Medical Reading

Bone And The Microenvironment In Prostate Cancer - AUA 2006 - Society Of Urologic Oncology Meeting

August 22, 2017

UroToday - The annual meeting of the Society of Urologic Oncology took place on Saturday, May 20, 2006 during the annual American Urological Association Meeting in Atlanta, Georgia. Dr. David Jarrard, University of Wisconsin moderated a session on "Bone and the Microenvironment".

Dr. Michael Cher, Wayne State University gave a lecture on "Proteases, Growth Factors and the Bone Microenvironment in Prostate Cancer". He described the environment of osteoclasts and osteoblasts as a dynamic homeostasis. Proteases are activated in CaP bone metastasis and result in the expansion of bone lesions. Chemokines such as CXCL12 activate signaling pathways (AKT) to result in enhanced bone lesion progression. Transmembrane MMP (MT1-MMP) is a matrix metalloprotease (MMP) shown in mouse models to enhance bone breakdown when overexpressed. MT1-MMP induced shedding of RANK ligand resulting in osteoclastogensesis. Dr. Cher also discussed platelet-derived growth factor (PDGF). CaP autoactivated PDGF D, which then increased the expression of serine proteases and induction of osteoblastic and osteoclastic lesions. He showed an overview model of how all these events can interact in the CaP bone environment.

Dr. Joel Nelson, University of Pittsburgh lectured on "Bone Targeted Therapies in Prostate Cancer". Dr. Nelson reviewed how androgen deprivation results in significant bone loss. About 30 months elapse during the M0 stage of advanced CaP, but this accelerates to about 3 months in stages M1 asymptomatic and M1 symptomatic patients. This rapid disease progression confounds planning of clinical trials. Trial designs for bone target therapies include purely survival and markers for disease progression. Bone markers for disease progression are limited. For Zoledronic Acid trials, pathologic fractures were the primary endpoint. Zoledronic acid is potent, but non-specific in its effects and thus endpoints should be better defined. Atrasentan, the endothelin-1 inhibitor was assessed by bone scan or clinical progression. Unfortunately, bone scans were not performed soon enough (in the first 90 days) and many patient endpoints were missed and did not contribute to the data. Serum markers such as alkaline phosphatase and PSA did show improvement with Atrasentan treatment, but these were not adequate for drug approval. As such, Dr. Nelson said the lessons learned include earlier assessment for disease progression in the face of stage M1 disease and that endpoints should be clinical meaningful, not just those requested by regulatory agencies.

By Christopher P. Evans, M.D.

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