Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and ... more Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevat...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve l... more 175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetect...
HER2+ breast tumors have been shown to express elevated levels of poly (ADPribose) polymerase 1 (... more HER2+ breast tumors have been shown to express elevated levels of poly (ADPribose) polymerase 1 (PARP1) protein. Yet, the mechanism by which PARP1 is upregulated in HER2+ breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2+ breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non-HER2 overexpressing cell line resulted in increased PARP1 protein. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a microRNA (miRNA) levels in breast cancer cells. Ectopic expression of let-7a miRNA resulted in downregulation of PARP1 protein while expression of the let-7a anti-miRNA increased PARP1 protein. Further, luciferase assays demonstrate that let-7a regulates PARP1 via its 3'UTR. Importantly, let-7a was significantly lower in human HER2-positive breast tumors compared to HER2-negative breast tumors and inversely correlated with...
Radiotherapy is a mainstay of treatment for head and neck cancer. However, the morbidity of treat... more Radiotherapy is a mainstay of treatment for head and neck cancer. However, the morbidity of treatment remains a clinical challenge. Molecular profiling has provided further insight into tumor biology and tumor sensitivity to radiation, and this information could be used to personalize treatment. In this review, we discuss published signatures of radiosensitivity and discuss the pathways that may be important in dictating radiation sensitivity. Applications of these signatures could result in less morbidity if dose de-escalation efforts are successful.
Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hype... more Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hyperactivation is a known mechanism of tumorigenesis. The phosphorylation status of the plasma membrane-associated protein myristoylated alanine rich C-kinase substrate (MARCKS) effector domain (ED) was previously established as being important in the sensitivity of lung cancer to radiation. Specifically, when MARCKS ED was in a non-phosphorylated state, lung cancer cells were more susceptible to ionizing radiation and experienced prolonged double-strand DNA breaks. Additional studies demonstrated that the phosphorylation status of MARCKS ED is important for gene expression and in vivo tumor growth. The present study used a peptide mimetic of MARCKS ED as a therapeutic intervention to modulate MARCKS phosphorylation. Culturing A549, H1792 and H1975 lung cancer cell lines with the MARCKS ED peptide led to reduced levels of phosphorylated MARCKS and phosphorylated Akt serine/threonine kinase 1. Further investigation demonstrated that the peptide therapy was able to reduce lung cancer cell proliferation and increase radiation sensitivity. In addition, the MARCKS peptide therapy was able to prolong double-strand DNA breaks following ionizing radiation exposure. The results of the present study demonstrate that a peptide mimetic of MARCKS ED is able to modulate MARCKS phosphorylation, leading to an increase in sensitivity to radiation.
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. P... more Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial ... more Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at...
Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass... more Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass can improve the prediction of noncancer death in men with localized prostate cancer. Materials and Methods Institutional review board approval was obtained, with waiver of informed consent. All patients who underwent radiation therapy for localized prostate cancer between 2001 and 2012 with height, weight, and past medical history documented and who underwent CT that included the L4-5 vertebral interspace were included. On a single axial CT section obtained at the mid-L5 level, the mean CT attenuation of the trabecular bone of the L5 vertebral body (L5HU) was measured. The height-normalized psoas cross-sectional area (PsoasL4-5) was measured on a single CT section obtained at the L4-5 vertebral interface. Multivariable Cox proportional hazards models were used to assess effects on noncancer death. By using parameter estimates from an adjusted model, a prognostic index for prediction of ...
Tremendous technological advancements in prostate radiotherapy have decreased treatment toxicity ... more Tremendous technological advancements in prostate radiotherapy have decreased treatment toxicity and improved clinical outcomes for men with prostate cancer. While these advances have allowed for significant treatment volume reduction and whole-organ dose escalation, further improvement in prostate radiotherapy has been limited by classic techniques for diagnosis and risk stratification. Developments in prostate imaging, image-guided targeted biopsy, next-generation gene expression profiling, and targeted molecular therapies now provide information to stratify patients and select treatments based on tumor biology. Image-guided targeted biopsy improves detection of clinically significant cases of prostate cancer and provides important information about the biological behavior of intraprostatic lesions which can further guide treatment decisions. We review the evolution of prostate magnetic resonance imaging (MRI) and MRI-ultrasound fusion-guided prostate biopsy. Recent advancements in radiation therapy including dose escalation, moderate and extreme hypofractionation, partial prostate radiation therapy, and finally dose escalation by simultaneous integrated boost are discussed. We also review next-generation sequencing and discuss developments in targeted molecular therapies. Last, we review ongoing clinical trials and future treatment paradigms that integrate targeted biopsy, molecular profiling and therapy, and prostate radiotherapy.
Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clin... more Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clinical outcomes compared to HPV-negative disease. However, the biology underlying differences in prognosis remains unclear. We characterized the expression of DNA-protein kinase catalytic subunit (DNA-PkCS ), a key DNA repair protein also associated with tumor progression, in 29 cases of oropharyngeal SCCs and correlated our findings with HPV status and disease recurrence. In addition, we assessed therapeutic response, migration, and invasion in head and neck cancer cell lines upon DNA-PkCS knockdown. DNA-PkCS expression was significantly decreased in HPV-positive compared to HPV-negative oropharyngeal SCC samples. Within the HPV-positive subgroup, DNA-PkCS expression was inversely related to HPV E6 and E7 expression and trended toward significance as a predictor of recurrence. DNA-PkCS knockdown in cell lines resulted in increased sensitivity to cisplatin and radiotherapy and reduced cell...
1,25(OH)2 vitamin D3 (1,25(OH) 2 D) exerts important actions on cellular growth and differentiati... more 1,25(OH)2 vitamin D3 (1,25(OH) 2 D) exerts important actions on cellular growth and differentiation in prostate. These growth effects occur mostly via regulation of the cell cycle. LNCaP, an androgen receptor (AR) positive, androgen-dependent prostate cancer cell line, exhibits the greatest antiproliferative effect upon 1,25(OH) 2 D treatment. Consistent with this growth inhibition, 1,25(OH) 2 D persistently upregulates the cyclin-dependent kinase inhibitor (CKI) p27Kip1, increases the association of p27 with cyclin-dependent kinase 2 (Cdk2), and inhibits phosphorylation of the retinoblastoma protein, which ultimately leads to accumulation of cells in the G1 phase of the cell cycle. In contrast, ALVA31, an AR negative, androgen-independent prostate cancer cell line, are minimally inhibited with 1,25(OH)2 D despite expressing nearly twice the levels of functional vitamin D receptor (VDR) as LNCaP. Because ALVA31 cells lack AR and are resistant to 1,25(OH) 2 D-mediated growth inhibition while LNCaP cells express AR and are the most sensitive to growth inhibition of the prostate cancer cell lines, it has been proposed that the antiproliferative effects of 1,25(OH)2 D involve androgen/AR.In this study, we investigated the mechanism of 1,25(OH)2 D-mediated upregulation of p27 and the possible role of androgens in 1,25(OH) 2 D mediated growth inhibition. 1,25(OH)2 D stabilizes p27 protein by decreasing Cdk2-mediated Thr187-phosphorylation of p27, the critical event that targets p27 for ubiquitin-dependent proteolysis. Cdk2 activation occurs in the nucleus. 1,25(OH)2 D treatment also results in decreased nuclear Cdk2, suggesting that 1,25(OH)2 D may be decreasing Cdk2 activation by keeping it in the cytoplasm.In addition, we found that 1,25(OH)2 D resistance in ALVA31 cells is not due to lack of AR. Heterologous stable expression of AR in ALVA31 cells does not confer enhanced growth inhibition by 1,25(OH)2 D even in the presence of androgens. Also, LNCaP-104R1 cells, an androgen-independent derivative of LNCaP, are profoundly growth inhibited by 1,25(OH)2 D in the absence of androgens or in the presence of antiandrogen Casodex. Similar to LNCaP, 1,25(OH)2 D-mediated antiproliferative effects in LNCaP-104R1 cells involve G1 accumulation and increased p27 associated with Cdk2. Thus, a critical determinant of 1,25(OH)2 D-mediated growth inhibition may be the capacity to regulate Cdk2 localization.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 20, 2016
Accurate detection and characterization of cancers is key for providing timely intervention and e... more Accurate detection and characterization of cancers is key for providing timely intervention and effective treatments. Current imaging technologies are particularly limited when it comes to detecting very small tumors in vivo, i.e. very early cancers or metastases, differentiating viable tumor from surrounding dead tumor tissue, and evaluating tumor metabolism within tissue. Optoacoustic imaging offers potential solutions to these imaging problems because of its ability to image optical absorption properties of both intrinsic tissue chromophores and exogenous contrast agents without the involvement of ionizing radiation. Optoacoustic imaging uses pulsed laser to induce localized thermoelastic expansion that generates acoustic waves detectable by an ultrasound transducer. To date, Multispectral optoacoustic tomography (MSOT) has primarily been utilized in preclinical research; however, its use in translational and clinical research is expanding. This review focuses on the current and ...
Purpose. To compare oncologic outcomes for patients with Gleason score (GS) ≥ 8 prostate adenocar... more Purpose. To compare oncologic outcomes for patients with Gleason score (GS) ≥ 8 prostate adenocarcinoma treated with radical prostatectomy (RP) versus external beam radiotherapy combined with androgen deprivation (RT + ADT). Methods. Between 2001 and 2014, 121 patients with GS ≥ 8 were treated at our institution via RT + ADT (n = 71) or RP (n = 50) with ≥ 1 year of biochemical follow-up. Endpoints included biochemical failure (BF), distant metastasis, and initiation of salvage ADT. Results. The RT + ADT group was older, had higher biopsy GS, and had greater risk of lymph node involvement. All other pretreatment characteristics were similar between groups. Mean number of lymph nodes (LNs) sampled for patients undergoing RP was 8.2 (±6.18). Mean biochemical follow-up for all patients was 61 months. Five-year estimates of BF for the RT + ADT and RP groups were 7.2% versus 42.3%, (p < 0.001). The RT + ADT group also had lower rates of distant metastasis (2% versus 7.8%) and salvage A...
Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and ... more Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevat...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2013
175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve l... more 175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetect...
HER2+ breast tumors have been shown to express elevated levels of poly (ADPribose) polymerase 1 (... more HER2+ breast tumors have been shown to express elevated levels of poly (ADPribose) polymerase 1 (PARP1) protein. Yet, the mechanism by which PARP1 is upregulated in HER2+ breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2+ breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non-HER2 overexpressing cell line resulted in increased PARP1 protein. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a microRNA (miRNA) levels in breast cancer cells. Ectopic expression of let-7a miRNA resulted in downregulation of PARP1 protein while expression of the let-7a anti-miRNA increased PARP1 protein. Further, luciferase assays demonstrate that let-7a regulates PARP1 via its 3'UTR. Importantly, let-7a was significantly lower in human HER2-positive breast tumors compared to HER2-negative breast tumors and inversely correlated with...
Radiotherapy is a mainstay of treatment for head and neck cancer. However, the morbidity of treat... more Radiotherapy is a mainstay of treatment for head and neck cancer. However, the morbidity of treatment remains a clinical challenge. Molecular profiling has provided further insight into tumor biology and tumor sensitivity to radiation, and this information could be used to personalize treatment. In this review, we discuss published signatures of radiosensitivity and discuss the pathways that may be important in dictating radiation sensitivity. Applications of these signatures could result in less morbidity if dose de-escalation efforts are successful.
Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hype... more Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hyperactivation is a known mechanism of tumorigenesis. The phosphorylation status of the plasma membrane-associated protein myristoylated alanine rich C-kinase substrate (MARCKS) effector domain (ED) was previously established as being important in the sensitivity of lung cancer to radiation. Specifically, when MARCKS ED was in a non-phosphorylated state, lung cancer cells were more susceptible to ionizing radiation and experienced prolonged double-strand DNA breaks. Additional studies demonstrated that the phosphorylation status of MARCKS ED is important for gene expression and in vivo tumor growth. The present study used a peptide mimetic of MARCKS ED as a therapeutic intervention to modulate MARCKS phosphorylation. Culturing A549, H1792 and H1975 lung cancer cell lines with the MARCKS ED peptide led to reduced levels of phosphorylated MARCKS and phosphorylated Akt serine/threonine kinase 1. Further investigation demonstrated that the peptide therapy was able to reduce lung cancer cell proliferation and increase radiation sensitivity. In addition, the MARCKS peptide therapy was able to prolong double-strand DNA breaks following ionizing radiation exposure. The results of the present study demonstrate that a peptide mimetic of MARCKS ED is able to modulate MARCKS phosphorylation, leading to an increase in sensitivity to radiation.
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. P... more Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial ... more Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at...
Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass... more Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass can improve the prediction of noncancer death in men with localized prostate cancer. Materials and Methods Institutional review board approval was obtained, with waiver of informed consent. All patients who underwent radiation therapy for localized prostate cancer between 2001 and 2012 with height, weight, and past medical history documented and who underwent CT that included the L4-5 vertebral interspace were included. On a single axial CT section obtained at the mid-L5 level, the mean CT attenuation of the trabecular bone of the L5 vertebral body (L5HU) was measured. The height-normalized psoas cross-sectional area (PsoasL4-5) was measured on a single CT section obtained at the L4-5 vertebral interface. Multivariable Cox proportional hazards models were used to assess effects on noncancer death. By using parameter estimates from an adjusted model, a prognostic index for prediction of ...
Tremendous technological advancements in prostate radiotherapy have decreased treatment toxicity ... more Tremendous technological advancements in prostate radiotherapy have decreased treatment toxicity and improved clinical outcomes for men with prostate cancer. While these advances have allowed for significant treatment volume reduction and whole-organ dose escalation, further improvement in prostate radiotherapy has been limited by classic techniques for diagnosis and risk stratification. Developments in prostate imaging, image-guided targeted biopsy, next-generation gene expression profiling, and targeted molecular therapies now provide information to stratify patients and select treatments based on tumor biology. Image-guided targeted biopsy improves detection of clinically significant cases of prostate cancer and provides important information about the biological behavior of intraprostatic lesions which can further guide treatment decisions. We review the evolution of prostate magnetic resonance imaging (MRI) and MRI-ultrasound fusion-guided prostate biopsy. Recent advancements in radiation therapy including dose escalation, moderate and extreme hypofractionation, partial prostate radiation therapy, and finally dose escalation by simultaneous integrated boost are discussed. We also review next-generation sequencing and discuss developments in targeted molecular therapies. Last, we review ongoing clinical trials and future treatment paradigms that integrate targeted biopsy, molecular profiling and therapy, and prostate radiotherapy.
Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clin... more Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clinical outcomes compared to HPV-negative disease. However, the biology underlying differences in prognosis remains unclear. We characterized the expression of DNA-protein kinase catalytic subunit (DNA-PkCS ), a key DNA repair protein also associated with tumor progression, in 29 cases of oropharyngeal SCCs and correlated our findings with HPV status and disease recurrence. In addition, we assessed therapeutic response, migration, and invasion in head and neck cancer cell lines upon DNA-PkCS knockdown. DNA-PkCS expression was significantly decreased in HPV-positive compared to HPV-negative oropharyngeal SCC samples. Within the HPV-positive subgroup, DNA-PkCS expression was inversely related to HPV E6 and E7 expression and trended toward significance as a predictor of recurrence. DNA-PkCS knockdown in cell lines resulted in increased sensitivity to cisplatin and radiotherapy and reduced cell...
1,25(OH)2 vitamin D3 (1,25(OH) 2 D) exerts important actions on cellular growth and differentiati... more 1,25(OH)2 vitamin D3 (1,25(OH) 2 D) exerts important actions on cellular growth and differentiation in prostate. These growth effects occur mostly via regulation of the cell cycle. LNCaP, an androgen receptor (AR) positive, androgen-dependent prostate cancer cell line, exhibits the greatest antiproliferative effect upon 1,25(OH) 2 D treatment. Consistent with this growth inhibition, 1,25(OH) 2 D persistently upregulates the cyclin-dependent kinase inhibitor (CKI) p27Kip1, increases the association of p27 with cyclin-dependent kinase 2 (Cdk2), and inhibits phosphorylation of the retinoblastoma protein, which ultimately leads to accumulation of cells in the G1 phase of the cell cycle. In contrast, ALVA31, an AR negative, androgen-independent prostate cancer cell line, are minimally inhibited with 1,25(OH)2 D despite expressing nearly twice the levels of functional vitamin D receptor (VDR) as LNCaP. Because ALVA31 cells lack AR and are resistant to 1,25(OH) 2 D-mediated growth inhibition while LNCaP cells express AR and are the most sensitive to growth inhibition of the prostate cancer cell lines, it has been proposed that the antiproliferative effects of 1,25(OH)2 D involve androgen/AR.In this study, we investigated the mechanism of 1,25(OH)2 D-mediated upregulation of p27 and the possible role of androgens in 1,25(OH) 2 D mediated growth inhibition. 1,25(OH)2 D stabilizes p27 protein by decreasing Cdk2-mediated Thr187-phosphorylation of p27, the critical event that targets p27 for ubiquitin-dependent proteolysis. Cdk2 activation occurs in the nucleus. 1,25(OH)2 D treatment also results in decreased nuclear Cdk2, suggesting that 1,25(OH)2 D may be decreasing Cdk2 activation by keeping it in the cytoplasm.In addition, we found that 1,25(OH)2 D resistance in ALVA31 cells is not due to lack of AR. Heterologous stable expression of AR in ALVA31 cells does not confer enhanced growth inhibition by 1,25(OH)2 D even in the presence of androgens. Also, LNCaP-104R1 cells, an androgen-independent derivative of LNCaP, are profoundly growth inhibited by 1,25(OH)2 D in the absence of androgens or in the presence of antiandrogen Casodex. Similar to LNCaP, 1,25(OH)2 D-mediated antiproliferative effects in LNCaP-104R1 cells involve G1 accumulation and increased p27 associated with Cdk2. Thus, a critical determinant of 1,25(OH)2 D-mediated growth inhibition may be the capacity to regulate Cdk2 localization.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 20, 2016
Accurate detection and characterization of cancers is key for providing timely intervention and e... more Accurate detection and characterization of cancers is key for providing timely intervention and effective treatments. Current imaging technologies are particularly limited when it comes to detecting very small tumors in vivo, i.e. very early cancers or metastases, differentiating viable tumor from surrounding dead tumor tissue, and evaluating tumor metabolism within tissue. Optoacoustic imaging offers potential solutions to these imaging problems because of its ability to image optical absorption properties of both intrinsic tissue chromophores and exogenous contrast agents without the involvement of ionizing radiation. Optoacoustic imaging uses pulsed laser to induce localized thermoelastic expansion that generates acoustic waves detectable by an ultrasound transducer. To date, Multispectral optoacoustic tomography (MSOT) has primarily been utilized in preclinical research; however, its use in translational and clinical research is expanding. This review focuses on the current and ...
Purpose. To compare oncologic outcomes for patients with Gleason score (GS) ≥ 8 prostate adenocar... more Purpose. To compare oncologic outcomes for patients with Gleason score (GS) ≥ 8 prostate adenocarcinoma treated with radical prostatectomy (RP) versus external beam radiotherapy combined with androgen deprivation (RT + ADT). Methods. Between 2001 and 2014, 121 patients with GS ≥ 8 were treated at our institution via RT + ADT (n = 71) or RP (n = 50) with ≥ 1 year of biochemical follow-up. Endpoints included biochemical failure (BF), distant metastasis, and initiation of salvage ADT. Results. The RT + ADT group was older, had higher biopsy GS, and had greater risk of lymph node involvement. All other pretreatment characteristics were similar between groups. Mean number of lymph nodes (LNs) sampled for patients undergoing RP was 8.2 (±6.18). Mean biochemical follow-up for all patients was 61 months. Five-year estimates of BF for the RT + ADT and RP groups were 7.2% versus 42.3%, (p < 0.001). The RT + ADT group also had lower rates of distant metastasis (2% versus 7.8%) and salvage A...
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Papers by Eddy Yang