Ganesh Raj - Independent Researcher (original) (raw)

Papers by Ganesh Raj

Emerging therapies in castration resistant prostate cancer

The Canadian Journal of Urology

Prostate cancer continues to be the second leading cause of cancer related mortality in men withi... more Prostate cancer continues to be the second leading cause of cancer related mortality in men within the United States. Despite a consistent decline in prostate cancer mortality over the past two decades, the prognosis for men with metastatic prostate cancer remains poor with no curative therapies. In this article, we review the recently approved and emerging therapeutics for patients with castrate resistant prostate cancer. An advanced search was conducted on the clinicaltrials.gov database, using search terms "metastatic prostate cancer", and limiting results to phase II-IV clinical trials. Clinically relevant emerging therapeutics were selected and a Medline search for supporting documents was performed. An emphasis was placed on newly approved and promising new therapeutics. A total of four Food and Drug Administration approved medications and eight investigational agents were chosen for review. The background and role of these therapeutics in the treatment of prostate c...

Journal of Virology

The transcriptional control region of the human neurotropic polyomavirus JC virus contains a cons... more The transcriptional control region of the human neurotropic polyomavirus JC virus contains a consensus NF-kappa B site which has been shown to enhance both basal and extracellular stimulus-induced levels of transcription of JC promoters. Here, we show that the expression of JC late promoter constructs containing the NF-kappa B site is decreased by cotransfection with the NF-kappa B/rel subunits, p50 and p52, but enhanced by the p65 subunit. However, JC promoter constructs lacking the NF-kappa B site were activated by p52 and p50 and repressed by p65. This antithetical response of the JC promoter mapped specifically to the D domain, which is a target site for the cellular transcription factor, YB-1. Band shift studies indicated that YB-1 and p65 modulate each other's binding to DNA: YB-1 augments the affinity of p65 for the NF-kappa B site, while p65 reduces the binding of YB-1 to the D domain. Results from coimmunoprecipitation followed by Western blot (immunoblot) analysis sugg...

Progesterone receptor modulates ERα action in breast cancer

Nature, 2015

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) functi... more Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Nucleic Acids Research, 2015

in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively a... more in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chro-matin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.

Association of distance to treatment facility on quality and survival outcomes after radical cystectomy for bladder cancer

Urology, 2015

To examine the association of travel distance on quality and survival outcome measures for bladde... more To examine the association of travel distance on quality and survival outcome measures for bladder cancer patients undergoing radical cystectomy for urothelial carcinoma. Four hundred eight patients who underwent radical cystectomy for bladder cancer at a single institution from 2007 to 2013 were included. Multivariate logistic regression was used to determine the association of distance from treatment facility with 90-day mortality and quality-of-care endpoints including neoadjuvant chemotherapy use and time to cystectomy. Survival was assessed by multivariate Cox regression. Fifty-seven percent of patients lived within 50 miles of the treatment facility. There was no difference in time to cystectomy or the utilization of neoadjuvant chemotherapy between patients in different distance groups. On multivariate analysis, distance to treatment facility was the only predictor of 90-day mortality (odds ratio, 11.20; 95% confidence interval, 2.27-55.43; P = .003, for patients traveling &g...

Journal of endourology / Endourological Society, 2014

EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer

Oncotarget, Jan 12, 2015

The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progressi... more The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARγ). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR ...

772 Renal cryosurgery: Worst case scenarios in a porcine model

European Urology Supplements, 2004

European Urology, 2011

BackgroundTargeted molecular therapies (TMTs) previously have demonstrated oncologic activity in ... more BackgroundTargeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases.

Urology, 2003

A 38-year-old man presented for evaluation of new-onset left testicular pain with swelling. Testi... more A 38-year-old man presented for evaluation of new-onset left testicular pain with swelling. Testicular ultrasound revealed multiple intraparenchymal hypoechoic areas in the inferior portion of the left testicle. The patient was treated with a radical inguinal orchiectomy. Pathologic evaluation revealed intratesticular vasculitis, with involvement of medium-sized arteries. This appears to be a rare case of isolated testicular vasculitis, in the absence of any systemic symptoms.

Malignant cystic nephroma

The Canadian journal of urology, 2006

To describe a malignant cystic nephroma in an asymptomatic man. Case report and review of the lit... more To describe a malignant cystic nephroma in an asymptomatic man. Case report and review of the literature. A 60 year old white male presented with an incidentally discovered right perirenal mass. An MRI demonstrated a large perinephric encapsulated mass with diffuse heterogeneity. Patient underwent a radical nephrectomy and retroperitoneal node dissection. Histopathological analyses of the resected specimen revealed malignant cystic nephroma. This represents the first published report of this rare tumor in an adult patient.

International Journal of Surgical Oncology, 2011

Radical cystectomy with pelvic lymphadenectomy represents the gold standard for treatment of musc... more Radical cystectomy with pelvic lymphadenectomy represents the gold standard for treatment of muscle-invasive bladder cancer. Extent of the lymph node dissection and lymph node involvement during radical cystectomy are the most powerful prognostic factors associated with poor oncological outcome. However, the optimal boundaries of the lymph node dissection during a radical cystectomy are controversial. The published literature based mostly on retrospective studies suggests that increasing the number of nodes excised may have therapeutic and diagnostic benefits without significantly increasing the surgical morbidity. These conclusions are, however, influenced by selection and surgeon biases, inconsistencies in the quality of the surgery, and node count variability. In this paper, we establish the current understanding about the utility of lymphadenectomy during a radical cystectomy for muscle-invasive bladder cancer.

Beyond BCG: Gemcitabine

Bladder Cancer, 2009

Page 1. 12 Beyond BCG: Gemcitabine Ganesh V. Raj and Guido Dalbagni Abstract Currently, recurrenc... more Page 1. 12 Beyond BCG: Gemcitabine Ganesh V. Raj and Guido Dalbagni Abstract Currently, recurrence of carcinoma in situ (CIS) after intravesical BCG mandates a radical cystectomy, as BCG-refractory CIS is aggressive with a high propensity for progression. ...

915 Clinical Management of Elderly Patients with Urothelial Carcinoma of the Bladder at an Academic Institution: Does It Meet Current Standard of Care?

European Urology Supplements, 2009

Urology, 2012

To assess the pre-and post-therapy glomerular filtration rate in patients with testicular germ ce... more To assess the pre-and post-therapy glomerular filtration rate in patients with testicular germ cell tumors to determine its effect on the natural history of renal function.

Urology, 2005

Objectives. To evaluate our experience with percutaneous radiofrequency ablation (pRFA) to determ... more Objectives. To evaluate our experience with percutaneous radiofrequency ablation (pRFA) to determine common characteristics of patients with complications, to elucidate possible relative contraindications to therapy. Methods. Medical records of all patients undergoing pRFA were reviewed for demographic data, medical and surgical history, indication, tumor characteristics, and treatment information (complications and management). The group of patients with complications was analyzed for common characteristics. Results. From January 2000 to September 2003, 24 patients (mean age 61 years, 5:1 male/female) with 32 renal tumors were treated with pRFA. Indications for pRFA included prior renal surgery and/or chronic renal insufficiency, significant medical disease, patient choice, von Hippel-Lindau disease, and treatment of a metastasis. Average pretreatment tumor size was 2.4 cm (range 0.5-8.6 cm). Of the 5 patients experiencing complications from pRFA treatment, 2 developed perinephric hematomas, 1 had a persistent urinoma and proximal ureteral stricture, and 2 had colonic injuries. Among patients with complications, 3 of 5 had undergone prior partial nephrectomy on the pRFA-treated kidney. Two of four patients treated for multiple tumors and 57% of patients (4 of 7) with anteriorly located tumors experienced complications. Conclusions. Early experience with pRFA for renal tumor seems promising, but patient selection criteria are evolving. On the basis of our limited experience, we recommend caution when using renal pRFA in patients with prior partial nephrectomy, multiple tumors treated in the same setting, and tumors located anteriorly or centrally. Further clinical experience will help establish guidelines for the use of this powerful technology in the management of renal tumors. UROLOGY 66: 1176-1180, 2005.

Urology, 2005

To determine the effect of prior benign prostate biopsies on the surgical and clinical outcomes o... more To determine the effect of prior benign prostate biopsies on the surgical and clinical outcomes of patients treated with radical perineal prostatectomy for prostate cancer.

Urology, 2007

Percutaneous radiofrequency ablation is a minimally invasive treatment that is currently used to ... more Percutaneous radiofrequency ablation is a minimally invasive treatment that is currently used to treat renal tumors. Despite its minimally invasive nature, potential serious complications can occur. We report the second case of ureteropelvic junction obstruction after radiofrequency ablation that resulted in nephrectomy. The use of radiofrequency ablation should be considered with caution, particularly when tumors are centrally located or abut the renal pelvis. Additional data are needed to better define the indications and contraindications to minimally invasive ablative technologies when used in the clinical setting. UROLOGY 69: 982.e3-982.e5, 2007.

Emerging therapies in castration resistant prostate cancer

The Canadian Journal of Urology

Prostate cancer continues to be the second leading cause of cancer related mortality in men withi... more Prostate cancer continues to be the second leading cause of cancer related mortality in men within the United States. Despite a consistent decline in prostate cancer mortality over the past two decades, the prognosis for men with metastatic prostate cancer remains poor with no curative therapies. In this article, we review the recently approved and emerging therapeutics for patients with castrate resistant prostate cancer. An advanced search was conducted on the clinicaltrials.gov database, using search terms "metastatic prostate cancer", and limiting results to phase II-IV clinical trials. Clinically relevant emerging therapeutics were selected and a Medline search for supporting documents was performed. An emphasis was placed on newly approved and promising new therapeutics. A total of four Food and Drug Administration approved medications and eight investigational agents were chosen for review. The background and role of these therapeutics in the treatment of prostate c...

Journal of Virology

The transcriptional control region of the human neurotropic polyomavirus JC virus contains a cons... more The transcriptional control region of the human neurotropic polyomavirus JC virus contains a consensus NF-kappa B site which has been shown to enhance both basal and extracellular stimulus-induced levels of transcription of JC promoters. Here, we show that the expression of JC late promoter constructs containing the NF-kappa B site is decreased by cotransfection with the NF-kappa B/rel subunits, p50 and p52, but enhanced by the p65 subunit. However, JC promoter constructs lacking the NF-kappa B site were activated by p52 and p50 and repressed by p65. This antithetical response of the JC promoter mapped specifically to the D domain, which is a target site for the cellular transcription factor, YB-1. Band shift studies indicated that YB-1 and p65 modulate each other's binding to DNA: YB-1 augments the affinity of p65 for the NF-kappa B site, while p65 reduces the binding of YB-1 to the D domain. Results from coimmunoprecipitation followed by Western blot (immunoblot) analysis sugg...

Progesterone receptor modulates ERα action in breast cancer

Nature, 2015

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) functi... more Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Nucleic Acids Research, 2015

in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively a... more in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chro-matin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.

Association of distance to treatment facility on quality and survival outcomes after radical cystectomy for bladder cancer

Urology, 2015

To examine the association of travel distance on quality and survival outcome measures for bladde... more To examine the association of travel distance on quality and survival outcome measures for bladder cancer patients undergoing radical cystectomy for urothelial carcinoma. Four hundred eight patients who underwent radical cystectomy for bladder cancer at a single institution from 2007 to 2013 were included. Multivariate logistic regression was used to determine the association of distance from treatment facility with 90-day mortality and quality-of-care endpoints including neoadjuvant chemotherapy use and time to cystectomy. Survival was assessed by multivariate Cox regression. Fifty-seven percent of patients lived within 50 miles of the treatment facility. There was no difference in time to cystectomy or the utilization of neoadjuvant chemotherapy between patients in different distance groups. On multivariate analysis, distance to treatment facility was the only predictor of 90-day mortality (odds ratio, 11.20; 95% confidence interval, 2.27-55.43; P = .003, for patients traveling &g...

Journal of endourology / Endourological Society, 2014

EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer

Oncotarget, Jan 12, 2015

The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progressi... more The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARγ). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR ...

772 Renal cryosurgery: Worst case scenarios in a porcine model

European Urology Supplements, 2004

European Urology, 2011

BackgroundTargeted molecular therapies (TMTs) previously have demonstrated oncologic activity in ... more BackgroundTargeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases.

Urology, 2003

A 38-year-old man presented for evaluation of new-onset left testicular pain with swelling. Testi... more A 38-year-old man presented for evaluation of new-onset left testicular pain with swelling. Testicular ultrasound revealed multiple intraparenchymal hypoechoic areas in the inferior portion of the left testicle. The patient was treated with a radical inguinal orchiectomy. Pathologic evaluation revealed intratesticular vasculitis, with involvement of medium-sized arteries. This appears to be a rare case of isolated testicular vasculitis, in the absence of any systemic symptoms.

Malignant cystic nephroma

The Canadian journal of urology, 2006

To describe a malignant cystic nephroma in an asymptomatic man. Case report and review of the lit... more To describe a malignant cystic nephroma in an asymptomatic man. Case report and review of the literature. A 60 year old white male presented with an incidentally discovered right perirenal mass. An MRI demonstrated a large perinephric encapsulated mass with diffuse heterogeneity. Patient underwent a radical nephrectomy and retroperitoneal node dissection. Histopathological analyses of the resected specimen revealed malignant cystic nephroma. This represents the first published report of this rare tumor in an adult patient.

International Journal of Surgical Oncology, 2011

Radical cystectomy with pelvic lymphadenectomy represents the gold standard for treatment of musc... more Radical cystectomy with pelvic lymphadenectomy represents the gold standard for treatment of muscle-invasive bladder cancer. Extent of the lymph node dissection and lymph node involvement during radical cystectomy are the most powerful prognostic factors associated with poor oncological outcome. However, the optimal boundaries of the lymph node dissection during a radical cystectomy are controversial. The published literature based mostly on retrospective studies suggests that increasing the number of nodes excised may have therapeutic and diagnostic benefits without significantly increasing the surgical morbidity. These conclusions are, however, influenced by selection and surgeon biases, inconsistencies in the quality of the surgery, and node count variability. In this paper, we establish the current understanding about the utility of lymphadenectomy during a radical cystectomy for muscle-invasive bladder cancer.

Beyond BCG: Gemcitabine

Bladder Cancer, 2009

Page 1. 12 Beyond BCG: Gemcitabine Ganesh V. Raj and Guido Dalbagni Abstract Currently, recurrenc... more Page 1. 12 Beyond BCG: Gemcitabine Ganesh V. Raj and Guido Dalbagni Abstract Currently, recurrence of carcinoma in situ (CIS) after intravesical BCG mandates a radical cystectomy, as BCG-refractory CIS is aggressive with a high propensity for progression. ...

915 Clinical Management of Elderly Patients with Urothelial Carcinoma of the Bladder at an Academic Institution: Does It Meet Current Standard of Care?

European Urology Supplements, 2009

Urology, 2012

To assess the pre-and post-therapy glomerular filtration rate in patients with testicular germ ce... more To assess the pre-and post-therapy glomerular filtration rate in patients with testicular germ cell tumors to determine its effect on the natural history of renal function.

Urology, 2005

Objectives. To evaluate our experience with percutaneous radiofrequency ablation (pRFA) to determ... more Objectives. To evaluate our experience with percutaneous radiofrequency ablation (pRFA) to determine common characteristics of patients with complications, to elucidate possible relative contraindications to therapy. Methods. Medical records of all patients undergoing pRFA were reviewed for demographic data, medical and surgical history, indication, tumor characteristics, and treatment information (complications and management). The group of patients with complications was analyzed for common characteristics. Results. From January 2000 to September 2003, 24 patients (mean age 61 years, 5:1 male/female) with 32 renal tumors were treated with pRFA. Indications for pRFA included prior renal surgery and/or chronic renal insufficiency, significant medical disease, patient choice, von Hippel-Lindau disease, and treatment of a metastasis. Average pretreatment tumor size was 2.4 cm (range 0.5-8.6 cm). Of the 5 patients experiencing complications from pRFA treatment, 2 developed perinephric hematomas, 1 had a persistent urinoma and proximal ureteral stricture, and 2 had colonic injuries. Among patients with complications, 3 of 5 had undergone prior partial nephrectomy on the pRFA-treated kidney. Two of four patients treated for multiple tumors and 57% of patients (4 of 7) with anteriorly located tumors experienced complications. Conclusions. Early experience with pRFA for renal tumor seems promising, but patient selection criteria are evolving. On the basis of our limited experience, we recommend caution when using renal pRFA in patients with prior partial nephrectomy, multiple tumors treated in the same setting, and tumors located anteriorly or centrally. Further clinical experience will help establish guidelines for the use of this powerful technology in the management of renal tumors. UROLOGY 66: 1176-1180, 2005.

Urology, 2005

To determine the effect of prior benign prostate biopsies on the surgical and clinical outcomes o... more To determine the effect of prior benign prostate biopsies on the surgical and clinical outcomes of patients treated with radical perineal prostatectomy for prostate cancer.

Urology, 2007

Percutaneous radiofrequency ablation is a minimally invasive treatment that is currently used to ... more Percutaneous radiofrequency ablation is a minimally invasive treatment that is currently used to treat renal tumors. Despite its minimally invasive nature, potential serious complications can occur. We report the second case of ureteropelvic junction obstruction after radiofrequency ablation that resulted in nephrectomy. The use of radiofrequency ablation should be considered with caution, particularly when tumors are centrally located or abut the renal pelvis. Additional data are needed to better define the indications and contraindications to minimally invasive ablative technologies when used in the clinical setting. UROLOGY 69: 982.e3-982.e5, 2007.