Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.

In Vivo Models for Prostate Cancer Research.

In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States-almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model. 2D cell lines, 3D organoids and spheroids, xenografts and allografts, and patient derived models are also included. The major applications, advantages and disadvantages, and ease of use and cost are unique to each type of model, but they all make it easier to translate the tumor progression that is seen in the mouse prostate to the human prostate. Although both human and mouse prostates are androgen-dependent, the fact that the native, genetically unaltered prostate in mice cannot give rise to carcinoma is an especially critical component of PCa models. Thanks to the similarities between the mouse and human genome, our knowledge of PCa has been expanded, and will continue to do so, through models of PCa.

Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma.

The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.

Incidental computed tomographic bladder wall abnormalities: harbinger or herring?

OBJECTIVE: To evaluate the outcomes of incidental radiographically identified bladder wall abnormalities in the absence of other urologic indications for evaluation. METHODS: All screening cystoscopy evaluations performed at our center over 4 years were identified using surgical logs. We identified patients for whom cystoscopy was performed for a radiographic bladder wall abnormality, defined as diffuse bladder wall thickening, focal bladder wall thickening, or intraluminal bladder mass. Patients with other indications for cystoscopy such as previous bladder cancer, pelvic radiation, or hematuria were excluded. The outcomes including any relevant biopsy or malignant diagnosis were recorded. RESULTS: A total of 2483 cystoscopies were performed in 1418 unique patients, with 34 (2%) performed for radiographic bladder wall abnormalities in the absence of other indications for cystoscopy. Eleven of 34 patients (32.4%) were evaluated for diffuse bladder wall thickening, of which 2 had high-grade carcinoma. Fifteen patients (44.1%) had focal bladder wall thickening, all negative at cystoscopy. Four of the 8 patients (23.5%) evaluated for bladder mass had disease (1 high grade, 3 low grade). CONCLUSION: Although generally nonspecific for malignancy, incidental radiographic finding of bladder wall abnormality led to diagnosis of urothelial carcinoma in >15% of our patients including 3 worrisome tumors. This finding argues for routine cystoscopy in patients with radiographic bladder wall abnormality even in the absence of hematuria.

Radical prostatectomy versus observation for localized prostate cancer.

BACKGROUND: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

Basal cell carcinoma of the prostate: a case report.

A 69-year-old man presented with gross hematuria and irritative urinary symptoms. He underwent transurethral resection of his prostate. The prostate chips revealed 70% poorly differentiated carcinoma with neuroendocrine features, initially read as small cell carcinoma, later as basal cell carcinoma. PSA at this time was 0.3. He received 4 cycles of etoposide and cisplatin. After which, rebiopsy of the prostate showed tumor consistent with poorly differentiated basal cell carcinoma. Given progression on chemotherapy, decision was made to proceed with radical prostatectomy. Metastatic workup was negative. Gross extraprostatic invasion was noted but lymph nodes were free of metastatic disease.

The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer.

BACKGROUND: Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. Ninety percent of men with prostate cancer are over aged 60 years, diagnosed by early detection with the prostate specific antigen (PSA) blood test and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy and interstitial radiation therapy (brachytherapy) and androgen deprivation. Little is known about the relative effectiveness and harms of treatments due to the paucity of randomized controlled trials. The VA/NCI/AHRQ Cooperative Studies Program Study #407: Prostate cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. METHODS: We describe the study rationale, design, recruitment methods and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy versus watchful waiting conducted in Scandinavia. RESULTS: We screened 13,022 men with prostate cancer at 52 United States medical centers for potential enrollment. From these, 5023 met initial age, comorbidity and disease eligibility criteria and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African-American. Approximately 85% reported they were fully active. The median prostate specific antigen (PSA) was 7.8 ng/mL (mean 10.2 ng/mL). In three-fourths of men the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade and tumor stage, approximately 43% had low risk, 36% had medium risk and 20% had high-risk prostate cancer. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the U.S. and quite different from men in the Scandinavian trial. CONCLUSIONS: PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared to watchful waiting for men with predominately PSA detected clinically localized prostate cancer.

Higher than expected association of clinical prostate and bladder cancers.

PURPOSE: In this study we evaluated the risk of a second malignancy of the bladder or prostate in patients with a previous diagnosis of prostate cancer (PCa) or urothelial cancer (TCC). MATERIALS AND METHODS: We retrospectively analyzed all cases of PCa and TCC diagnosed between January 1996 and June 2003. Only PCa diagnosed due to abnormal digital rectal examination or increased prostate specific antigen were included. All patients with TCC presented with hematuria or irritative voiding symptoms and the diagnoses were confirmed with a tissue diagnosis. The incidence of lung, colon and renal cancers was also analyzed. RESULTS: A total of 816 men were diagnosed with PCa and/or TCC. Of 673 men initially diagnosed with PCa 21 had TCC. Of 149 men initially diagnosed with TCC 18 had PCa. Average age at PCa and TCC diagnosis +/- SD was 68.2 +/- 7.9 and 68.2 +/- 10.4 years, respectively. The standardized incidence ratio (SIR) of TCC in patients with PCa (SIR 4.31, 95% CI 2.411 to 7.110) and of PCa in patients with TCC (SIR 3.83, 95% CI 1.911 to 6.858) was significantly increased. There was no statistical significant difference in SIR for TCC in men with or without radiotherapy. SIR for lung, renal or colon cancer was not significantly different from what was expected. CONCLUSIONS: Patients with PCa have higher incidence of bladder cancer and those with bladder cancer have a higher incidence of PCa. This study has clinical implications in the care of these patients and it may stimulate research interest that may identify common pathways of carcinogenesis.

Higher than expected association of clinical prostate and bladder cancers.

PURPOSE: In this study we evaluated the risk of a second malignancy of the bladder or prostate in patients with a previous diagnosis of prostate cancer (PCa) or urothelial cancer (TCC). MATERIALS AND METHODS: We retrospectively analyzed all cases of PCa and TCC diagnosed between January 1996 and June 2003. Only PCa diagnosed due to abnormal digital rectal examination or increased prostate specific antigen were included. All patients with TCC presented with hematuria or irritative voiding symptoms and the diagnoses were confirmed with a tissue diagnosis. The incidence of lung, colon and renal cancers was also analyzed. RESULTS: A total of 816 men were diagnosed with PCa and/or TCC. Of 673 men initially diagnosed with PCa 21 had TCC. Of 149 men initially diagnosed with TCC 18 had PCa. Average age at PCa and TCC diagnosis +/- SD was 68.2 +/- 7.9 and 68.2 +/- 10.4 years, respectively. The standardized incidence ratio (SIR) of TCC in patients with PCa (SIR 4.31, 95% CI 2.411 to 7.110) and of PCa in patients with TCC (SIR 3.83, 95% CI 1.911 to 6.858) was significantly increased. There was no statistical significant difference in SIR for TCC in men with or without radiotherapy. SIR for lung, renal or colon cancer was not significantly different from what was expected. CONCLUSIONS: Patients with PCa have higher incidence of bladder cancer and those with bladder cancer have a higher incidence of PCa. This study has clinical implications in the care of these patients and it may stimulate research interest that may identify common pathways of carcinogenesis.

Carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss.

We report a case involving a 45-year-old man with a 12-year history of Wegener granulomatosis, who developed a carcinosarcoma of the urinary bladder after long-term cyclophosphamide therapy. Cyclophosphamide is well recognized as an etiologic agent for urothelial carcinoma of the urinary bladder. However, only 5 cases of carcinosarcoma of the urinary bladder following cyclophosphamide therapy have been reported. We used loss of heterozygosity studies and microsatellite markers to define the molecular basis of this rare neoplasm. These studies revealed evidence supporting a monoclonal origin for the 2 components of this tumor. We also demonstrated allelic loss of chromosome 9p. This loss associated with carcinosarcoma of the urinary bladder is in agreement with previous studies, suggesting a possible role for the tumor suppressor gene p16 in the pathogenesis of this tumor.