Advanced Bladder Cancer Patients Research Articles

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

For several decades, chemotherapy regimens for advanced urothelial cancer of the urinary bladder have not changed, and they include methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) and gemcitabine and cisplatin (GC) with similar efficacy and relatively less toxicity (1). Moreover, there are a few second-line chemotherapeutic agents demonstrating substantial therapeutic responses in patients who are resistant to platinum-based treatments (2). Although the novel targeted agents may offer alternative therapeutic options, their efficacies are still limited and further investigations are needed (3). Recently, many researchers have shown great interest in the role of local and systemic immune responses, which interplay with cancer cells, as a novel therapeutic target (4).

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

Durvalumab (MEDI4736; anti-PD-L1 inhibitor): to shed light on the treatment of advanced urothelial bladder cancer patients refractory to systemic chemotherapy

Characterization of urothelial carcinoma with seminal vesicle involvement in locally advanced bladder cancer.

440 Background: Muscle-invasive bladder cancer is associated with poor clinical outcomes, especially in locally advanced (pT4) disease. There is a paucity of data, however, regarding the clinical impact of seminal vesicle (SV) involvement. Therefore, we sought to characterize clinicopathologic features of patients with urothelial carcinoma involving seminal vesicles, and evaluate clinical outcomes in patients with locally advanced (pT4) bladder cancer with or without SV involvement. Methods: After institutional review board (IRB) approval, we retrospectively identified all men with pT4 (per the 7th edition of the AJCC Cancer Staging Manual) bladder cancer who underwent radical cystectomy between 2002 and 2013 at a single large academic institution. Clinicopathologic and follow-up data for all patients were obtained from the electronic medical record. The presence or absence of divergent differentiation, including aggressive forms (plasmacytoid, nested, micropapillary, and sarcomatoid), was recorded. Estimates of overall survival (OS) were compared by plotting Kaplan-Meier curves and using log-rank test. Results: A total of 62 patients were eligible for analysis. The median age and follow-up duration were 72 (range: 46 – 87) years and 12 (range: 0 – 141) months respectively. SV involvement was present in 17.7% (11/62) of patients. The frequency of divergent differentiation (including aggressive forms), angiolymphatic invasion, nodal disease (pN1-3), and positive soft tissue margins was relatively higher among those with SV involvement (not significant, all p >0.05). The 1 and 2-year OS for patients with SV involvement were 32.7% and 0% respectively, compared with 51.0 % and 24.9% respectively for patients without SV involvement. There was no statistically significant difference between the median OS of men with and without SV involvement (9 vs. 13 months, respectively; p = 0.19). Conclusions: In this relatively limited sample size cohort, we did not observe any difference in the overall survival of locally advanced bladder cancer patients with and without SV involvement.

Pretreatment Neutrophil-to-Lymphocyte Ratio Can Predict the Prognosis in Bladder Cancer Patients Who Receive Gemcitabine and Nedaplatin Therapy.

Introduction and Objectives. Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a simple marker of the systemic inflammatory response in critical care patients. We previously assessed the utility of NLR as a biomarker to predict tumor recurrence and cancer death in bladder cancer patients who underwent radical cystectomy. In this study, we evaluated the prognostic impact of NLR in bladder cancer patients who received gemcitabine and nedaplatin (GN) chemotherapy. Methods. A total of 23 patients who received GN chemotherapy for advanced bladder cancer were enrolled in this study. The cut-off point of NLR according to the sensitivity and specificity levels was derived from the area under receiver operator characteristics (AUROC) curve plotted for disease progression or overall mortality. Results. The NLR cut-off point was determined as 4.14 for both tumor progression and overall mortality. Median progression-free survival (PFS)/overall survival (OS) in the higher NLR group (NLR ≥ 4.14) and lower NLR group (NLR < 4.14) were 194/468 days versus 73/237 days, respectively. Kaplan-Meier analysis showed that higher NLR significantly correlated with poorer PFS (p = 0.011) and OS (p = 0.045). Conclusions. NLR may serve as a new biomarker to predict responses to GN-based chemotherapy in advanced bladder cancer patients and/or their prognosis.

Advanced small cell carcinoma of the bladder: clinical characteristics, treatment patterns and outcomes in 960 patients and comparison with urothelial carcinoma.

To describe the clinical characteristics, treatment patterns and outcomes in advanced small cell bladder cancer (aSCBC) patients and compare to those with urothelial carcinoma (UC). Individuals in the National Cancer Data Base with a diagnosis of either nodal (TxN+M0) or distant metastatic (TxNxM1) disease were identified from 1998 to 2010. We assessed the relationships between stage, treatment modalities and survival in the aSCBC cohort and compared these to UC patients. In the 960 patient aSCBC cohort (62% M1), 50% received palliative therapy alone, 68% in M1 versus 21% in M0 groups (P<0.0001). Single modality local therapy (15%) and surgical (21%) or radiation-based (14%) multimodal therapy (MMT) were used in the other 50%. Cystectomy-based MMT was utilized in 45% of N+M0 versus 6.4% of NxM1 patients (P<0.0001). Median overall survival (OS) for aSCBC patients was 8.6months; 13.0months in N+M0 versus 5.3months in NxM1 patients (P<0.0001). Survival was similar between TxN1M0 and TxN2-3M0 patients (14.8months vs. 12.1months, P=0.15). Urothelial carcinoma patients (n=27,796, 45% M1) lived longer compared to aSCBC patients in the N+M0 group (17.3months vs. 13.0months, P=0.0007). There were not clinically significant differences in OS between UC and aSCBC patients in the M1 group. Advanced SCBC is a rare disease with a poor survival and palliative therapy is common, especially in M1 patients. In comparison to UC, the outcomes for aSCBC patients are worse in those with lymph node only involvement but similar in those with distant disease.

FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients.

There is no standard second-line chemotherapy after progression on first-line therapy including gemcitabine and platinum combination in advanced gall bladder cancer patients. So this study was undertaken to assess the efficacy and safety of FOLFOX-4 regimen in this setting. In this observational study, patients with performance status ≤2, who progressed on first-line therapy, were enrolled from May 2010 to June 2014. FOLFOX-4 based treatment was administered until progression, unacceptable toxicity or up to 12 cycles. A total of 66 patients were enrolled in this study. The median age of patients was 52.5 years (32-66 years),of which 24 (36.36%) were males and 42 (63.63%) were females. The median number of cycles could be given were 9.5 (2-12). Only 43.93% patients in this study completed full 12 cycles of chemotherapy. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 39 (59.09%) patients, with complete response in none, partial response in 16 (24.24%), stable disease in 23 (34.84%) and progressive disease in 27 (40.90%) patients. The median progression free survival was 3.9 months; median overall survival was 7.6 months. The main Grade 3/4 side effects seen were hematological in 31.81% (n = 21) and gastrointestinal in 25.75% (n = 17) patients. Majority of patients (46%) had Grade 1/2 peripheral neuropathy. FOLFOX-4 is an effective and well-tolerated regimen as a second-line treatment in advanced gall bladder cancer patients. Further studies are required, especially in the Indian subcontinent.

MicroRNA-203 Is a Prognostic Indicator in Bladder Cancer and Enhances Chemosensitivity to Cisplatin via Apoptosis by Targeting Bcl-w and Survivin.

Resistance to cisplatin-based chemotherapy is a major cause of treatment failure in advanced bladder cancer (BC) patients. There is increasing evidence that microRNAs are involved in the development and progression of BC. However, little is known about the function of microRNAs in predicting the effect of adjuvant chemotherapy on BC survival and regulating response to cisplatin. To address this issue, we employed RT-qPCR to evaluate the clinical significance of miR-203 expression in 108 tissues of BC patients receiving cisplatin-based adjuvant chemotherapy, and performed in vitro studies to explore chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. We found miR-203 levels were significantly lower in BC progression group than non-progression group (P<0.001). ROC curve analysis illustrated miR-203 could significantly distinguish progressed patients from those without progression (P<0.001), yielding an area under the ROC curve of 0.839 (95% CI, 0.756–0.903). Moreover, low miR-203 expression correlated with shortened progression free survival (PFS) and overall survival (OS) of BC patients, and was an independent prognostic factor. Overexpression of miR-203 in 5637 and T24 BC cells could decrease cell viability, enhance cisplatin cytotoxicity, and promote apoptosis. Western blotting and luciferase reporter assay showed Bcl-w and Survivin were direct downstream targets of miR-203. There was also a significant inverse association between miR-203 and Bcl-w or Survivin expression in BC tissues (r = -0.781, -0.740, both P<0.001). In conclusion, decreased miR-203 predicts progression and poor prognosis for BC patients treated with cisplatin-based chemotherapy while miR-203 overexpression can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

2637 Baseline circulating tumor cells (CTC) and serum heat shock protein 27 (Hsp27) levels are increased in advanced bladder cancer (BC) patients with poor prognostic factors: Results from the randomized phase 2 Borealis-1™ trial of first-line gemcitabine/cisplatin plus apatorsen or placebo

2637 Baseline circulating tumor cells (CTC) and serum heat shock protein 27 (Hsp27) levels are increased in advanced bladder cancer (BC) patients with poor prognostic factors: Results from the randomized phase 2 Borealis-1™ trial of first-line gemcitabine/cisplatin plus apatorsen or placebo

Survival benefit of adjuvant radiotherapy in stage III and IV bladder cancer: results of 170 patients.

Background:Radical cystectomy (RC) with or without neoadjuvant chemotherapy is the standard treatment for muscle-invasive bladder cancers. However, the locoregional recurrence rate is still significantly higher for locally advanced cases post-RC. The underuse of postoperative radiotherapy (PORT) in such cases after RC is related mainly to a lack of proven survival benefit. Here we are reporting our long-term Egyptian experience with bladder cancer patients treated with up-front RC with or without conformal PORT.Patients and methods:This retrospective study included 170 locally advanced bladder cancer (T3–T4, N0/N1, M0) patients who had RC performed with or without PORT at Damietta Cancer Institute during the period of 1998–2006. The treatment outcomes and toxicity profile of PORT were evaluated and compared with those of a non-PORT group of patients.Results:Ninety-two patients received PORT; 78 did not. At median follow-up of 47 months (range, 17–77 months), 33% locoregional recurrences were seen in the PORT group versus 55% in the non-PORT group (P<0.001). The overall distant metastasis rate in the whole group was 39%, with no difference between the two groups. The 5-year disease-free survival for the whole group of patients was 53%±11%, which was significantly affected by additional PORT, and 65%±13% compared with 40%±9% for the non-PORT group (P=0.04). The pathological subtypes did not affect 5-year disease-free survival significantly (P=0.9). The 5-year overall survival was 44%±10%. Using multivariate analysis, PORT, stage, and extravesical extension (positive surgical margins) were found to be important prognostic factors for locoregional control. Stage and lymph node status were important prognosticators for distant metastasis control.Conclusion:PORT was found to be a safe and effective tool in decreasing local recurrence rates and improving disease-free survival.

Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study

BackgroundSeventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer.MethodsMTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured.ResultsMTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability.ConclusionsMTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.

Cisplatin-Ineligible and Chemotherapy-Ineligible Patients Should Be the Focus of New Drug Development in Patients With Advanced Bladder Cancer

Figure 1 Therapeutic Regimens Administered in Patients Presenting With Unresectable Locally Advanced or Metastatic Urothelial Carcinoma in the SEER-Medicare Database (N [ 1031) Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced bladder cancer (ABC) based on randomized trials. The median survival with these regimens is 13 to 15 months, and 5% to 15% of patients attain long-term survival. However, cisplatin ineligibility is common because of renal dysfunction (creatinine clearance 70 years (45 of 148 [30.4%]) (P 1⁄4 .05). Moreover, in patients with locally advanced bladder cancer undergoing radical cystectomy, the proportion of patients ineligible for cisplatin because of renal dysfunction ranged from 28% by the CockroftGault formula and 52% by the Jelliffe formula, and an agedependent increase in incidence of renal dysfunction was observed. To better capture the use of cisplatin administration in patients presenting with ABC (unresectable or metastatic disease) in a population database that captures chemotherapy administration more completely through medical claims, we examined the Surveillance, Epidemiology and End Results (SEER)-Medicare linked fee-for-service database. We identified incident ABC patients aged 66 years presenting with the following stages of bladder cancer between 2004 and 2007: T4bN0M0, anyTN1-3M0, and anyTanyNM1. These patients were followed up to December 31, 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used, which was classified as cisplatin based, carboplatin based, no platinum treatment, or no chemotherapy. Descriptive analyses were performed to examine associations between receiving chemotherapy and patient demographics, tumor characteristics, and survival. A total of 1031 patients with ABC met inclusion criteria. The median age was 74 years—69.8% were men and 88.75% were white Americans. When examining by presenting stage, 4.6% were T4bN0M0, 55.3% were anyTN1-3M0, and 40.1% were anyTanyNM1 according to the American Joint Committee on Cancer,

Docetaxel as second line after failure of gemcitabine/cisplatin regimen in advanced and/or metastatic urinary bladder cancer patients in Egypt

Docetaxel as second line after failure of gemcitabine/cisplatin regimen in advanced and/or metastatic urinary bladder cancer patients in Egypt

Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: A large Medicare database study.

4551 Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients (≥66 years) presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use of and overall survival (OS) with chemotherapy regimens employed in elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4bN0M0; Any TN1–N3M0; Any T, Any N, M1 between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between chemotherapy regimen, clinical characteristics and OS. Results: A total of 1,031 patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 4.6% (n=47) were T4bN0M0, 55.3% (n=570) were anyT,N1-3M0 and 40.1% (n=414) were any T, any N, M1. Overall, 20.5% (n=211) received cisplatin, 26.1% (n=269) received carboplatin, 5% (n=52) received no platinum and 48.4% (n=499) received no chemotherapy. There were no differences in regimen according to gender, race, stage and age. The median OS for cisplatin, carboplatin, no platinum and no chemotherapy groups were 1.67, 1.41, 1.5 and 1.41 years, respectively (F=5.36, p&lt;0.001). Patients with Any TN1–N3M0; Any T, Any N, M1 receiving cisplatin had better OS compared to carboplatin. T4bN0M0 patients receiving carboplatin exhibited better OS relative to those receiving cisplatin, but this finding is limited by the small number of patients. Conclusions: Among patients presenting with ABC in the Medicare database aged ≥66 years, only 20.5% received cisplatin and 48.4% received no chemotherapy. Those with distant and nodal metastasis displayed better OS with cisplatin. Further analysis will control for baseline prognostic factors and comorbidities. Drug development in the ABC population, especially the elderly, should focus on chemotherapy-ineligible and cisplatin-ineligible patients.

A phase II study of gemcitabine and oxaliplatin in advanced transitional cell carcinoma of the bladder

Cisplatin-based chemotherapy is recommended for use as first-line treatment for patients with advanced transitional cell carcinoma of the bladder. Unfortunately, 30-50 % of patients are ineligible for cisplatin due to renal insufficiency. Oxaliplatin is a less nephrotoxic platin which can be used for patients with impaired renal function. We carried out a phase II study of gemcitabine (1,200 mg/m²) in combination with oxaliplatin (100 mg/m²) given on days 1 and 14 every 28 days (GEMOX) in predominantly cisplatin-'unfit' stage IV transitional cell bladder cancer patients to determine whether this combination exhibited a clinical activity profile similar to cisplatin plus gemcitabine. Eighteen patients with a median GFR of 49 ml/min were enrolled. GEMOX treatment led to a 36 % response rate in assessable patients. Median progression-free survival was 4.9 months, with a median overall survival (OS) of 10.4 months and a one-year survival rate of 44.4 %. GEMOX in bladder cancer patients exhibited a tolerable side effects profile, with thrombocytopenia as the most frequent grade 3/4 toxicity. These findings suggest that GEMOX is an active combination in advanced bladder cancer patients with reduced renal function.

ERCC1 and XRCC1 expression predicts survival in bladder cancer patients receiving combined trimodality therapy

Combined trimodality therapy, including transurethral resection and platinum-based chemoradiotherapy, has shown promising results for muscle-invasive bladder cancer. However, this type of treatment may decrease survival as a result of delayed cystectomy in patients with non-responding tumors. DNA repair proteins may affect survival of bladder cancer patients receiving combined trimodality therapy, by affecting the perioperative nature of the tumor cells or by repairing DNA damaged by platinum agents and radiation. We investigated the associations of excision repair cross-complementing group 1 (ERCC1), X-ray repair cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with response and survival in 157 locally advanced bladder cancer patients receiving combined trimodality therapy, in order to determine the predictive value of the expression of these proteins in patient selection for therapy. We examined ERCC1, XRCC1 and APE1 expression in tumor specimens using immunohistochemistry. Patients positive for ERCC1, positive for XRCC1 and positive for either ERCC1 or XRCC1, exhibited significantly improved disease-specific survival rates (P=0.023, 0.025 and 0.0091, respectively). In multivariate analysis, combined ERCC1 and XRCC1 expression was independently associated with disease-specific mortality [risk ratio (RR): 0.64; 95% confidence interval (CI), 0.43-0.94 and P=0.024]. Thus, combined ERCC1 and XRCC1 expression may serve as an independent prognostic marker for survival in bladder cancer patients receiving combined trimodality therapy. Prospective studies with a larger sample size are required to confirm these results.

Proportion of elderly patients with advanced bladder cancer receiving cisplatin-based chemotherapy: A large Medicare database study.

276 Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use and pattern of chemotherapy in Medicare fee-for-service elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4b, N0, M0; Any T, N1–N3, M0; Any T, Any N, M1) between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between receiving chemotherapy and patient demographics, and clinical characteristics. Results: A total of 1,031 Medicare FFS elderly patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 40.1% were T4bN0M0, 55.3% were any N1-3M0 and 4.6% were any T, any N, M1. Overall use of chemotherapy occurred in 51.6% of the study patients. Of these patients receiving chemotherapy, carboplatin accounted for 50.6% in the initial treatment, followed by cisplatin in 39.7% and other agents in 9.8%. 37.5% of patients received chemotherapy within 6 months, 14.1% after 6 months, and 48.4% had not receive any chemotherapy over the study period. There were no statistical differences according to gender, race, and age. There were variations in receiving chemotherapy by stage: T4bN0M0 (51%), any T, N1-3, M0 (52.3%) or any T, any N, MI (48.9%), p&lt;0.05. Conclusions: Among elderly patients presenting with ABC in the SEER-Medicare linked database, only 51.6% received chemotherapy and of these only 39.7% received cisplatin. Drug development for this population should focus on chemotherapy-ineligible and cisplatin-ineligible patients. Further analysis will explore practice patterns in prescribing chemo regiments in the initial treatment of ABC and its impacts on patient outcomes.

Abstract 802: A key role for ARF in drug resistance in invasive bladder cancer

Abstract Although most superficial bladder cancers can be removed transurethrally with excellent prognosis, clinical outcome is much more problematic for patients with muscle-invasive disease. Indeed, invasive bladder cancer is a major clinical challenge since it is highly associated with postoperative recurrence and metastasis. Current treatments for those lethal forms of bladder cancer include systemic chemotherapy and molecular targeted therapy; however, survival is poor since most patients develop resistance to the drugs within a short timeframe. Clearly, there is a need to identify novel therapeutic options for invasive bladder cancer as well as a greater understanding of the molecular mechanisms of drug resistance. We have been investigating mechanisms of drug resistance using genetically-engineered mouse models of invasive bladder cancer based on the combinatorial deletion of p53 and Pten in bladder epithelium. p53 and PTEN are frequently inactivated in human bladder cancers, particularly those with poor prognosis. Indeed, allograft tumors established from these mice responded initially to the treatment with cisplatin, docetaxel, or rapamycin but eventually developed resistance. We have observed that these p53; PTEN deficient tumors express robust levels of p19Arf, while targeted deletion of Arf retards the aquisition of resistance following drug treatment. The significance of this expression was further suggested by analysis of a published gene expression profile of human bladder cancers which revealed that high Arf expression is an independent predictor of poor survival of invasive bladder cancer patients. Furthermore, following drug treatment in the mouse model, the Arf-positive, compared to the Arf-negative, tumors were significantly enriched in extracellular matrix/integrin signaling gene signature consistent with activation of downstream PI3K-mTOR pathway, suggesting that a model for drug resistance is via PI3K pathway activation. We have observed similar results in human bladder cancer cell lines either following knock-down of p14Arf in J82 cells that express endogenous p14Arf or following forced expression of p14Arf in ARF-negative UMUC3 human bladder cancer cells, and in both cases it was coincident with deregulated activation of PI3K-mTOR pathway. Thus, we propose that Arf confers drug resistance on bladder cancer by activating PI3K-mTOR pathway, highlighting a potential therapeutic target for advanced invasive bladder cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 802. doi:1538-7445.AM2012-802

554 A KEY ROLE FOR ARF IN DRUG RESISTANCE IN INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVES: Although most superficial bladder cancers can be removed transurethrally with excellent prognosis, clinical outcome is much more problematic for patients with muscle-invasive disease. Indeed, invasive bladder cancer is a major clinical challenge since it is highly associated with postoperative recurrence and metastasis. Current treatments for those lethal forms of bladder cancer include systemic chemotherapy and molecular targeted therapy; however, survival is poor since most patients develop resistance to the drugs within a short timeframe. Clearly, there is a need to identify novel therapeutic options for invasive bladder cancer as well as a greater understanding of the molecular mechanisms of drug resistance. METHODS: We have been investigating mechanisms of drug resistance using genetically-engineered mouse models of invasive bladder cancer based on the combinatorial deletion of p53 and Pten in bladder epithelium. p53 and PTEN are frequently inactivated in human bladder cancers, particularly those with poor prognosis. Indeed, allograft tumors established from these mice responded initially to the treatment with cisplatin, docetaxel, or rapamycin but eventually developed resistance. RESULTS: We have observed that these p53; PTEN deficient tumors express robust levels of p19Arf, while targeted deletion of Arf retards the aquisition of resistance following drug treatment. The significance of this expression was further suggested by analysis of a published gene expression profile of human bladder cancers which revealed that high Arf expression is an independent predictor of poor survival of invasive bladder cancer patients. Furthermore, following drug treatment in the mouse model, the Arf-positive, compared to the Arf-negative, tumors were significantly enriched in extracellular matrix/ integrin signaling gene signature consistent with activation of downstream PI3K-mTOR pathway, suggesting that a model for drug resistance is via PI3K pathway activation. We have observed similar results in human bladder cancer cell lines either following knock-down of p14Arf in J82 cells that express endogenous p14Arf or following forced expression of p14Arf in ARF-negative UMUC3 human bladder cancer cells, and in both cases it was coincident with deregulated activation of PI3K-mTOR pathway. CONCLUSIONS: Thus, we propose that Arf confers drug resistance on bladder cancer by activating PI3K-mTOR pathway, highlighting a potential therapeutic target for advanced invasive bladder cancer patients.

Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer‐initiating cells

For metastatic bladder cancer patients, systemic cisplatin (CDDP)-based combination chemotherapy is the first-line choice of treatment. Although up to 70% of advanced bladder cancer patients initially show good tumor response to this form of combination chemotherapy, over 90% of good responders relapse and eventually die of the disease. According to the cancer stem cell theory, this phenomenon is attributable to the re-growth of bladder cancer-initiating cells (BCICs) that have survived chemotherapy. In this study, the authors have isolated BCICs from cultured human bladder cancer cells to analyze their sensitivity to CDDP and to investigate whether heat-shock protein 90 (Hsp90) inhibitors potentiate the cytotoxicity of CDDP on BCICs. First, the authors have confirmed that a CD44+ subpopulation of 5637 cells met the requirements to be considered tumor-initiating cells. These BCICs were more resistant to CDDP and exhibited more activity in the Akt and ERK oncogenic signaling pathways when compared with their CD44- counterparts. The Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which simultaneously inactivated both Akt and ERK signaling at noncytocidal concentrations, synergistically potentiated the cytotoxicity of CDDP against BCICs by enhancing CDDP-induced apoptosis in vitro. The potentiating effect of 17-DMAG was more effective than a combination of the two inhibitors specific for the Akt and ERK pathways. Finally, the authors have confirmed that, though human BCIC xenografts exhibited resistance to a single administration of CDDP and the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-AAG sensitized them to CDDP in a mouse model. These data encourage clinical trials of Hsp90 inhibitors as they may improve therapeutic outcomes of CDDP-based combination chemotherapy against advanced bladder cancer.

Biomarkers for prognosis and treatment selection in advanced bladder cancer patients

Patients with locally 'advanced' or muscle invasive bladder cancer have higher mortality rates than patients with nonmuscle invasive ('superficial') bladder cancer. Biomarkers can stratify clinical outcomes and thus promise to more accurately prognosticate and thus help assign patients to the appropriate treatments. The aim of this review is to summarize biomarker developments in the past year and to discuss their implications in prognosis and treatment selection in locally advanced bladder cancer. Prognostic biomarkers for bladder cancer are identified at the DNA, RNA and/or protein levels. Some are new markers, whereas others are established markers with new roles in bladder cancer. Markers can report on the risk of disease recurrence or metastasis, or treatment responsiveness and thus are useful in determining 'who to treat' and 'what to treat with'. The list of biomarkers for prognosis and treatment selection for advanced bladder cancer is growing. For most, their clinical relevance is unclear due to their lack of validation in external datasets. MicroRNAs and new techniques including next-generation sequencing offer additional opportunities for biomarker discovery, validation, and clinical applications.