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The Association of the Phosphatidylinositol-3-kinase Pathway to Gleason Score, Prostate-specific Antigen and Pathologic Stage in Prostate Cancer
S474
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Conclusions: We have demonstrated that 31P MRSI can be used as a reliable monitor of the evolution of RILD following PHRT. Since, RILD inhibits hepatic regeneration following PH, the reduced ATP/Pi ratio in the PHRT group indicates persistence of RT-induced hepatic metabolic injury. Further studies are underway to examine whether MRS can assess mitochondrial function and detect the amelioration of RILD following treatment with hepatocyte transplantation. 1. Guha et al., Cancer Res. 1999 Dec 1;59(23):5871– 4.
2412
The Association of the Phosphatidylinositol-3-kinase Pathway to Gleason Score, Prostate-specific Antigen and Pathologic Stage in Prostate Cancer
A.R. Gottschalk,1,2 V. Weinberg,2 P. Carroll,3,2 J. Simko4,2 Radiation Oncology, University of California, San Francisco, CA, 2Comprehensive Cancer Center, University of California, San Francisco, CA, 3Urology, University of California, San Francisco, CA, 4Pathology, University of California, San Francisco, CA
1
Purpose/Objective: The tumor suppressor gene PTEN is one of the most commonly mutated genes found in a variety of human cancers. PTEN is known to negatively regulate signaling through the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. Loss of PTEN causes activation of AKT and is associated with increased proliferation, resistance to death and increased angiogenesis, thereby allowing tumors a theoretic growth advantage. AKT is thought to affect a number of downstream proteins, including p27 and BAD. This investigation examines radical prostatectomy (RP) specimens for several molecular markers involved in the PI3K pathway: PTEN, phospho-serine-473-AKT (pAKT), phospho-serine-112-BAD (pBAD) and p27. A better understanding of the PI3K/AKT signal transduction pathway may prompt the use of these proteins as prognostic markers, initiate the development of new treatment guidelines, and ultimately lead to the development of novel therapies for patients with prostate cancer. Materials/Methods: This is an analysis of 95 patients with newly diagnosed localized prostate cancer and initially treated with RP. The patients were included from low-, intermediate- and high-risk populations. Patients receiving hormonal therapy prior to RP or poorly fixed tissue were excluded from the analysis. Representative tumor sections for each patient were stained with H&E to confirm the Gleason Score (GS) and to determine the quality of the tissue prior to immunohistochemistry (IHC). Each tumor was stained for PTEN, pAKT, pBAD and p27. A single pathologist evaluated the degree of staining in 4 tissue types: stroma, benign tissue, tumor and PIN. Only the tumor staining data are presented here. The analysis of the degree of IHC staining of p27, pAKT, PTEN and pBAD markers in tumor compared to GS, PSA and T stage is presented using chi square statistics to test for association or trend. Results: The distribution of patients was as follows: GS ⬍ 7, 7 and ⬎ 7 were 40%, 25% and 35%, respectively; PSA ⬍ 10, 10 –20 and ⬎ 20 were 54%, 34% and 12%, respectively; stage T2a/b, T2c and T3 were 34%, 36% and 30%, respectively. The most significant findings were observed with pAKT staining in tumor specimens with 17% staining 2⫹ and 10% staining 3⫹. There is a increase in 3⫹ AKT staining with an increase in pGS (GS ⬍ 7, 0%; GS 7, 9% vs GS ⬎ 7, 23%) which is of borderline significance (trend test: p ⫽ 0.06). In addition, there is a significant difference in the frequency of 3⫹ pAKT staining between primary Gleason grades 3 vs. 4 or 5 for tumor samples, 0% vs 24%, respectively (p ⫽ 0.001). When analyzing pre-RP PSA to the tumor markers, there is no difference in the frequency of 3⫹ staining for any tumor marker based upon pre-RP PSA level. Finally, when comparing 3⫹ pAKT staining to pathologic T stage, there is a significant association between stage and 3⫹ AKT staining for tumor samples, with 5% of pT2 tumors and 21% of pT3 tumors, staining 3⫹ for pAKT (p ⫽ 0.02). Conclusions: Increased pAKT staining in tumors is associated with higher GS sum, primary GS and pathologic T stage. These data support the growing body of literature on the importance of PI3K and AKT signaling in prostate caner. Using the UCSF clinical database, we will evaluate the degree of pAKT staining with clinical outcome.
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Conclusions: We have demonstrated that 31P MRSI can be used as a reliable monitor of the evolution of RILD following PHRT. Since, RILD inhibits hepatic regeneration following PH, the reduced ATP/Pi ratio in the PHRT group indicates persistence of RT-induced hepatic metabolic injury. Further studies are underway to examine whether MRS can assess mitochondrial function and detect the amelioration of RILD following treatment with hepatocyte transplantation. 1. Guha et al., Cancer Res. 1999 Dec 1;59(23):5871– 4.
2412
The Association of the Phosphatidylinositol-3-kinase Pathway to Gleason Score, Prostate-specific Antigen and Pathologic Stage in Prostate Cancer
A.R. Gottschalk,1,2 V. Weinberg,2 P. Carroll,3,2 J. Simko4,2 Radiation Oncology, University of California, San Francisco, CA, 2Comprehensive Cancer Center, University of California, San Francisco, CA, 3Urology, University of California, San Francisco, CA, 4Pathology, University of California, San Francisco, CA
1
Purpose/Objective: The tumor suppressor gene PTEN is one of the most commonly mutated genes found in a variety of human cancers. PTEN is known to negatively regulate signaling through the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. Loss of PTEN causes activation of AKT and is associated with increased proliferation, resistance to death and increased angiogenesis, thereby allowing tumors a theoretic growth advantage. AKT is thought to affect a number of downstream proteins, including p27 and BAD. This investigation examines radical prostatectomy (RP) specimens for several molecular markers involved in the PI3K pathway: PTEN, phospho-serine-473-AKT (pAKT), phospho-serine-112-BAD (pBAD) and p27. A better understanding of the PI3K/AKT signal transduction pathway may prompt the use of these proteins as prognostic markers, initiate the development of new treatment guidelines, and ultimately lead to the development of novel therapies for patients with prostate cancer. Materials/Methods: This is an analysis of 95 patients with newly diagnosed localized prostate cancer and initially treated with RP. The patients were included from low-, intermediate- and high-risk populations. Patients receiving hormonal therapy prior to RP or poorly fixed tissue were excluded from the analysis. Representative tumor sections for each patient were stained with H&E to confirm the Gleason Score (GS) and to determine the quality of the tissue prior to immunohistochemistry (IHC). Each tumor was stained for PTEN, pAKT, pBAD and p27. A single pathologist evaluated the degree of staining in 4 tissue types: stroma, benign tissue, tumor and PIN. Only the tumor staining data are presented here. The analysis of the degree of IHC staining of p27, pAKT, PTEN and pBAD markers in tumor compared to GS, PSA and T stage is presented using chi square statistics to test for association or trend. Results: The distribution of patients was as follows: GS ⬍ 7, 7 and ⬎ 7 were 40%, 25% and 35%, respectively; PSA ⬍ 10, 10 –20 and ⬎ 20 were 54%, 34% and 12%, respectively; stage T2a/b, T2c and T3 were 34%, 36% and 30%, respectively. The most significant findings were observed with pAKT staining in tumor specimens with 17% staining 2⫹ and 10% staining 3⫹. There is a increase in 3⫹ AKT staining with an increase in pGS (GS ⬍ 7, 0%; GS 7, 9% vs GS ⬎ 7, 23%) which is of borderline significance (trend test: p ⫽ 0.06). In addition, there is a significant difference in the frequency of 3⫹ pAKT staining between primary Gleason grades 3 vs. 4 or 5 for tumor samples, 0% vs 24%, respectively (p ⫽ 0.001). When analyzing pre-RP PSA to the tumor markers, there is no difference in the frequency of 3⫹ staining for any tumor marker based upon pre-RP PSA level. Finally, when comparing 3⫹ pAKT staining to pathologic T stage, there is a significant association between stage and 3⫹ AKT staining for tumor samples, with 5% of pT2 tumors and 21% of pT3 tumors, staining 3⫹ for pAKT (p ⫽ 0.02). Conclusions: Increased pAKT staining in tumors is associated with higher GS sum, primary GS and pathologic T stage. These data support the growing body of literature on the importance of PI3K and AKT signaling in prostate caner. Using the UCSF clinical database, we will evaluate the degree of pAKT staining with clinical outcome.