Since many decades bone tumours have stimulated imagination
Since many decades, bone tumours have stimulated imagination of researchers and numerous therapeutic alternatives have been proposed [134,135, Fig. 4]. The better knowledge of OPG/RANK/RANKL system leads to the development of peptides mimicking OPG and blocking RANK–RANKL interactions [136–139]. Inhibitors of NF-KB signalling showed interesting anti-resorptive activities [140–143]. The targeting of integrins more specifically αvβ3 strongly reduced the osteolytic process and the development of bone tumours [144–150]. Specific blockade of enzymatic activities has been envisaged with a great success. MMP9 involved in osteoclast migration and its targeting blocked by antisense oligodeoxyribonucleotide strongly affects osteoclast migration and resorption . Cathepsin K, a key cysteine-proteinase related to osteolytic process [152,153], stimulates a huge enthusiasm in the world of bone research. Several companies have then developed chemical inhibitors of cathepsin K to treat malignant and non-malignant bone loss with interesting results [154–157]. Thus, forty-three women suffering from breast metastatic disease have been recently randomized in a double-blind study to evaluate the impact of oral cathepsin K inhibitors [odanacatib 5mg daily for 4 weeks or 4 mg zoledronic CA074 i.v] on bone resorption markers . Odanacatib appeared generally safe and well tolerated and has suppressed osteolytic markers similar to zoledronic acid after 4 weeks of treatment. These results strengthen the therapeutic interest of cathepsin K for oncologic bone loss.
Conclusions Bone tissue massively attracts tumour cells where they find a favourable environment to maintain the stem cell dormancy and where they find a fertile ground for their development. This “fatal attraction” linked to the specific bone niche has boosted therapeutic innovations targeting the tumour cells and/or their microenvironment . During the last past decade, RANK/RANKL axis emerged in bone biology as predominant protagonists of bone remodelling and as therapeutic targets of bone loss diseases. Better knowledge of RANK/RANKL biology will better define their relevance as biomarkers in bone oncology, and a complete cartography of RANK expression will be very useful to predict good responders to anti-RANKL therapies. Although anti-RANKL therapy progressively competes with approaches by bisphosphonates, a lot of prospect including signal transduction inhibitors, peptides or enzymatic inhibitors has been already identified and pre-clinical data as well as clinical trials allow personalised therapies in bone oncology.
Background Following the publication of a number of preclinical studies suggesting that bisphosphonate treatment could significantly impair the growth of osseous breast tumours, and stabilise bone metastases, a number of clinical studies were initiated to evaluate the effects of adjuvant bisphosphonate treatment in newly diagnosed breast cancer patients. Now that many of these studies have reached clinical maturity, their published results have been either positive [1–4] negative [5–8], or even detrimental , (see Table 1). Although certain factors have been suggested to influence the clinical responses noted with bisphosphonate use (Fig. 1), formal demonstration of their association has yet to be determined. Given these conflicting clinical outcomes and the extensive preclinical data that was supposed to support the adjuvant development of these agents, it is time to revisit the published preclinical results in order to determine whether they predicted the current clinical outcomes.
Preclinical studies: Of mice, rats and women?
Factors that may modulate response to bisphosphonate therapy
Bone metastases as a clinical problem Many cancers metastasize to bone, with the most common sites of origin of primary disease being breast, lung, thyroid, kidney, prostate, and malignant melanoma of the skin. The presence of tumor in the bone can lead to local symptoms such as pain, spinal cord compression, and pathologic fracture, as well as systemic effects caused by hypercalcemia. The work-up and treatment of bone metastases requires input and interventions from many medical disciplines, including radiologists, orthopedic surgeons or neurosurgeons, radiation oncologists, medical oncologists, pain medicine specialists, physical medicine and rehabilitation physicians, and palliative care professionals. The delivery of radiation therapy to these patients requires communication and coordination of scheduling with these other specialists. Furthermore, the aggressiveness of treatment must take into account patient factors such as performance status and co-morbidities, tumor factors such as stage and histology, and treatment factors such as sequencing and risks of concurrent therapy [1–3].