Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.NIH 1RO1CA142805National Research Foundation of Korea (NRF) grant (NRF-2017R1C1B1006072

Clinical Significance of a Large Difference (≥ 2 points) between Biopsy and Post-prostatectomy Pathological Gleason Scores in Patients with Prostate Cancer

We investigated the clinical significance of large difference (≥ 2 points) between biopsy-derived (bGS) and post-prostatectomy Gleason scores (pGS). At 14 medical centers in Korea, 1,582 men who underwent radical prostatectomy for prostate cancer were included. According to the difference between bGS and pGS, the patients were divided into three groups: A (decreased in pGS ≥ 2, n = 30), B (changed in pGS ≤ 1, n = 1,361; control group), and C (increased in pGS ≥ 2, n = 55). We evaluated various clinicopathological factors of prostate cancer and hazards for biochemical failure. Group A showed significantly higher mean maximal percentage of cancer in the positive cores (max%) and pathological T stage than control. In group C, the number of biopsy core was significantly smaller, however, tumor volume and max% were significantly higher and more positive biopsy cores were presented than control. Worse pathological stage and more margin-positive were observed in group A and C than in control. Hazard ratio for biochemical failure was also higher in group A and C (P = 0.001). However, the groups were not independent factors in multivariate analysis. In conclusion, large difference between bGS and pGS shows poor prognosis even in the decreased group. However it is not an independent prognostic factor for biochemical failure

Establishment of Prospective Registry of Active Surveillance for Prostate Cancer: The Korean Urological Oncology Society Database

Purpose: To establish a prospective registry for the active surveillance (AS) of prostate cancer (PC) using the Korean Urological Oncology Society (KUOS) database and to present interim analysis. Materials and Methods: The KUOS registry of AS for PC (KUOS-AS-PC) was organized in May 2019 and comprises multiple institutions nationwide. The eligibility criteria were as follows: patients with (1) pathologically proven PC; (2) pre-biopsy prostate-specific antigen (PSA) ≤20 ng/mL; (3) International Society of Urological Pathology (ISUP) grade 1 or 2 (no cribriform pattern 4); (4) clinical T stage ≤T2c; (5) positive core ratio ≤50%; and (6) maximal cancer involvement in the core ≤50%. Detailed longitudinal clinical information, including multi-parametric magnetic resonance imaging and disease-specific outcomes, was recorded. Results: From May 2019 to June 2021, 296 patients were enrolled, and 284 were analyzed. The mean±standard deviation (SD) age at enrollment was 68.7±8.2 years. The median follow-up period was 11.2 months (5.9–16.8 mo). Majority of patients had pre-biopsy PSA ≤10 ng/mL (91.2%), PSA density <0.2 ng/mL2 (79.7%), ISUP grade group 1 (94.4%), single positive core (65.7%), maximal cancer involvement in the core ≤20% (78.1%), and clinical T stage of T1c or lower (72.9%). Fifty-two (18.3%) discontinued AS for various reasons. Interventions included radical prostatectomy (80.8%), transurethral prostatectomy (5.8%), primary androgen deprivation therapy (5.8%), radiation (5.8%), and focal therapy (1.9%). The mean±SD time to intervention was 8.9±5.2 months. The reasons for discontinuation included pathologic reclassification (59.6%), patient preference (25.0%), and radiologic reclassification (9.6%). Two (4.8%) patients with pathologic Gleason score upgraded to ISUP grade group 4, no biochemical recurrence. Conclusions: The KUOS established a successful prospective database of PC patients undergoing AS in Korea, named the KUOS-AS-PC registry

Characteristics and prognosis of chromophobe non-metastatic renal cell carcinoma: A multicenter study

Objectives: To analyze the characteristics and the prognostic significance of chromophobe renal cell carcinomas (chRCC). Methods: Data about 2981 patients with non-metastatic renal cell carcinomas (RCC) at the time of surgery were retrospectively collected from 26 institutions between 1998 and 2008. All patients had undergone partial or radical nephrectomies. Of the 2981 patients, 2602 patients with conventional RCC (cRCC) and 148 with chRCC were studied. Clinical and pathological parameters were determined in all patients. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed. Results: Patients with chRCC differed significantly from those with cRCC on the following parameters: younger age (P = 0.026), greater female ratio (P < 0.001), and larger tumor diameter (P < 0.001). Both groups were alike with respect to body mass index (P = 0.943), Eastern Cooperative Oncology Group performance status (P = 0.163), T stage (P = 0.375), and Fuhrman`s grade (P = 0.134). The 5-year RFS rates in patients with chRCC and cRCC were 82.7% and 83.3%, respectively (P = 0.762). The 5-year CSS rates in patients with chRCC and cRCC were 88.8% and 92.2%, respectively (P = 0.980). Both groups showed equivalent oncological outcomes in terms of RFS and CSS for cases stratified by T stage and Fuhrman`s grade. In multivariate analysis, the histological subtype was not retained as an independent prognostic variable (RFS: P = 0.893; CSS: P = 0.729). Conclusions: Despite being significantly different from cRCC in terms of several clinical and pathological parameters, chRCC shows equivalent oncological outcomes.Leibovich BC, 2010, J UROLOGY, V183, P1309, DOI 10.1016/j.juro.2009.12.035Waldert M, 2010, EUR UROL, V57, P661, DOI 10.1016/j.eururo.2009.05.009Teloken PE, 2009, J UROLOGY, V182, P2132, DOI 10.1016/j.juro.2009.07.019Stec R, 2009, J EXP CLIN CANC RES, V28, DOI 10.1186/1756-9966-28-134Jemal A, 2009, CA-CANCER J CLIN, V59, P225, DOI 10.3322/caac.20006Capitanio U, 2009, BJU INT, V103, P1496, DOI 10.1111/j.1464-410X.2008.08259.xEichelberg C, 2009, EUR UROL, V55, P851, DOI 10.1016/j.eururo.2009.01.003Amin MB, 2008, AM J SURG PATHOL, V32, P1822Klatte T, 2008, UROL ONCOL-SEMIN ORI, V26, P604, DOI 10.1016/j.urolonc.2007.07.015Tickoo SK, 2008, UROL CLIN N AM, V35, P551, DOI 10.1016/j.ucl.2008.07.001Raj GV, 2008, J UROLOGY, V179, P2146, DOI 10.1016/j.juro.2008.01.101Karakiewicz PI, 2007, J CLIN ONCOL, V25, P1316, DOI 10.1200/JCO.2006.06.1218Pignot G, 2007, UROLOGY, V69, P230, DOI 10.1016/j.urology.2006.09.052Delahunt B, 2007, PATHOLOGY, V39, P459, DOI 10.1080/00313020701570061CAMPBELL SC, 2007, CAMPBELLWALSH UROLOG, P2762Shuch BM, 2006, SEMIN ONCOL, V33, P563, DOI 10.1053/j.seminoncol.2006.06.006Cohen HT, 2005, NEW ENGL J MED, V353, P2477Cindolo L, 2005, CANCER, V104, P1362, DOI 10.1002/cncr.21331Schuetz AN, 2005, J MOL DIAGN, V7, P206Patard JJ, 2005, J CLIN ONCOL, V23, P2763, DOI 10.1200/JCO.2005.07.055LAM JS, 2005, CURR UROL REP, V6, P7Kim H, 2004, HUM PATHOL, V35, P1556, DOI 10.1016/j.humpath.2004.06.011Patard JJ, 2004, J CLIN ONCOL, V22, P3316, DOI 10.1200/JCO.2004.09.104Furge KA, 2004, CANCER RES, V64, P4117Beck SDW, 2004, ANN SURG ONCOL, V11, P71, DOI 10.1245/ASO.2004.06.016EBLE JN, 2004, WHO CLASSIFICATION T, P12GREENE FL, 2002, AJCC CANC STAGING MA, P323Kattan MW, 2001, J UROLOGY, V166, P63Kovacs G, 1997, J PATHOL, V183, P131Delahunt B, 1997, MODERN PATHOL, V10, P537FUHRMAN SA, 1982, AM J SURG PATHOL, V6, P655