The weekend prostate cancer news: February 7, 2009

After yesterday’s glut of interesting new publications, we have only one significant new report today — a review article on the potential of so-called Src inhibitors in the management of metastatic, hormone-refractory disease.

Saad has reviewed this topic in the current issue of BJU International, and the entire review is available on line.

We should first make clear what an Src inhibitor is. Src is an enzyme (strictly known as a “proto-oncogene tyrosine-protein kinase,” but let’s not get too technical) that seems to have a ubiquitous role in many tumor- and bone-signaling processes involved in prostate cancer progression, driving proliferation, survival, migration and transition to androgen-independent growth. Therefore an Src inhibitor is a molecule that can shut down (either completely or partially) the activities of Src.

When prostate cancer starts to spread beyond the prostate, it is usually responsive to androgen deprivation therapy (ADT) in its early stages, but the cancer will eventually become hormone-resistant, and spreads (metastasizes) preferentially to bone. Once this happens, the disease is incurable and has significant potential for additional problems (morbidities) such as deterioration of the bones, bone pain, and fractures.

The process of bone metastasis involves a complex interplay between tumor 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. (An osteoblast is a type of cell that is a precursor to actual bone cells; therefore “osteoblastic” means “relating to the osteoblast.”)

Src is also involved in the regulation of osteoclast physiology. (An osteoclast is a type of cell that gradually breaks down bone and is responsible for resorption of bone into the bloodstream.) Src therefore represents an attractive target for the management of progressive prostate cancer. To date, some encouraging results have been seen in preclinical and clinical studies using such Src inhibitors as the investigational drug AZD0530 and the marketed drug dasatinib (Sprycel®/Bristol-Myers Squibb). Both compounds reduced markers of bone resorption in patients with cancer and in 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.

In this review, Saad discusses Src inhibition as a strategy for managing bone metastasis in prostate cancer, with a particular focus on targeting the critical osteoclastic response. While the “real world” value of Src inhibitors in the management of hormone-refractory prostate cancer is still unknown, it does seem possible that these drugs will be able to offer the ability to extend the time period from failure of classical hormone therapy until chemotherapy or simple pain management (as palliative care) becomes essential. Such an effect could again extend the time period for which men with late stage prostate cancer could live productive and relatively pain-free lives.

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