Heat shock protein 90 targeting therapy

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a role in stabilizing and activating more than 200 client proteins. It is required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Since the initial discovery of the first Hsp90 inhibitor in the 1970s, multiple phase II and III clinical trials of several Hsp90 inhibitors have been undertaken. This review provides an overview of the current status on clinical trials of Hsp90 inhibitors and future perspectives on novel anticancer strategies using Hsp90 inhibitors

A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) associated renal cell carcinoma (RCC) is an aggressive form of type 2 papillary RCC caused by deficiency of the fumarate hydratase gene. For patients with metastatic disease, no standard treatment has been established with dismal prognosis. We report a case of metastatic HLRCC-associated RCC in a 65-year-old Japanese male whose clinical features mimicked advanced renal pelvic cancer. A durable response was achieved with a sequence of axitinib and nivolumab after cytoreductive and diagnostic nephrectomy. Their potential therapeutic roles in the management of metastatic HLRCC-associated RCC have been discussed based on its molecular and biological backgrounds

Case Reports of TFE3-Rearranged Renal Cell Carcinoma: FDG-PET Uptake Might Help Diagnosis

Translocation and transcription factor E3 (TFE3)-rearranged renal cell carcinoma (RCC) is a rare subtype of RCCs characterised by the fusion of the TFE3 transcription factor genes on chromosome Xp11.2 with one of the multiple genes. TFE3-rearranged RCC occurs mainly in children and adolescents, although middle-aged cases are also observed. As computed tomography (CT)/magnetic resonance imaging (MRI) findings of TFE3-rearranged RCC overlap with those of other RCCs, differential diagnosis is often challenging. In the present case reports, we highlighted the features of the fluorine-18-labelled fluorodeoxyglucose positron emission tomography with CT (FDG PET-CT) in TFE3-rearranged RCCs. Due to the rarity of the disease, FDG PET-CT features of TFE3-rearranged RCC have not yet been reported. In our cases, FDG PET-CT showed high standardised uptake values (SUVmax) of 7.14 and 6.25 for primary tumours. This might imply that TFE3-rearranged RCC has high malignant potential. This is conceivable when the molecular background of the disease is considered in terms of glucose metabolism. Our cases suggest that a high SUVmax of the primary tumour is a clinical characteristic of TFE3-rearranged RCCs

ErbB2 and NFκB Overexpression as Predictors of Chemoradiation Resistance and Putative Targets to Overcome Resistance in Muscle-Invasive Bladder Cancer

Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC

Impact of sarcopenia in the management of urological cancer patients

<p><b>Introduction</b>: Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, develops as a consequence of the progression of cancer cachexia. Recent studies suggest that sarcopenia may be used as a biomarker in the management of patients with several cancers.</p> <p><b>Areas covered</b>: In this article, the authors review 1) the methods to simply and optimally evaluate and define sarcopenia using computed tomography images in daily clinical practice and 2) the impact of sarcopenia in the management of urological cancers, specifically focusing on the usefulness in predicting treatment-related complications and prognosis. The authors also discuss the prognostic importance of changes in skeletal muscle mass in the course of treatment and the potential roles of nutritional support and exercise to prevent progression of sarcopenia.</p> <p><b>Expert commentary</b>: Sarcopenia is associated with treatment-related complications and unfavorable prognosis in urological cancer patients. Nutritional support and exercise might be helpful in improving sarcopenia. The impact of these interventions on clinical outcomes would be elucidated by ongoing or future clinical studies.</p

Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

Bladder cancer (BC), the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs), which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory

Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer

Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have a favorable prognosis and quality of life with a preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting the clinical outcomes of chemoradiation-based BPT. The biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, the Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both the chemoradiation response and the prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients