Src as a therapeutic target in men with prostate cancer and bone metastases.
While responsive to androgen ablation in its early stages, prostate cancer eventually becomes castration-resistant and metastasizes preferentially to bone. Once this happens, the disease carries considerable morbidity and is incurable. The process of bone metastasis involves a complex interplay between tumour and bone tissue. The eventual characteristic clinical presentation of disorganized osteoblastic bone lesions is preceded by a facilitatory osteoblastic phase; an osteoblastic component then continues to underlie the process. Increasing evidence has shown a ubiquitous role for Src (a proto-oncogene tyrosine-protein kinase) in multiple tumour and bone-signalling processes involved in prostate tumour progression, driving proliferation, survival, migration and transition to androgen-independent growth. It is also intimately involved in positively regulating osteoclast physiology. As such, this molecule represents an attractive target for managing progressing prostate cancer. Encouraging results have been obtained in preclinical and clinical studies using Src inhibitors like AZD0530 and dasatinib. Both compounds reduced markers of bone resorption, in patients with cancer and those with advanced castration-resistant prostate cancer, respectively. Moreover, because Src is central to many mechanisms thought to be responsible for the development of castration resistance, adding Src inhibitors to a treatment regimen might reverse this phenomenon. As a result, many Src inhibitors are in preclinical development. This review explores Src inhibition as a strategy for managing bone metastasis in prostate cancer, with a particular focus on targeting the critical osteoclastic response. Other emerging and novel approaches are also considered.
Saad
Fred
F
CHUM, University of Montreal, Montreal, Quebec, Canada. fredsaad@videotron.ca
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D000069439:Dasatinib; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D000970:Antineoplastic Agents; D052117:Benzodioxoles; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D011799:Quinazolines; D011944:Receptors, Androgen; D013844:Thiazoles; C515233:saracatinib; D019061:src-Family Kinases; D000069439:Dasatinib