The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.

BACKGROUND:Prostate cancer is one of the most common cancers in men in Europe. Several classes of agents can be considered for the treatment of metastatic prostate carcinoma, and their use is supported by extensive guidelines. In the treatment of metastatic castration-resistant prostate cancer (mCRPC), it is currently unclear which sequence of systemic therapies is most effective. Currently approved system therapies in the castration-resistant setting generally include hormone-manipulating agents, taxane-based chemotherapies, radioactive agents, or inhibitiors of DNA repair mechanisms. This study aims to summarize real world data of mCRPC therapy. METHODS:Retrospectively, 90 mCRPC patients undergoing treatment at the University Hospital Schleswig-Holstein, Lübeck Campus between February 2006 and March 2020 were identified. The patient data were analyzed for their treatment sequence and disease progression. Due to the inclusion period, the mCRPC therapy sequences studied were limited to: Abiraterone, Cabazitaxel, Docetaxel, Enzalutamide, Lutetium-177-PSMA and Radium-223. The analysis includes the therapy sequences and their duration, clinical information of the respective cohort, overall and cancer-specific survival (OS/CSS) as well as time to second-line therapy in relation to the respective first-line therapy. RESULTS:Approximately two-thirds of patients underwent a true therapy sequence (at least two of the drugs listed above), with this proportion halving by the third line.The majority of patients received the sequence (first/second line) abiraterone/docetaxel (n=13), followed by docetaxel/abiraterone (n=12) and abiraterone/enzalutamid (n=10) and docetaxel/docetaxel (n=8).Within the different docetaxel sequences, first-line (mean 4.7 months ± SD 3.1; median 4.0) and rechallenge (mean 5.3 months ± SD 5.9; median 3.0) therapy durations were the longest. The subjective side effect rate of docetaxel was lower in the second line, so that a better tolerability can be assumed here.The abiraterone/docetaxel sequence was used mainly in patients with metachronous metastases. Among the different sequences of abiraterone, first-line (mean 10.8 months ± SD 10.2; median 9.0) and second-line (mean 10.6 months ± SD 9.0; median 7.0) therapy durations were the longest.The sequence abiraterone/enzalutamide was prescribed mainly to older patients with synchronous metastases. Among the different enzalutamide sequences first-line (mean 9.6 months ± SD 7.1; median 7.0) and rechallenge (mean 11.0 ± SD 0.0; median 11.0) therapy durations were the longest.In contrast, the sequence docetaxel/docetaxel was used mainly in younger patients with a high initial PSA.The evaluation shows a trend that both abiraterone and enzalutamide can account for a survival advantage in the first line. CONCLUSION:Ultimately, an optimal treatment sequence cannot be confidently derived from these data.However, it was found that only a small proportion of patients underwent fourth- or even fifth-line treatment at all. Thus, the focus on first- and second-line in this study seems reasonable. It could be shown in a trend that docetaxel as first-line therapy seems to be disadvantegous regarding OS as well as CSS when compared to abiraterone or enzalutamide. However, due to the small number of patients in this study, a clear significance cannot be derived. Moreover, the subjectively better tolerability of docetaxel in the second-line setting could provide an impetus for treatment planning in multimorbid elderly patients in the future. The sequence abiraterone/docetaxel may offer a beneficial option for initial mCRPC therapy.

Hintergrund Das Prostatakarzinom zählt zu den häufigsten Krebserkrankungen bei Männern in Europa. Für die Behandlung des metastasierten Prostatakarzinoms kommen verschiedene Substanzklassen in Betracht, wobei die Verwendung durch umfangreiche Leitlinien gestützt wird. In der Therapie des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) ist derzeitig unklar, welche Reihenfolge (Sequenz) der applizierten Systemtherapien am zielführendsten ist. Derzeitig zugelassene Systemtherapien in der kastrationsresistenten Situation umfassen im Allgemeinen hormonmanipulierende Präparate, Taxan-basierte Chemotherapien, radioaktive Substanzen oder Inhibitoren von DNA-Reparaturmechanismen. Diese Studie soll die Anwendungsrealität der mCRPC-Therapie zusammenfassen. Methoden Retrospektiv konnten 90 mCRPC-Patienten ermittelt werden, welche sich zwischen Februar 2006 und März 2020 im Universitätsklinikum Schleswig-Holstein, Campus Lübeck in Behandlung befanden. Die Patientendaten wurden daraufhin auf ihre Therapiesequenz und ihren Krankheitsverlauf untersucht. Die untersuchten mCRPC-Therapiesequenzen beschränken sich aufgrund der Einschlussperiode auf: Abirateron, Cabazitaxel, Docetaxel, Enzalutamid, Lutetium-177-PSMA und Radium-223. Die Auswertung beinhaltet die Therapiesequenzen und ihre -dauer, klinische Informationen der jeweiligen Kohorte, das allgemeine und krebsspezifische Überleben (OS/CSS) sowie die Zeit bis zur Zweitlinientherapie in Relation zur jeweiligen Erstlinientherapie. Ergebnisse Etwa zwei Drittel der Patienten wurden einer echten Therapiesequenz (mind. zwei der oben aufgeführten Medikamente) unterzogen, wobei sich dieser Anteil bereits in der Drittlinie halbierte. Die Mehrheit der Patienten erhielt dabei die Sequenz (Erst-/Zweitlinie) Abirateron/Docetaxel (n=13), gefolgt von Docetaxel/Abirateron (n=12) sowie Abirateron/Enzalutamid (n=10) und Docetaxel/Docetaxel (n=8). Innerhalb der verschiedenen Docetaxel-Sequenzen war die Therapiedauer der Erstlinie (Mittelwert 4,7 Monate ± SD 3,1; Median 4,0) sowie die der Rechallenge (Mittelwert 5,3 Monate ± SD 5,9; Median 3,0) am längsten. Die subjektive Nebenwirkungsrate von Docetaxel war in der in der Zweitlinie deutlich geringer, sodass hierbei von einer besseren Verträglichkeit ausgegangen werden kann. Die Sequenz Abirateron/Docetaxel fand vor allem bei Patienten mit metachroner Metastasierung Anwendung. In den verschiedenen Sequenzen von Abirateron war die Therapiedauer der Erstlinie (Mittelwert 10,8 Monate ± SD 10,2; Median 9,0) sowie die der Zweitlinie (Mittelwert 10,6 Monate ± SD 9,0; Median 7,0) am längsten. Die Sequenz Abirateron/Enzalutamid wurde vor allem älteren Patienten mit synchroner Metastasierung verabreicht. In den verschiedenen Enzalutamid-Sequenzen war die Therapiedauer der Erstlinie (Mittelwert 9,6 Monate ± SD 7,1; Median 7,0) und die der Rechallenge (Mittelwert 11,0 ± SD 0,0; Median 11,0) am längsten. Die Sequenz Docetaxel/Docetaxel fand dagegen vor allem bei jüngeren Patienten mit einem hohen initialen PSA-Wert Anwendung. Die Auswertung zeigt in einem Trend auf, dass sowohl Abirateron als auch Enzalutamid in der Erstlinie einen Überlebensvorteil ausmachen könnten. Schlussfolgerung Letztlich lässt sich eine optimale Therapiesequenz anhand dieser Daten nicht sicher ableiten. Es zeigte sich jedoch, dass nur ein geringer Anteil an Patienten überhaupt einer Viert- oder sogar Fünftlinie unterzogen wurde. Somit scheint der in dieser Studie gesetzte Fokus auf die Erst- und Zweitlinie sinnvoll. Es konnte in einem Trend gezeigt werden, dass Docetaxel als Erstlinientherapie einen eher nachteiligen Einfluss auf das OS sowie CSS zu nehmen scheint im Vergleich zu Abirateron oder Enzalutamid. Aufgrund der geringen Patientenanzahl dieser Studie ist eine deutliche Signifikanz hierbei jedoch nicht abzuleiten. Die subjektiv bessere Verträglichkeit von Docetaxel in der Zweitlinie könnte darüber hinaus zukünftig einen Impuls für die Therapieplanung multimorbider älterer Patienten geben. Die Sequenz Abirateron/Docetaxel bietet daher möglicherweise einen guten Einstieg in die mCRPC-Therapie.

Research on penile cancer (PeCa) is predominantly conducted in countries with centralized treatment of PeCa-patients. In Germany and Austria (G + A), no state-regulated centralization is established, and no information is available on how PeCa-research is organized. Current research competence in PeCa was assessed by a 36-item questionnaire sent to all chairholders of urological academic centers in G + A. Based on PubMed records, all scientific PeCa-articles of 2012–2022 from G + A were identified. Current research trends were assessed by dividing the literature search into two periods (P1: 2012–2017, P2: 2018–2022). A bibliometric analysis was supplemented. Response rate of the questionnaire was 75

Zusammenfassung Hintergrund Pro Jahr erkranken derzeit in Deutschland 959, in Österreich 67 Männer an einem Peniskarzinom, wobei es in der letzten Dekade zu einer Zunahme um etwa 20% kam [RKI 2021, Statcube.at 2023]. Trotz steigender Inzidenz bleiben die Fallzahlen je Klinik auf einem niedrigen Niveau. Die mediane jährliche Peniskarzinomfallzahl an Uniklinika der DACH-Region lag 2017 bei 7 Patienten (IQR 5–10) [E-PROPS-Gruppe 2021]. Die durch geringe Fallzahlen zwangsläufig kompromittierte institutionelle Expertise wird durch eine in mehreren Studien belegte unzureichende Adhärenz an Peniskarzinom-Leitlinien potenziert. Die z.B. in Großbritannien stringent umgesetzte Zentralisierung ermöglichte eine jeweils signifikante Zunahme organerhaltender Primärtumoroperationen und stadienadaptierter Lymphadenektomien sowie ein verbessertes Überleben der Patienten mit Peniskarzinom, sodass zunehmend auch in Deutschland und Österreich eine Zentralisierung gefordert wird. Ziel der hier vorliegenden Studie war eine aktuelle Erfassung fallzahlabhängiger Effekte auf peniskarzinombezogene Behandlungsangebote an Uniklinika in Deutschland und Österreich. Material und Methoden Ein Fragebogen u.a. zu Fallzahlen für 2021 (stationär gesamt und Peniskarzinom), Behandlungsangeboten für Primärtumor und inguinale Lymphadenektomie (ILAE), zum Vorhalten einer Peniskarzinom-Hauptoperateur*in sowie zur fachlichen Verantwortung für die systemischen Therapien bei Peniskarzinom wurde im Januar 2023 an die Leitung von 48 urologischen Uniklinika in Deutschland und Österreich versandt. Fallzahlbezogene Zusammenhänge bzw. Unterschiede wurden unadjustiert statistisch geprüft. Ergebnisse Die Rücklaufquote betrug 75% (n=36/48). Insgesamt wurden 2021 an den 36 antwortenden Uniklinika 626 Peniskarzinompatienten behandelt, entsprechend etwa 60% der in Deutschland und Österreich zu erwartenden Inzidenz. Die jährliche mediane Gesamtfallzahl lag bei 2807 (IQR 1937–3653), für das Peniskarzinom bei 13 (IQR 9–26). Es bestand keine signifikante Korrelation zwischen der stationären Gesamt- und der Peniskarzinomfallzahl (p=0,34). Die Anzahl der organerhaltenden Therapieverfahren für den Primarius, das Angebot moderner ILAE-Verfahren, das Vorhalten einer Hauptoperateur*in für das Peniskarzinom und die Verantwortung für die Durchführung der systemischen Therapien wurden weder durch die stationäre Gesamtfallzahl noch die Peniskarzinomfallzahl der behandelnden Kliniken signifikant beeinflusst – und zwar sowohl bei Dichotomisierung der Fallzahlen am Median als auch am oberen Quartil. Unterschiede zwischen Deutschland und Österreich konnten nicht gezeigt werden. Schlussfolgerung Trotz einer deutlichen Zunahme der jährlichen Peniskarzinomfallzahl an Universitätskliniken in Deutschland und Österreich gegenüber den Daten von 2017 konnten wir keine fallzahlabhängigen Effekte auf die Strukturqualität hinsichtlich der Therapie des Peniskarzinoms feststellen. Wir werten dieses Ergebnis vor dem Hintergrund der erwiesenen Vorteile einer Zentralisierung als Argument für die Notwendigkeit der Etablierung überregional organisierter Peniskarzinomzentren mit im Vergleich zum Status quo nochmals deutlich höheren Fallzahlen.

Background Currently, 959 men in Germany and 67 in Austria are diagnosed with penile cancer each year, with an increase of approximately 20% in the last decade [RKI 2021, Statcube.at 2023]. Despite the rising incidence, the number of cases per hospital remains low. The median annual number of penile cancer cases at university hospitals in the DACH region was 7 patients (IQR 5-10) in 2017 [E-PROPS group 2021]. The compromised institutional expertise due to low case numbers is compounded with inadequate adherence to penile cancer guidelines, as shown in several studies. The centralization, which is rigorously implemented in countries such as the UK, enabled a significant increase in organ-preserving primary tumor surgery and stage-adapted lymphadenectomies, as well as improved patient survival in cases of penile cancer, resulting in a claim for a similar centralization in Germany and Austria. The aim of this study was to determine the current effects of case volume on penile cancer related treatment options at university hospitals in Germany and Austria.Materials and Methods In January 2023, a survey was sent to the heads of 48 urological university hospitals in Germany and Austria, including questions regarding case volume in 2021 (total number of inpatient and penile cancer cases), treatment options for primary tumors and inguinal lymphadenectomy (ILAE), the availability of a designated penile cancer surgeon, and the professional responsibility for systemic therapies in penile cancer. Correlations and differences related to case volume were statistically analyzed without adjustments.Results The response rate was 75% (n=36/48). In total, 626 penile cancer patients were treated at the 36 responding university hospitals in 2021, representing approximately 60% of the expected incidence in Germany and Austria. The annual median total number of cases was 2807 (IQR 1937-3653), and for penile cancer, it was 13 (IQR 9-26). There was no significant correlation between the total inpatient and penile cancer caseloads (p=0.34). The number of organ-preserving therapy procedures for the primary tumor, the availability of modern ILAE procedures, the presence of a designated penile cancer surgeon, and the responsibility for systemic therapies were not significantly influenced by the total inpatient or penile cancer case volume of the treating hospitals, regardless of whether the case volumes were dichotomized at the median or upper quartile. No significant differences between Germany and Austria were observed.Conclusion Despite a significant increase in the annual number of penile cancer cases at university hospitals in Germany and Austria compared to 2017, we found no case volume-related effects on structural quality with respect to penile cancer therapy. In the light of the proven benefits of centralization, we interpret this result as an argument for the necessity of establishing nationally organized penile cancer centers with even higher case volumes compared to the status quo, in light of the proven benefits of centralization.

Hasanali et al Supplementary Materials

INTRODUCTION:In countries characterized by a centralization of therapy management, patients with penile cancer (PeCa) have shown improvements in guideline adherence and ultimately, improved carcinoma-specific survival. Germany and Austria (G + A) have no state-regulated centralization of PeCa management, and the perspectives of urological university department chairs (UUDCs) in these countries, who act as drivers of professional and political developments, on this topic are currently unknown.METHODS:Surveys containing 36 response options, including specific questions regarding perspectives on PeCa centralization, were sent to the 48 UUDC in G + A in January 2023. In addition to analyzing the responses, closely following the CROSS checklist, a modeling of the real healthcare situation of in-house PeCa patients in G + A was conducted.RESULTS:The response rate was 75% (36/48). 94% and 89% of the UUDCs considered PeCa centralization meaningful and feasible in the medium term, respectively. Among the UUDCs, 72% estimated centralization within university hospitals as appropriate, while 28% favored a geographically oriented approach. Additionally, 97% of the UUDCs emphasized the importance of bridging the gap until implementation of centralization by establishing PeCa second-opinion portals. No country-specific differences were observed. The median number of in-house PeCa cases at the university hospitals in G + A was 13 (interquartile range: 9-26). A significant positive correlation was observed between the annual number of in-house PeCa cases at a given university hospital and the perspective of the UUDCs that centralization as meaningful by its UUDC (0.024). Under assumptions permissible for modeling, the average number of in-house PeCa cases in academic hospitals in G + A was approximately 30 times higher than in nonacademic hospitals.CONCLUSION:This study provides the first data on the perspectives of UUDCs in G + A concerning centralization of PeCa therapy management. Even without state-regulated centralization in G + A, there is currently a clear focusing of PeCa treatments in university hospitals. Further necessary steps toward a structured PeCa centralization are discussed in this manuscript.

You have accessJournal of UrologyCME1 May 2022PD01-02 CITRATE TRANSPORTER – A POTENTIAL TUMOR SUPPRESSOR AND BIOMARKER IN RENAL CELL CARCINOMA Andre Jordan, Huabin Zhu, Soum Lokeshwar, Semih Sarcan, Karina, Aguilar, Anuj Sharma, Martha Terris, and Vinata Lokeshwar Andre JordanAndre Jordan More articles by this author , Huabin ZhuHuabin Zhu More articles by this author , Soum LokeshwarSoum Lokeshwar More articles by this author , Semih SarcanSemih Sarcan More articles by this author , KarinaKarina More articles by this author , Aguilar Aguilar More articles by this author , Anuj SharmaAnuj Sharma More articles by this author , Martha TerrisMartha Terris More articles by this author , and Vinata LokeshwarVinata Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002516.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Five-year survival of metastatic renal cell carcinoma (mRCC) patients is < 10% and African American (AA) males have the highest incidence. Identification of the molecular determinants of mRCC and racial disparity in RCC is critical for biomarker development and targeted therapy. NaDC3 expressed in kidney epithelial cells is a succinate/citrate transporter, however its role has not been examined in any disease. We examined NaDC3 expression in normal and RCC tissues and correlated it with clinical outcome and racial disparity. We also evaluated biological functions and molecular signaling regulated by NaDC3 in RCC cells. METHODS: Differential gene expression in the matched normal and RCC tissues (n=6/category) was evaluated by microarray analysis; results were validated by QPCR and immunoblotting in tissues from 83 patients (White=46; Hispanic=24; AA=13). VHL+ and VHL- RCC cells were stably transfected with a NaDC3 construct. Transfectants were characterized for cell proliferation, cell cycle, motility, succinate/citrate transport and reactive oxygen species (ROS) measurement assays under normoxia and hypoxia. SDCT2 induction was evaluated following 5-azacytidine plus Trichostatin A treatment. RESULTS: NADC3 was 63- and 100-fold downregulated in low- and high-stage RCC tissues. Q-PCR validation showed 40-fold downregulation of NaDC3 in RCC tissues when compared to normal kidney (P< 0.0001). Downregulation was 40-fold in White and Hispanic patients, but 198-fold in AA patients (P=0.0049) and correlated with tumor stage and metastasis (P=0.009). Under hypoxia, NADC3 expression caused 3-4-fold inhibition of proliferation, cell-cycle, motility in both VHL+ and VHL- cells (P<0.01); only VHL+ cells were inhibited under normoxia. NADC3 expression induced ROS levels and succinate transport by >3-fold (P<0.01) and activated p16INK4a-RB pathway and apoptosis (caspase-3 and PARP activation). 5-AZA+TSA treatment induced NADC3 expression by 50-fold (P<0.001). CONCLUSIONS: This is the first study on a functional biomarker in RCC, NADC3, that is a possible a novel tumor suppressor gene. NADC3 loss promotes RCC growth, survival and inhibits cellular senescence and its downregulation correlates with metastasis and racial disparity. Source of Funding: 1R01CA227277-01A1 (VBL); Department of Defence -PRCRP (W81XWH1810277 (CA170470; PRCRP) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e30 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andre Jordan More articles by this author Huabin Zhu More articles by this author Soum Lokeshwar More articles by this author Semih Sarcan More articles by this author Karina More articles by this author Aguilar More articles by this author Anuj Sharma More articles by this author Martha Terris More articles by this author Vinata Lokeshwar More articles by this author Expand All Advertisement PDF downloadLoading ...

BACKGROUND:The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases.METHODS AND RESULTS:We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care.CONCLUSION:In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.

Within the last forty years, seminal contributions have been made in the areas of bladder cancer (BC) biology, driver genes, molecular profiling, biomarkers, and therapeutic targets for improving personalized patient care. This overview includes seminal discoveries and advances in the molecular oncology of BC. Starting with the concept of divergent molecular pathways for the development of low- and high-grade bladder tumors, field cancerization versus clonality of bladder tumors, cancer driver genes/mutations, genetic polymorphisms, and bacillus Calmette-Guérin (BCG) as an early form of immunotherapy are some of the conceptual contributions towards improving patient care. Although beginning with a promise of predicting prognosis and individualizing treatments, "-omic" approaches and molecular subtypes have revealed the importance of BC stem cells, lineage plasticity, and intra-tumor heterogeneity as the next frontiers for realizing individualized patient care. Along with urine as the optimal non-invasive liquid biopsy, BC is at the forefront of the biomarker field. If the goal is to reduce the number of cystoscopies but not to replace them for monitoring recurrence and asymptomatic microscopic hematuria, a BC marker may reach clinical acceptance. As advances in the molecular oncology of BC continue, the next twenty-five years should significantly advance personalized care for BC patients.

Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6–1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

You have accessJournal of UrologyCME1 May 2022MP03-03 TARGETING V1/CHASE TO OVERCOME GEMCITABINE RESISTANCE Semih Sarcan, Daley S. Morera, Marie C. Hupe, Karina Aguilar, Anuj Sharma, Sung Alexander, Joseph McDaniels, Huabin Zhu, Martin Hennig, Martha Terris, Axel S. Merseburger, and Vinata B. Lokeshwar Semih SarcanSemih Sarcan More articles by this author , Daley S. MoreraDaley S. Morera More articles by this author , Marie C. HupeMarie C. Hupe More articles by this author , Karina AguilarKarina Aguilar More articles by this author , Anuj SharmaAnuj Sharma More articles by this author , Sung AlexanderSung Alexander More articles by this author , Joseph McDanielsJoseph McDaniels More articles by this author , Huabin ZhuHuabin Zhu More articles by this author , Martin HennigMartin Hennig More articles by this author , Martha TerrisMartha Terris More articles by this author , Axel S. MerseburgerAxel S. Merseburger More articles by this author , and Vinata B. LokeshwarVinata B. Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Precision-based treatment approaches could improve the prognosis of patients with bladder cancer (BC). We recently discovered a first-in-class human Chondroitinase (Chase) that degrades chondroitin sulfate. This Chase is a splice variant of HYAL4 (V1) and promotes a malignant phenotype and chemoresistance in BC cells. We evaluated V1/Chase expression and functions in BC and inhibitors to overcome V1/Chase-mediated Gemcitabine (Gem) resistance. METHODS: Cohort 1: 86 bladder tissues (normal (NBL)=34; tumor (TBL)=52); cohort 2: 40 cystectomy specimens from MIBC patients who received adjuvant Gemcitabine plus cisplatin (G+C) treatment. Cohort 3: 144 urine specimens (BCA=42, non-BCa=102). Gene expression was measured by q-PCR in all cohorts and urine was assayed for Chase activity. V1/Chase was stably expressed or silenced in normal urothelial and three BC cell lines. Transfectants were analyzed for sensitivity to Gemcitabine and Cisplatin. The mechanism of Gem resistance was evaluated in preclinical in vitro and in vivo models. RESULTS: In cohort 1, V1 mRNA levels were an independent predictor of metastasis and death due to BC (P=0.0008). In cohort 2, high V1 levels significantly predicted with G+C treatment failure (P <0.0001). In cohort 3, Chase levels were 13 to 75-fold elevated in low and high-grade BC patients’ urine compared to non-BC cases (92.7% sensitivity; 88.2% specificity). V1-expressing urothelial and BC cells were resistant to Gem but not to Cisplatin. V1 expression increased Gem metabolism and subsequent efflux of an inactive metabolite dFdU. V1 increased CD44 shedding the conditioned media. This triggered intracellular activation of the JAK2/STAT3 pathway, resulting in the upregulation of cytidine deaminase (CDA). CDA induces Gem metabolism and dFdU efflux. JAK2, STAT3 and CDA inhibitors, (some FDA-approved), synergistically re- sensitized V1-expressing cells to Gem. V1-induced muscle invasive tumors that were metastatic. While Gem inhibited BC xenograft growth, V1-expressing tumors were resistant. Combination of Gem with a CDA inhibitor (tetrahydrouridine) abrogated V1 tumor growth with minimal toxicity. CONCLUSIONS: V1 is a functional biomarker that drives muscle-invasion, metastasis and Gem resistance in BC. Inhibitors of the JAK2/STAT3/CDA pathway overcome V1- mediated Gem resistance, suggesting a precision-based treatment approach to improve treatment response. Source of Funding: 1R01CA227277-01A1 (VBL); Department of Defence-PRCRP (W81XWH1810277 (CA170470; PRCRP) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e19 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Semih Sarcan More articles by this author Daley S. Morera More articles by this author Marie C. Hupe More articles by this author Karina Aguilar More articles by this author Anuj Sharma More articles by this author Sung Alexander More articles by this author Joseph McDaniels More articles by this author Huabin Zhu More articles by this author Martin Hennig More articles by this author Martha Terris More articles by this author Axel S. Merseburger More articles by this author Vinata B. Lokeshwar More articles by this author Expand All Advertisement PDF downloadLoading ...

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-07 NEWLY DISCOVERED CHONDROITINASE HYAL4-V1 DRIVES GEMCITABINE RESISTANCE AND PREDICTS GEMCITABINE/CISPLATIN FAILURE IN BLADDER CANCER PATIENTS Marie Christine Hupe, Martin J P Hennig, Soum Lokeshwar, Sarrah L Hasanali, Daley S Morera, Semih Sarcan, Martha K Terris, Axel S Merseburger, and Vinata B Lokeshwar Marie Christine HupeMarie Christine Hupe More articles by this author , Martin J P HennigMartin J P Hennig More articles by this author , Soum LokeshwarSoum Lokeshwar More articles by this author , Sarrah L HasanaliSarrah L Hasanali More articles by this author , Daley S MoreraDaley S Morera More articles by this author , Semih SarcanSemih Sarcan More articles by this author , Martha K TerrisMartha K Terris More articles by this author , Axel S MerseburgerAxel S Merseburger More articles by this author , and Vinata B LokeshwarVinata B Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Due to better tolerability, Gemcitabine+Cisplatin is a preferred chemotherapy regimen for advanced bladder cancer (BC). Predicting treatment failure and overcoming resistance remain as unmet clinical needs. We discovered that a splice variant (V1) of the gene HYAL-4 is a first-in-class human chondroitinase. V1 is upregulated in BC and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. METHODS: Cohort 1: 86 bladder tissues (normal=34; BC=52); cohort 2: 44 specimens from patients with muscle invasive BC (MIBC) who received Gemcitabine+Cisplatin (G+C) treatment for metastatic disease. V1 expression was measured by RT-qPCR and immunohistochemistry (IHC). HYAL-4 wildtype (Wt) and V1 were stably expressed or silenced in normal urothelial and 3 BC cell lines. Transfectants were analyzed for sensitivity to Gemcitabine and Cisplatin. The mechanism of chemoresistance was evaluated in preclinical models. Chemosensitivity of V1-expressing chemoresistant tumors to Tetrahydrouridie and Gemcitabine combination was evaluated in BC xenograft. RESULTS: In cohort 1, V1 transcript and IHC staining levels were significantly (6-13-fold) elevated in BC tissues vs. normal bladder (p <0.001) and 7-fold elevated in MIBC (p=0.0087). In cohort 2, the levels were elevated 3-5-fold in MIBC specimens from patients who failed G+C treatment and/or died from BC and were independent predictors (p=0.0002). V1-expressing urothelial and BC cells were resistant to Gemcitabine but not to Cisplatin. V1 expression neither affected Gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased Gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression by up-regulating CD44-JAK2/STAT3 signaling. CDA inhibitor Tetrahydrourine re-sensitized V1-expressing cells to Gemcitabine. V1-induced muscle invasive tumors that were metastatic. While Gemcitabine (25–50 mg/kg) inhibited BC xenograft growth, V1-expressing tumors were resistant. Gemcitabine (25 mg/kg) and Tetrahydrouridine (20 mg/kg) combination abrogated V1 tumor growth with minimal toxicity. CONCLUSIONS: V1 drives Gemcitabine resistance and potentially predicts G+C failure. Combination with Tetrahydrouridine overcomes Gemcitabine resistance. Since Gemcitabine is included in several chemotherapy regimens, our study could have broad significance. Source of Funding: 1R01CA227277-01A1 (VBL); Department of Defence -PRCRP (W81XWH1810277 (CA170470; PRCRP) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e657-e657 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marie Christine Hupe More articles by this author Martin J P Hennig More articles by this author Soum Lokeshwar More articles by this author Sarrah L Hasanali More articles by this author Daley S Morera More articles by this author Semih Sarcan More articles by this author Martha K Terris More articles by this author Axel S Merseburger More articles by this author Vinata B Lokeshwar More articles by this author Expand All Advertisement Loading ...

AbstractPurpose: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. Experimental Design: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. Results: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44–JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25–50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. Conclusions: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.