Resistance and Progression Mechanisms in Prostate Cancer

Summary

Dr Aytes’s research exploits genetically engineered mouse prostate cancer models to uncover mechanisms of progressión towards advanced, therapy resistant prostate cancer. The group uses computational approaches for cross-species analysis of phentoypic and preclinical data from a range of high-throuhput molecular profiling. Of particular interest is the role of the epigenetically modulated changes in gene regulatory programs in therapy resistance. The lab is also interested in identifying molecular biomarkers for patients stratification and to preddict responses to standard of care and experimental therapies. Finally the lab is also heavily invested in identifying new targets through synthetic lethal interactions with AR signaling inhibitors and other approved drugs using CRISPR/Cas screening s in vitro and in vivo.

40 Publications

Strategic lines

1. Mechanisms for the acquisition of the AR independent phenotype: We exploit our Genetically Engineered Mouse (GEM) prostate cancer models to identify mechanisms of progression and resistance to anti-AR therapies. Further, we have embarked ourselves in the ambitious endeavor of identifying synthetic lethal interactions with standard of care abiraterone and enzalutamide using genome-wide CRISPR/Cas9 screen. Also within this research topic we are invested in a basic research project aiming at elucidating the role of chromatin conformation change and epigenetic dysregulation in the acquisition of the lineage plasticity observed in patients that progress to androgen independent state with neuroendocrine features or squamous variants that no longer use AR signaling to sustain growth and differentiation.

2. Experimental therapeutics for high-risk prostate cancer. Predicting patients likely to respond to standard of care treatments as well as those inherently resistant is a major challenge in translational research and clinical oncology. Molecular profiling of drug-perturbed cancer models allows cross-species analysis to compare to human datasets in an attempt to identify molecular biomarkers of response and resistance as well as predict drugs that bet inhibit specific cancer drivers or vulnerabilities. Within our research line in experimental therapeutics we have initiated projects aiming at expanding this therapeutic use of such treatments in prostate patients even without evident homologous recombination or mismatch repair deficiencies. Hence we have on the one hand initiated a CRISPR/Cas9 screen for synthetic lethal interaction with Rucaparib, a novel PARP inhibitor, using in vivo and in vitro cancer models based on Pten;Kras or Pten:p53 alterations, and on the other hand, we are interest in investigating potential synergies between PARP inhibitors and drugs targeting master regulators of chromatin conformation.

3. Prostate cancer progression and metastasis. Following from the work developed during the postdoctoral stage of the Dr. Aytes, the group has since his establishment in IDIBELL in 2016, continued this research line, which aims at identifying functional drivers and dependencies in prostate cancer metastatic progression. We are particularly interested in the cross-talk between the regulatory program executed by this FOXM1-CENPF module and (i) the acquisition of the resistant phenotype to standard of care therapies, (ii) the emergence of increased cellular plasticity, neuroendocrine features and pluripotent characteristics, and (iiI) the potential actionability of this oncogenic program

Selected Publications

Suárez JF, Zamora V, Garin O, Gutiérrez C, Pont À, Pardo Y, Goñi A, Mariño A, Hervás A, Herruzo I, Cabrera P, Sancho G, Ponce de León J, Macías V, Guedea F, Vigués F, Castells M, Ferrer M, Multicentric Spanish Group of Clinically Localized Prostate C. Mortality and biochemical recurrence after surgery, brachytherapy, or external radiotherapy for localized prostate cancer: a 10-year follow-up cohort study. Sci Rep. 2022;12(1):12589-12589. doi:10.1038/s41598-022-16395-w.

Pané Foix M, Fernandez Calvo D, Condom Mundó I, Suarez Novo JF, Merino Serra E, Garcia Benett JR, Gomà Gàllego M, Yun Viladomat S, Vigués Julià F, Vidal Bel I. Clinical relevance of amyloid in prostate samples: a report on 40 patients. Histopathology. 2022;doi:10.1111/his.14717.

Rodríguez Barrueco,R;Latorre,J;Devis Jáuregui,L; Lluch,A; Bonifaci,N; Llobet,FJ; Olivan, M et al, A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG., Adv. Sci., 2022;9(4):doi:10.1002/advs.202104759

Peremiquel Trillas P, Paytubi S, Pelegrina B, Frias Gomez J, Carmona Á, Martínez JM, de Francisco J, Benavente Y, Barahona M, Briansó F, Canet Hermida J, Caño V, Vidal A, Zanca A, Baixeras N, Rodríguez A, Fernández Gonzalez S, Dueñas N, Càrdenas L, Aytés Á, Bianchi I, Pavón MÀ, Reventós J, Capellà G, Gómez D, Diaz M, Ponce J, Brunet J, Matias Guiu X, Bosch FX, de Sanjosé S, Alemany L, Pineda M, Marin F, Costas L. An Integrated Approach for the Early Detection of Endometrial and Ovarian Cancers (Screenwide Study): Rationale, Study Design and Pilot Study. J. Pers. Med. 2022;12(7):doi:10.3390/jpm12071074.

Plata Bello A, Apatov SE, Benfante NE, Rivero Belenchón I, Picola Brau N, Mercader Barrull C, Jenjitranant P, Vickers AJ, Fine SW, Touijer KA. Prevalence of High-Risk Prostate Cancer Metastasis to Cloquet's Ilioinguinal Lymph Node. J Urol. 2022;207(6):1222-1226. doi:10.1097/JU.0000000000002439.

Selected Projects

18INT004. Mechanisms ant therapeutic targeting of NSD2 in advanced prostate cancer. DEPARTMENT OF DEFENSE. Budget: 352372,94. 2018-2023. PI: Aytes Meneses, Alvaro.

USA21005. Dissecting the role of cancer cell chromatin remodeling on the landscape of tumor immune microenvironment. DEPARTMENT OF DEFENSE. Budget: 465431,26. 2022-2025. PI: Aytes Meneses, Alvaro.

AEC21002. Dissecting EZH2-SWI/SNF antagonism to target cell plasticity in therapy resistant prostate cancer. Asociación Española Contra el Cáncer (AECC). Budget: 299363,42. 2021-2024. PI: Aytes Meneses, Alvaro.

20CEE005. RegARcis: Role of the SWI/SNF complex in the Androgen Receptor cistrome regulation. COMISSIÓ EUROPEA. Budget: 160932,48. 2020-2022. PI: EL BIZRI, RANA.

18PNJ004. IDENTIFYING SYNERGISTIC INTERACTIONS TO ANDROGEN RECEPTOR BLOCKADE WITH APALUTAMIDE IN GENETICALLY MODIFIED MOUSE MODELS OF CASTRATION RESISTANT PROSTATE CANCER: FOCUS ON BTK/BMX INHIBITORS AND EPIGENETIC DRUGS. Jansen . Budget: 161700. 2018-2023. PI: Aytes, Alvaro.

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