Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation via Manipulation of the MDM2 Pathway

Abstract

Abstract : MDM2 is a feedback regulator of p53 and is central to apoptotic response of prostate cancer cells to radiotherapy (RT), androgen deprivation (AD) and RT+AD. Our in vitro measurements demonstrate that antisense-MDM2 (AS-MDM2) significantly enhances apoptosis in response to all of these treatments. The increase in apoptosis translates into an increase in overall cell death, determined using clonogenic assay. An orthotopic model using LNCaP cells injected into the prostates of nude mice corroborates the in vitro findings, particularly in terms of sensitization to AD. The mouse model involves determinations of growth inhibition through measurements of serum PSA and micro-MRI-based tumor volume. Treatment with AS-MDM2+AD and AS-MDM2+AD+RT resulted in the greatest growth inhibition, compared to the other groups. All prostate cancer risk groups stand to benefit. We have also measured MDM2 expression using immunohistochemistry in men treated on Radiation Therapy Oncology group trials 86-10 and 92-02. MDM2 overexpression is associated with a higher rate of distant metastasis and mortality, independent of conventional factors, treatment, ki-67 and p53. We now have a method not only for identifying men at high risk of treatment failure, but also for selecting men who would have the greatest potential benefit from therapeutically targeting MDM2.