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Institut Català d'Oncologia

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Javier A. Menéndez

Institut Català d'Oncologia

Elisabet Cuyàs

Institut Català d'Oncologia

Joaquim Bosch‐Barrera

Institut Català d'Oncologia

Begoña Martı́n-Castillo

Institut d'Investigació Biomèdica de Girona

Montse Sánchez‐Céspedes

Josep Carreras Leukaemia Research Institute

Jorge Joven

Institut d'Investigació Sanitària Pere Virgili

Alberto Villanueva

Institut d'Investigació Biomédica de Bellvitge

August Vidal

Institut d'Investigació Biomédica de Bellvitge

Ruth Lupu

Mayo Clinic

Julián Carretero

Universitat de València

Cooperative Institutions

Institut Català d'Oncologia

Institut d'Investigació Biomèdica de Girona

Institut d'Investigació Biomédica de Bellvitge

Hospital Universitari de Girona Doctor Josep Trueta

Universitat de Barcelona

Centro de Investigación Biomédica en Red de Cáncer

Bellvitge University Hospital

University of Girona

Instituto de Salud Carlos III

Catalan Institute for Water Research

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Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer

Journal of Clinical Medicine (2019)

Eugeni López‐Bonet María Buxó Elisabet Cuyàs Sònia Pernas Joan Dorca

The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.

Taxane

Regimen

Tolerability

Neoadjuvant Therapy

10.3390/jcm8122180

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Citations (15)

Data from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

<div>AbstractCorrect apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. Cancer Res; 75(7); 1287–97. ©2015 AACR.</div>

Cell polarity

10.1158/0008-5472.c.6507201

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Supplementary Figures 1 - 8 from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Figure S1. PARD3-inactivation in the H157 lung cancer cell line. Figure S2. Ratio charts of the multiplex ligation-dependent probe amplification (MLPA) depicting a large intragenic deletion (from exon 4 to 23) in one of the LSCCs but not a normal DNA. Figure S3. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to determine the presence of promoter hypermethylation of PARD3. Figure S4. Relative abundance of the PARD3 transcriptsFigure S5. Western blot showing ectopic and transient expression of the indicated PAR3 proteins in the H157 cell line, immunoblotted with HA or PAR3 antibodies. Figure S6. Immunofluorescence with the anti-PAR3 antibody in the indicated T98G-derived cells, after (Dox+) induction of PAR3 expression with doxycycline (1 ng/µl, 24h). Scale bar, 50 µm. Figure S7. Western blot depicts the endogenous PAR3 protein in the indicated lung cancer cells and the ectopic expression of PAR3 in the H157tr-pD41_R74del cells (dox, 1 ng/µl; 24 h). Figure S8. Immunostaining of PAR3 in lung primary tumors and head and neck squamous cell carcinomas (HNSCCs).

Ectopic expression

10.1158/0008-5472.22406967

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P1.13-29 Overall Response Rate of Nintedanib and Docetaxel in Combination with the Nutraceutical Use of Silibinin in Advanced NSCLC

Journal of Thoracic Oncology (2018)

J. Bosch Barrera J.C. Ruffinelli Enric Carcereny Elia Sais Sara Verdura

Silibinin

Nintedanib

10.1016/j.jtho.2018.08.886

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P1.03-035 Efficacy of Nintedanib and Docetaxel in Combination with the Nutraceutical Use of Silibinin in Advanced NSCLC

Journal of Thoracic Oncology (2017)

J. Bosch Barrera Elia Sais Sara Verdura Elisabet Cuyàs Diana Roa

Silibinin

Nintedanib

Nutraceutical

10.1016/j.jtho.2017.09.839

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Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer

Neoplasia (2025)

Travis Vander Steen Ingrid Espinoza Cristina Duran Guillem Casadevall Eila Serrano‐Hervás

10.1016/j.neo.2025.101143

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Abstract P1-10-01: Safety and efficacy of neoadjuvant metformin with trastuzumab and chemotherapy in women with HER2-positive early breast cancer: A randomized, open-label, multicenter, phase 2 trial

Cancer Research (2018)

Sònia Pernas Joan Dorca Isabel Álvarez Susana Torres Cristina Saura

Abstract Background: Epidemiological, pre-clinical, and window-of-opportunity trials have suggested that the anti-diabetic drug metformin (MET) may have beneficial effects on breast cancer (BC). The clinical relevance of combining MET with current standards of care for first-line treatment of BC is unknown. We investigated the safety and efficacy of adding MET to neoadjuvant chemotherapy plus trastuzumab (TTZ) in patients with HER2-positive early BC. Methods: In a randomized, multicenter, open-label phase 2 study, women with operable, locally advanced, or inflammatory HER2+ BC were randomly assigned in a 1:1 ratio to receive daily MET (1,700 mg) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus TTZ followed by four cycles of fluorouracil, epirubicin, cyclophosphamide/3w plus TTZ (arm A) or equivalent sequential chemotherapy plus TTZ without MET (arm B), followed by surgery. Patients were stratified by age, extent of disease (cT2 cN0-1 vs ≥ T3 or ≥ N2), and hormone receptor (HR)-status. The intention-to-treat (ITT) safety population comprised all women who underwent randomization and received at least one treatment dose. Primary endpoint was the rate of pathological complete response (pCR) analyzed in the per-protocol (PP) efficacy population. pCR was defined as absence of invasive cancer in the breast and axillary nodes, irrespective of carcinoma in situ (ypT0/is ypN0). Results: From June 1, 2012 to March 17, 2016, 98 patients were assessed for eligibility at 10 centers in Spain. Of 84 (85.7%) patients who were randomized, 41 patients were allocated to arm A and 43 to arm B. The most common adverse effects (AEs) in the 79 ITT patients were fatigue, diarrhea, nausea, alopecia, sensory neuropathy, mucositis, neutropenia, and elevated AST/ALT. Most AEs were grades 1–2 (>90% in both arms). The most common AEs grade ≥3 were neutropenia (7/38 women in arm A and 5/41 women in arm B) and diarrhea (5 and 0, respectively). The number of serious AEs was 3 in arm A (none of them was deemed to be MET-related) and 2 in arm B. At week 12, one (2.9%) patient in arm A and 6 (15%) in arm B exhibited asymptomatic decreases in the left ventricular ejection fraction (LVEF). At week 24, none (0%) of the patients in arm A and 3 (7.9%) patients in arm B presented decreases of LVEF below 50% and >10% from baseline. Only one patient (2.7%) in arm B experienced symptomatic heart failure. The rates of breast-conserving surgery were 79.3% and 58.6% in PP arms A and B, respectively. Also, 19/29 PP patients in arm A (65.5%, 95% CI 47–80) had a pCR versus 17/29 PP patients (58.6%, 95% CI 41–74) in arm B (OR 1.34 [95% CI 0.46–3.89], p=0.589). The combined rates of pCR and near-pCR (ypT1aN0) were 79.3% in arm A and 72.4% in arm B. Significantly fewer pCR were noted for tumors that were HR-positive regardless of which arm the patients were randomized. Conclusion: The higher pCR rate in HER2+ BC patients receiving MET-containing neoadjuvant therapy and TTZ did not reach statistical significance. Evaluation of long-term outcome data such as 5-year disease-free survival and correlative biological studies are needed to evaluate the clinico-molecular relevance of these findings. Citation Format: Pernas S, Dorca J, Álvarez-López I, Martínez S, Saura C, Batista López N, Rodríguez-Sánchez CA, Amillano K, Domínguez-Fernández S, Luque Cabal M, Morilla I, Viñas G, Cortés J, Cuyàs E, Verdura S, Fernández-Arroyo S, Joven J, Pérez E, García M, Bosch N, López-Bonet E, Saidani S, Buxó M, Menendez JA, Martin-Castillo B. Safety and efficacy of neoadjuvant metformin with trastuzumab and chemotherapy in women with HER2-positive early breast cancer: A randomized, open-label, multicenter, phase 2 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-01.

Epirubicin

Clinical endpoint

Neoadjuvant Therapy

10.1158/1538-7445.sabcs17-p1-10-01

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Citations (2)

Abstract 3940: Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness

Cancer Research (2015)

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Abstract Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the partitioning defective 3 gene, PARD3, to the carcinogenesis of lung squamous cell carcinomas (LSCCs). Tumor-specific PARD3 alterations were found in eight per cent of the tumors, placing PARD3 among the most common tumor suppressor genes in LSCC. Some PAR3 mutant proteins prevented the formation of contacts between neighboring cells, i.e. had reduced ability to form tight junctions and actin-based protrusions. This affected subsequent downstream signaling, i.e. binding to aPKC and activation of RAC1. Further, we discovered that PAR3 wild type triggered the expression of cell adhesion and polarity-related transcripts and the activation of STAT3, by cell confluence. Finally, restitution of PAR3 in vivo significantly reduced the formation of metastasis. In conclusion, PARD3 is recurrently inactivated in LSCC and its deficiency contributes to the tumor aggressiveness. Citation Format: Ester Bonastre, Sara Verdura, Ilse Zondervan, Federica Facchinetti, Sylvie Lantuejoul, Maria Dolores Chiara, Juan Pablo Rodrigo, Julian Carretero, David Sidransky, Alberto Villanueva, Enric Condom, Agustin Vidal, Luca Roz, Elisabeth Brambilla, Suvi Savola, Montse Sanchez-Cespedes. Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3940. doi:10.1158/1538-7445.AM2015-3940

10.1158/1538-7445.am2015-3940

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Revisiting silibinin as a novobiocin-like Hsp90 C-terminal inhibitor: Computational modeling and experimental validation

Food and Chemical Toxicology (2019)

Elisabet Cuyàs Sara Verdura Vicente Micol Jorge Joven Joaquim Bosch‐Barrera

Silibinin

Silybum marianum

Novobiocin

Geldanamycin

10.1016/j.fct.2019.110645

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Citations (17)

Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

International Journal of Molecular Sciences (2020)

Javier A. Menéndez Inderjit Mehmi Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs

HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.

Fulvestrant

Neuregulin

ErbB

10.3390/ijms21207661

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Citations (25)