EM3: Urological Oncology and tuberous sclerosis disease. Search for new therapeutic targets.

The Urological Oncology group is focused on the study of the genetics and cell biology of urological tumors, mainly metastatic castration-resistant prostate cancer (mCRPC), and the rare disease Tuberous Sclerosis (TS). The main objective is to identify new therapeutic targets and markers for early detection and progression of the disease to achieve a more personalized treatment in patients. Our group studies the impact of the Primary Cilium-cellular organelle where the platforms of the Hedgehog, Notch, WNT signaling pathways and some tyrosine kinase pathways are located- on tumor progression and ET. To do this, we analyze abnormalities of the Primary Cilium in tumors and the consequences of these defects for the initiation, progression and response to treatment in tumor cells, correlating them with the degree of the disease. In our studies we mainly use in vitro cell models, advanced imaging techniques, liquid biopsy samples (exosomes and circulating tumor cells) and solid tissue from patients.

Our mission is to transfer our discoveries to improve the quality of life of patients with urological tumors and patients with Tuberous Sclerosis.

• Metastatic Castration-Resistant Prostate Cancer (mCRPC) and urological tumors (kidney and bladder): study of the genetics and cell biology of the disease to identify new treatments that have the process of ciliogenesis and the structure of the Primary Cilium as a therapeutic target.
• Identification of early detection markers.
• Ciliopathies: apply new advanced imaging tools to identify therapies for Lebel Congenital Amaeurosis (LCA), and other ciliopathies caused by mutations in the CEP290 gene.
• Tuberous Sclerosis (TS): application of state-of-the-art massive sequencing and advanced imaging techniques to identify new therapeutic targets that suppress renal defects associated with TS.

Prostate cancer Tuberous Sclerosis Urologic cancer Liquid biopsy Primary cilium Centrosome

• Principal Investigators:
  • Álvaro Juárez Suarez (PI).
  • Elena Reales Rodríguez (Co-PI).
• Investigators:
  • F. Javier Amores Bermúdez (FEA-Urology).
  • Rocío Saiz Marenco (FEA-Urology).
  • Nelson Andrés Canales Casco (R1 and FEA-Urology).
  • Inés Saucedo Giménez (FEA-Urology).
  • Álvaro Luís Bisonó Castillo (Resident and R1).
  • José Pablo Pedraza Sánchez (FEA-Urology).
  • Marina Murillo Pineda (Researcher).
• Nursing, Technical and Administrative Staff:
  • Manuela Sánchez Sánchez (Nurse).
  • Rafael Gamaza Martínez (Nurse).
  • María José Castro Dorantes (Nurse).

• Title: "Application of new probes and super-resolution nanoscopes to advance knowledge of ciliary genetic disorders (ciliopathies)".Andalucia Talent Hub- Marie Curie grant 2015-2017. "Consejería de Economía y Conocimiento"- Agencia Andaluza del Conocimiento de la Junta de Andalucia (Spain) y FP7-PEOPLE-COFUND-Marie Curie Action. Participating labs: Dr. Derek Toomre (Yale University) y Dr. Bhattacharya (Cabimer). Principal investigator: Elena Reales Rodríguez.

• Title: Application of new integrated imaging tools to identify therapeutics for ciliary genetic disorders (ciliopathies). Entity: Junta de Andalucia y Unión Europea. Proyectos I+D+I FEDER Andalucia 2014-2020. Principal investigator, Elena reales Rodríguez. 2020-2023. Code: UCA18-108266.
• Title: Aplicación de secuenciación masiva de última generación y técnicas de imagen avanzadas para identificar nuevas dianas terapéuticas que supriman los defectos renales asociados a Esclerosis Tuberosa. Entity: Unión Europea Fondo Europeo de Desarrollo Regional- Junta de Andalucía. Principal investigator, Álvaro Juárez Soto. 2020-2023. Code: ITI-0020-2019.

1. Rodriguez-Vida A, Rodríguez-Alonso A, Useros-Rodríguez E, Lopez-Campos F, Amor-Carro O, Arribas-Ruiz A, Martinez-Torres J, Roca-Pardiñas J, Quesada-García A, Muñoz-Del-Toro JR, Juárez-Soto Á. Impact of New Systemic Therapies in Overall Survival in Non-Metastatic Castration Resistant Prostate Cancer: Systematic Review and Meta-Analysis. Clin Genitourin Cancer. 2021 Nov 21: S1558-7673(21)00219-6. doi: 10.1016/j.clgc.2021.11.008. Epub ahead of print. PMID: 34920959. Q1.
2. Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Özgüroğlu M, Juárez Soto Á, Merseburger AS, Uemura H, Ye D, Given R, Basch E, Miladinovic B, Lopez-Gitlitz A, Chi KN. Reply by Authors. J Urol. 2021 Oct;206(4):923. doi: 10.1097/JU.0000000000001841.03. Epub 2021 Jul 23. PMID: 34296946. Q1.
3. Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Özgüroğlu M, Juárez Soto Á, Merseburger AS, Uemura H, Ye D, Given R, Basch E, Miladinovic B, Lopez-Gitlitz A, Chi KN. Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study. J Urol. 2021 Oct ;206(4):914-923. doi: 10.1097/JU.0000000000001841. Epub 2021 May 27. PMID: 34039013. Q1.
4. Cózar Olmo JM, Carballido Rodríguez J, Rubio-Briones J, Useros Rodríguez E, Muñoz Del Toro J, García García-Porrero Á, Juárez-Soto Á; en nombre del grupo de investigadores del estudio IDENTIFICA. Clinical drivers for imaging testing in non-metastatic castration-resistant prostate cancer in clinical practice: Results of the IDENTIFICA study. Actas Urol Esp (Engl Ed). 2021 Apr;45(3):198-206. English, Spanish. doi: 10.1016/j.acuro.2020.12.001. Epub 2021 Feb 6. PMID: 33558084. Q3.
5. Rivera-Molina FE, Xi Z, Reales E, Wang B, Toomre D. (2021). Exocyst complex mediates recycling of internal cilia. Curr Biol. Oct 19. Q1 (INIBICA appears).
6. Ponce M, Zuasti E, Reales E, Anguís V, Fernández-Díaz C. (2021). Evaluation of an oral DNA nanovaccine against photobacteriosis in Solea senegalensis. Fish and Sellfish Immunology. Volume 117, 157-168. Q1. (INIBICA appears).
7. Murillo-Pineda M, Valente LP, Dumont M, Mata JF, Fachinetti D, Jansen LET (2021). Induction of spontaneous human neocentromere formation and long-term maturation. J Cell Biol. Mar 1; 220(39. Q1.

1. A. Juárez Soto. Treatment for castration-resistant prostate cancer and drug interaction risk in polymedicated patients. Actas Urol Esp. 2020, Aug 21. Q3.
2. Álvarez-Ossorio JL, Cozar-Olmo JM, Juárez-Soto Á,…et al. Update of the Andalusian Association of Urology protocol for the management of metastatic castration-resistant prostate cáncer. Actas Urol Esp. 2020 Apr. Q3.

1. A. Juárez-Soto, J.M. Garín-Ferreira, A. Rodríguez-Fernández, J.L. Tirado-Hospital, M.T. González-Serrano, J. Moreno-Jiménez, R. Medina-López y V. Baena-González. (2019). Diagnóstico de metástasis en pacientes con cáncer de próstata resistente a la castración: algoritmo de decisión en pruebas de imagen. Actas Urol Esp.2019;43(2)55-61. Q3.
2. Mario Alvarez-Maestro, Jose Quesada Olarte, Juan Gómez Rivas, Diego M. Carrión, Alvaro Juarez Soto, Emilio Rios Gonzalez, Alfredo Aguilera Bazan and Luis Martinez- Piñeiro.(2019). High-risk prostate cancer. Optimal treatment. New evidences. Arch. Esp. Urol. 2019; 72 (1). Q3.
3. Álvaro Juárez Soto.(2019). Metastases-free survival rate in non-metastatic castration-resistant prostate cancer: Now living on its own!. Actas Urol Esp.2019;43(4):167-168. Q3.
4. Kim N. Chi, M.D., Neeraj Agarwal, M.D., Anders Bjartell, M.D.,Byung Ha Chung, M.D., Andrea J. Pereira de Santana Gomes, M.D., Robert Given, M.D., Álvaro Juárez Soto, M.D., Axel S. Merseburger, M.D., Mustafa Özgüroğlu, M.D., Hirotsugu Uemura, M.D., Dingwei Ye, M.D.,Kris Deprince, M.D., Vahid Naini, Pharm.D., Jinhui Li, Ph.D., Shinta Cheng, M.D., Margaret K. Yu, M.D., Ke Zhang, Ph.D., Julie S. Larsen, Pharm.D.,Sharon McCarthy, B.Pharm., and Simon Chowdhury, M.D.,for the TITAN Investigators. (2019). Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019 Jul 4; 381(1):13-24- Q1.
5. Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Özgüroglu M, Juárez Soto Á, Merseburger AS, Uemura H, Ye D, Given R, Cella D, Basch E, Miladinovic B, Dearden L, Deprince K, Naini V, Lopez-Gitlitz A, Chi KN, TITAN investigators. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cáncer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019 Nov; 20(11):1518-1530 Q1.

1. Giovannone AJ, Winterstein C, Bhattaram P, Reales E, Low SH, Baggs JE, Xu M, Lalli MA, Hogenesch JB, Weimbs T. (2018) Soluble syntaxin 3 functions as a transcriptional regulator. J Biol Chem. Feb 23 doi:10.1074 Q2.
2. Giovannone AJ*, Reales E*, Bhattaram P, Fraile-Ramos A, Weimbs T (2018) Tracking Endocytosis and Intracellular Trafficking of Epitope-tagged Syntaxin 3 by Antibody Feeding in Live, Polarized MDCK Cells . Bio-protocol. Vol 8. Iss03. Feb 05.

1. Giovannone AJ*, Reales E*, Bhattaram P, Fraile-Ramos A, Weimbs T. (2017) Mono-ubiquitination of syntaxin 3 leads to retrieval from basolateral plasma membrane and facilitates cargo recruitment to exosomes. Mol Biol Cell. 2017 Aug 16 E17-07-0461 (* first co-authors) Q1.

1. Reales E., Bernabé-Rubio M., Casares-Arias J., Rentero C., Fernández-Barrera J., Rangel L., Correas I., Enrich C., Andrés G., Alonso M.A. (2015) The MAL protein is crucial for proper membrane condensation at the ciliary base, which is required for primary cilium elongation. J Cell Sci. 2015 Jun 15; 128(12): 2261-70 Q1.

1. Gómez-Jaramillo L, Delgado-Pérez L, Reales E, Mora-López F, Mateos, R, García-Poley A, Brieva JA, and Campos-Caro A. (2014) Syntaxin-4 is implicated in the secretion of antibodies by human plasma cells. J Leukoc Biol. 2014 Feb; 95(2): 305-12 Q2.

• SPONSOR – PROTOCOL CODE NUMBER: UC-0160/1717. VERSION (NUMBER & DATE): 4.0 – NOVEMBER 15, 2019. TRIAL TITLE: An open label, randomized, phase III trial, evaluating efficacy of Atezolizumab in addition to one year BCG (Bacillus CaLmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive Bladder cANcer. ABBREVIATED TITLE: ALBAN. COORDINATING INVESTIGATORS: Prof. Morgan ROUPRET & Dr Yohann LORIOT. PI: Álvaro Juárez. Collaborators: Nelson Canales Casco, Inés Saucedo GIménez, Rafael Gamaza. Start date 2021.
• Título del Ensayo: Estudio aleatorizado, doble ciego, controlado con placebo de fase III de niraparib en combinación con acetato de abiraterona y prednisona frente a acetato de abiraterona y prednisona para el tratamiento de participantes con cáncer de próstata metastásico sensible a la castración (CPSCm) con mutaciones deletéreas en la línea germinal o somáticas en los genes de reparación por recombinación homóloga (HRR). Promotor: Janssen-Cilag International N.V. Fármaco del Ensayo: JNJ-67652000 (Niraparib+Abiraterona). Protocolo: 67652000PCR3002 (AMPLITUDE). Número EUdraCT: 2020-002209-25. PI: Álvaro Juárez. Collaborators: Maria José Castro, Javier Amores, Rocío Sáiz, Pablo Pedraza, Maria Jiménez, Juan Anillo. Start year 2021.
• Título del estudio: “Estudio de fase 3, aleatorizado, abierto, controlado, de cabozantinib (XL184) en combinación con atezolizumab frente a una segunda terapia hormonal novedosa (THN) en pacientes con cáncer de próstata metastásico y resistente a la castración.” Código: XL184-315. EudraCT: 2020-000348-77. PI: Álvaro Juárez. Collaborators: Maria José Castro, Javier Amores, Rocío Sáiz, Pablo Pedraza, Maria Jiménez, Juan Anillo. Start year 2021.
• TRATAMIENTO DE LOS TUMORES VESICALES NO MÚSCULO INFILTRANTE DE ALTO RIESGO CON IMUNO BCG MOREAU RJ COMO PROFILAXIS DE RECIDIVA Y PROGRESIÓN Nº EudraCT: 2017-002928-24 CÓDIGO PROMOTOR: ENCORE-01 PROMOTOR: BIOFABRI & FIU. PI: Nelson Canales Casco. Collaborators: Maria José Castro, Javier Amores, Rocío Sáiz, Pablo Pedraza, Maria Jiménez, Juan Anillo. Start year 2019.
• A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Subjects with Metastatic Prostate Cancer. EudraCT NUMBER: 2017-003364-12. Protocol 64091742PCR3001, Phase 3. PI: Álvaro Juárez. Collaborators: Maria José Castro, Javier Amores, Rocío Sáiz, Pablo Pedraza, Maria Jiménez, Juan Anillo. Start year 2020.
• Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Apalutamide in Subjects with High-risk, Localized or Locally Advanced Prostate Cancer Who are Candidates for Radical Prostatectomy. Protocol 56021927PCR3011; Phase 3. JNJ-56021927 (apalutamide). EudraCT NUMBER: 2018-001746-34. PI: Álvaro Juárez. Collaborators: Maria José Castro, Javier Amores, Rocío Sáiz, Pablo Pedraza, Maria Jiménez, Juan Anillo. Start year 2019.
• Phase 2b Clinical Study Evaluating Efficacy and Safety of TAR-200 in Combination with Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants with High-Risk Non- Muscle Invasive Bladder Cancer Unresponsive to Intravesical Bacillus Calmette-Guerin who are Ineligible for or Elected Not to Undergo Radical Cystectomy. Protocol 17000139BLC2001 JNJ-17000139 (TAR-200). Regulatory Agency Identifier Number(s):. IND: 149505. EudraCT NUMBER: 2020-002646-16. PI: Álvaro Juárez. Collaborators: Nelson Canales, Inés Saucedo, Rafael Gamaza. Start year 2021.
• A Phase 3, Multi-center, Randomized Study Evaluating Efficacy of TAR-200 in Combination With Cetrelimab Versus Concurrent Chemoradiotherapy in Participants With Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder who are not Receiving Radical Cystectomy. EudraCT NUMBER: 2020-002620-36. PI: Álvaro Juárez. Collaborators: Nelson Canales, Inés Saucedo, Rafael Gamaza. Start year 2021.