Klein MA

Background: Therapeutic options for men with metastatic castrate-resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including 2 oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (DXT) use and gained expanded approval in 2012 for pre-DXT use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-DXT) and indication was expanded in 2014 (pre-DXT).

Purpose: The objective is to provide insight into the uptake of novel therapeutics and its impact on treatment for patients with mCRPC.

Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Sequencing patterns and treatment duration were assessed. Descriptive statistics were employed.

Results: During the study period, 8,774 patients initiated advanced lines of therapy associated with mCRPC. AA, DXT, and ketoconazole (KCZ) were the most commonly used firstlines of advanced therapies (24.6%, 24.8%, 47.0%, respectively). Between 2008 and 2013, the proportion of mCRPC patients treated with first-line DXT or KCZ dropped from 98% to 38% (P < .0001) while the proportion who received first-line AA increased to 58% (P < .0001). Furthermore, among the 4,169 patients treated with AA between 2011 and 2014, the proportion treated pre-DXT increased from 32% to 80% (P < .0001). AA was also the most common second-line treatment received. Between 2012 and 2013, ENZ use was low but increased dramatically. Among patients who initiated DXT, KCZ, or AA as first-line treatment in 2011/2012, median time on initial treatment was 5.9, 9.1, 11.5 months, respectively.

Conclusions: The FDA approval of AA and ENZ had a significant impact on treatment patterns for men with mCRPC within VA and was associated with decreased use of KCZ and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes.

Background: Therapeutic options for men with metastatic castrate-resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including 2 oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (DXT) use and gained expanded approval in 2012 for pre-DXT use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-DXT) and indication was expanded in 2014 (pre-DXT).

Purpose: The objective is to provide insight into the uptake of novel therapeutics and its impact on treatment for patients with mCRPC.

Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Sequencing patterns and treatment duration were assessed. Descriptive statistics were employed.

Results: During the study period, 8,774 patients initiated advanced lines of therapy associated with mCRPC. AA, DXT, and ketoconazole (KCZ) were the most commonly used firstlines of advanced therapies (24.6%, 24.8%, 47.0%, respectively). Between 2008 and 2013, the proportion of mCRPC patients treated with first-line DXT or KCZ dropped from 98% to 38% (P < .0001) while the proportion who received first-line AA increased to 58% (P < .0001). Furthermore, among the 4,169 patients treated with AA between 2011 and 2014, the proportion treated pre-DXT increased from 32% to 80% (P < .0001). AA was also the most common second-line treatment received. Between 2012 and 2013, ENZ use was low but increased dramatically. Among patients who initiated DXT, KCZ, or AA as first-line treatment in 2011/2012, median time on initial treatment was 5.9, 9.1, 11.5 months, respectively.

Conclusions: The FDA approval of AA and ENZ had a significant impact on treatment patterns for men with mCRPC within VA and was associated with decreased use of KCZ and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes.

Background: Therapeutic options for men with metastatic castrate-resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including 2 oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (DXT) use and gained expanded approval in 2012 for pre-DXT use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-DXT) and indication was expanded in 2014 (pre-DXT).

Purpose: The objective is to provide insight into the uptake of novel therapeutics and its impact on treatment for patients with mCRPC.

Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Sequencing patterns and treatment duration were assessed. Descriptive statistics were employed.

Results: During the study period, 8,774 patients initiated advanced lines of therapy associated with mCRPC. AA, DXT, and ketoconazole (KCZ) were the most commonly used firstlines of advanced therapies (24.6%, 24.8%, 47.0%, respectively). Between 2008 and 2013, the proportion of mCRPC patients treated with first-line DXT or KCZ dropped from 98% to 38% (P < .0001) while the proportion who received first-line AA increased to 58% (P < .0001). Furthermore, among the 4,169 patients treated with AA between 2011 and 2014, the proportion treated pre-DXT increased from 32% to 80% (P < .0001). AA was also the most common second-line treatment received. Between 2012 and 2013, ENZ use was low but increased dramatically. Among patients who initiated DXT, KCZ, or AA as first-line treatment in 2011/2012, median time on initial treatment was 5.9, 9.1, 11.5 months, respectively.

Conclusions: The FDA approval of AA and ENZ had a significant impact on treatment patterns for men with mCRPC within VA and was associated with decreased use of KCZ and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes.

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.