is a derivative of the naturally occurring ansamycin antibiotic geldanamycin and inhibitor of HSP90 with anticancer activity. Kosan Biosciences is currently evaluating 17-AAG in multiple Phase I and Phase Ib clinical trials in collaboration with the NCI. Kosan plans to initiate Phase I clinical trials of KOS-953 (a novel formulation of 17-AAG) and its second-generation geldanamycin analog.

In their Cancer Res study John Price from St Vincent’s Institute of Medical Research and colleagues investigate the effect of 17-AAG on the biology of MDA-MB-231SA human breast cancer cells. These cells overexpressed both the alpha and the beta isoforms of HSP90 and as with other breast cancer cell lines their proliferation was inhibited by 17-AAG. Likewise 17-AAG also inhibited the migration of MDA-MB-231SA cells towards growth factors suggesting anti-metastatic potential. Despite this potential the Australian group found detrimentally that 17-AAG also increased the incidence and severity of osteolytic bone metastasis in a murine model in which the cancer cells were injected directly into the hearts of mice, a procedure that induced the selective development of bone metastases. The increase in metastatic incidence occurred at the same dose of 17-AAG shown to reduce the growth of tumors growing in the mammary fat pad.

Further investigation demonstrated that the increased incidence of osteolytic bone metastasis following 17-AAG treatment was due at least in part to a stimulation of osteoclast progenitors and consequently osteoclastogenesis. This was a class effect with other HSP90 inhibitors having a similar effect. Osteopenia was seen following 17-AAG treatment of mice even in the absence of MDA-MB-231SA inoculation and it seems reasonable to suggest that against this background of osteopenia the release of factors that target cancer cells to bone and support metastatic growth may be enhanced.

The effect of 17-AAG on osteolytic bone metastasis is of considerable concern not only to the development of this drug but of the HSP90 inhibitor class in general. Careful monitoring of osteolytic lesions is deserved in ongoing and future clinical studies, as is the adjuvant use of agents that target bone resorption, notably the bisphosphonates. This class of drug currently dominates the osteoporosis therapeutics market with 2004 sales of Merck & Co's Fosamax (alendronate), the leading bisphosphonate, exceeding $3 billion. The bisphosphonates have now also become a recognized palliative approach to the treatment of patients with bone metastasis and the use of such therapeutics may be especially warranted alongside HSP90 inhibitors.