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

Androgen deprivation (AD) is a common treatment for prostate cancer, yet the mechanisms of action are poorly understood. Radiotherapy (RT) is also often used in the treatment of localized disease and AD+RT in more high risk cases. Our results indicate that MDM2 is central to prostate cancer response to AD, RT, and AD+RT. Our data establish that by reducing the expression of MDM2 with an antisense oligonucleotide (AS-MDM2) the apoptotic response of LNCaP cells in vitro to AD, RT, and AD+RT is increased. The enhancements in apoptosis translated into gains in overall cell death (measured by clonogenic assay) . These interactions were reduced in LNCaP-MST cells that overexpressed MDM2. Preliminary findings in vivo indicate that AS-MDM2 sensitizes LNCaP cells to AD; the experiments are still in progress. We have also found that MDM2 overexpression was evident in 48% of a cohort of locally advanced men treated on Radiation Therapy Oncology Group protocol 86-10, correlated with Gleason score and was associated with a trend for increased distant metastasis. MDM2 is a promising target for enhancing prostate cancer response to AD, RT, and AD+RT, which could potentially impact men with virtually any stage of disease.

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  • "Androgen deprivation (AD) is a common treatment for prostate cancer, yet the mechanisms of action are poorly understood. Radiotherapy (RT) is also often used in the treatment of localized disease and AD+RT in more high risk cases. Our results indicate that MDM2 is central to prostate cancer response to AD, RT, and AD+RT. Our data establish that by reducing the expression of MDM2 with an antisense oligonucleotide (AS-MDM2) the apoptotic response of LNCaP cells in vitro to AD, RT, and AD+RT is increased. The enhancements in apoptosis translated into gains in overall cell death (measured by clonogenic assay) . These interactions were reduced in LNCaP-MST cells that overexpressed MDM2. Preliminary findings in vivo indicate that AS-MDM2 sensitizes LNCaP cells to AD; the experiments are still in progress. We have also found that MDM2 overexpression was evident in 48% of a cohort of locally advanced men treated on Radiation Therapy Oncology Group protocol 86-10, correlated with Gleason score and was associated with a trend for increased distant metastasis. MDM2 is a promising target for enhancing prostate cancer response to AD, RT, and AD+RT, which could potentially impact men with virtually any stage of disease."@en
  • "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."@en
  • "MDM2 is a feedback regulator of p53. We found that MDM2 is central to the apoptotic response of prostate cancer cells to radiotherapy (RT), androgen deprivation (AD) and RT+AD. In vitro measurements in androgen sensitive and insensitive cells revealed that antisense- MDM2 (AS-MDM2) significantly enhanced apoptosis and overall cell death (clonogen survival) in response to all of these treatments. An orthotopic model using wild-type LNCaP cells injected into the prostates of nude mice corroborated the in vitro findings, particularly in terms of sensitization to AD. The mouse model involved determinations of growth inhibition through measurements of serum PSA and 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. We have also measured MDM2 expression using immunohistochemistry in men treated on Radiation Therapy Oncology Group trials 86-10 and 92-02. MDM2 overexpression was 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. Men in all prostate cancer risk groups should benefit."@en

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  • "Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation via Manipulation of the MDM2 Pathway"@en
  • "Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation Via Manipulation of the MDM2 Pathway"@en

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