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- Serum and tissue expression levels of leptin and leptin receptor are putative markers of specific feline mammary carcinoma subtypesPublication . Gameiro, Andreia; Nascimento, Catarina; Urbano, Ana Catarina; Correia, Jorge Manuel de Jesus; Ferreira, FernandoABSTRACT - Obesity is an established risk factor for breast cancer in post-menopausal women, being associated with elevated serum levels of leptin. Although overweight is a common condition in cat, the role of leptin and its receptor in feline mammary carcinoma remains unsettled. In this study, serum leptin and leptin receptor (ObR) levels were investigated in 58 cats with mammary carcinoma and compared with those of healthy animals, as were the expression levels of leptin and ObR in tumor tissues. The results showed that the Free Leptin Index is significantly decreased in cats with mammary carcinoma (p = 0.0006), particularly in those with luminal B and HER2-positive tumors, and that these animals also present significantly lower serum leptin levels (p < 0.0001 and p < 0.005, respectively). Interestingly, ulcerating tumors (p = 0.0005) and shorter disease-free survival (p = 0.0217) were associated to serum leptin levels above 4.17 pg/mL. In contrast, elevated serum ObR levels were found in all cats with mammary carcinoma (p < 0.0001), with levels above 16.89 ng/mL being associated with smaller tumors (p = 0.0118), estrogen receptor negative status (p = 0.0291) and increased serum levels of CTLA-4 (p = 0.0056), TNF-alpha (p = 0.0025), PD-1 (p = 0.0023), and PD-L1 (p = 0.0002). In tumor samples, leptin is overexpressed in luminal B and triple-negative carcinomas (p = 0.0046), whereas ObR is found to be overexpressed in luminal B tumors (p = 0.0425). Altogether, our results support the hypothesis that serum levels of leptin and ObR can be used as biomarkers of specific feline mammary carcinoma subtypes, and suggests the use of leptin antagonists as a therapeutic tool, reinforcing the utility of the cat as a cancer model.
- Tyrosine kinase inhibitors are promising therapeutic tools for cats with HER2-positive mammary carcinomaPublication . Gameiro, Andreia; Almeida, Filipe; Nascimento, Catarina; Correia, Jorge Manuel de Jesus; Ferreira, FernandoABSTRACT - Feline mammary carcinoma (FMC) is a common neoplasia in cat, being HER2-positive the most prevalent subtype. In woman’s breast cancer, tyrosine kinase inhibitors (TKi) are used as a therapeutic option, by blocking the phosphorylation of the HER2 tyrosine kinase domain. Moreover, clinical trials demonstrated that TKi produce synergistic antiproliferative effects in combination with mTOR inhibitors, overcoming resistance to therapy. Thus, to uncover new chemotherapeutic strategies for cats, the antiproliferative effects of two TKi (lapatinib and neratinib), and their combination with a mTOR inhibitor (rapamycin), were evaluated in FMC cell lines (CAT-M, FMCp and FMCm) and compared with a human breast cancer cell line (SkBR-3). Results revealed that both TKi induced antiproliferative effects in all feline cell lines, by blocking the phosphorylation of EGFR members and its downstream effectors. Furthermore, combined treatments with rapamycin presented synergetic antiproliferative effects. Additionally, the DNA sequence of the her2 TK domain (exons 18 to 20) was determined in 40 FMC tissue samples, and despite several mutations were found none of them were described as inducing resistance to therapy. Altogether, our results demonstrated that TKi and combined protocols may be useful in the treatment of cats with mammary carcinomas, and that TKi-resistant FMC are rare.
- Histone deacetylase inhibitors and microtubule inhibitors induce apoptosis in feline luminal mammary carcinoma cellsPublication . Almeida, Filipe; Gameiro, Andreia; Correia, Jorge Manuel de Jesus; Ferreira, FernandoSimple Summary: Feline mammary tumors (FMT) are very common in cats, associated with very aggressive behavior and a short life expectancy. Surgery is the most used treatment but tumor recurrence is common. Currently, available therapies are insufficient, therefore, new molecular targets are needed to develop more efficient therapeutics. Histone deacetylases inhibitors (HDACis) have been developed to target tumor cells, by disrupting gene expression and leading to cell death. Microtubules inhibitors (MTIs) have also been a focus of research, to target polymerization of microtubules, and consequently disturbing the cytoskeleton and leading to cell cycle arrest and apoptosis. However, there are few studies on the use of HDACis and MTIs in cats. In this study, we addressed if these two drug classes could be used as new therapeutic options in FMTs. All HDACis and MTIs exhibited suitable and dose-dependent antitumor effects in FMT cell lines. Immunoblot analysis confirmed that the mode of action of HDACis is conserved in feline mammary tumor cell lines. Finally, flow cytometry showed that exposure with HDACis and MTIs lead to the induction of cellular apoptosis. In summary, HDACis and MTIs possess antitumor properties suggesting further studies on their use in the treatment of feline mammary tumors.
- Diagnostic value of VEGF-A, VEGFR-1 and VEGFR-2 in feline mammary carcinomaPublication . Nascimento, Catarina; Gameiro, Andreia; Ferreira, Fernando; Correia, Jorge Manuel de Jesus; Ferreira, JoãoVascular endothelial growth factor (VEGF-A) plays an essential role in tumor-associated angiogenesis, exerting its biological activity by binding and activating membrane receptors, as vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2). In this study, serum VEGF-A, VEGFR1, and VEGFR-2 levels were quantified in 50 cats with mammary carcinoma and 14 healthy controls. The expression of these molecules in tumor-infiltrating lymphocytes (TILs) and in cancer cells was evaluated and compared with its serum levels. Results obtained showed that serum VEGF-A levels were significantly higher in cats with HER2-positive and Triple Negative (TN) Normal-Like subtypes, when compared to control group (p = 0.001, p = 0.020). Additionally, serum VEGFR-1 levels were significantly elevated in cats presenting luminal A, HER2-positive and TN Normal-Like tumors (p = 0.011, p = 0.048, p = 0.006), as serum VEGFR-2 levels (p = 0.010, p = 0.046, p = 0.005). Moreover, a positive interaction was found between the expression of VEGF-A, VEGFR-1, and VEGFR-2 in TILs and their serum levels (p = 0.002, p = 0.003, p = 0.003). In summary, these findings point to the usefulness of VEGF-A and its serum receptors assessment in clinical evaluation of cats with HER2-positive and TN Normal-Like tumors, suggesting that targeted therapies against these molecules may be effective for the treatment of these animals, as described in human breast cancer.
- VISTA is a diagnostic biomarker and immunotherapy target of aggressive feline mammary carcinoma subtypesPublication . Gameiro, Andreia; Nascimento, Catarina; Correia, Jorge; Ferreira, FernandoABSTRACT - Feline mammary carcinoma (FMC) is a common neoplasia, showing aggressive clinicopathological features, without viable therapeutic options. The study of tumor microenvironment has gained importance, due to the ability to control tumor progression by regulating the immune response. Considering the lack of knowledge, feline serum VISTA levels from cats with mammary carcinoma were compared with healthy controls, and with serum levels of PD-1/PD-L1, CTLA-4, LAG-3, IL-6, and TNF-α. In parallel, VISTA tumor expression was evaluated in FMC samples. The obtained data revealed that serum VISTA levels were significantly higher in cats presenting HER2-positive (p = 0.0025) or triple-negative subtypes (p = 0.0019), with higher serum levels in luminal A (p = 0.0025) correlated to the presence of metastasis (p = 0.0471). Furthermore, in HER2- positive or triple-negative tumors, correlations were obtained between serum VISTA levels and the serum levels of the above-mentioned molecules. In tumors, VISTA expression revealed a stronger intensity in cancer cells, when compared to TILs (p < 0.0001). Stratifying the samples by subtypes, a higher number of VISTA-positive TILs was observed in the HER2-positive subtype, compared with triple-negative tumors (p = 0.0138). In conclusion, results support the development of therapeutic strategies for HER2-positive and triple-negative FMC subtypes, reinforcing the use of cats as a human oncology model.
- Emerging biomarkers and targeted therapies in feline mammary carcinomaPublication . Gameiro, Andreia; Urbano, Ana Catarina; Ferreira, FernandoABSTRACT - : Feline mammary carcinoma (FMC) is a common aggressive malignancy with a low survival rate that lacks viable therapeutic options beyond mastectomy. Recently, increasing efforts have been made to understand the molecular mechanisms underlying FMC development, using the knowledge gained from studies on human breast cancer to discover new diagnostic and prognostic biomarkers, thus reinforcing the utility of the cat as a cancer model. In this article, we review the current knowledge on FMC pathogenesis, biomarkers, and prognosis factors and offer new insights into novel therapeutic options for HER2-positive and triple-negative FMC subtypes.
- Improving feline mammary carcinoma treatment through HER2-related immunochemotherapy agents and biomarkersPublication . Gameiro, Andreia; Ferreira, Fernando António da Costa; Correia, Jorge Manuel de JesusABSTRACT - Improving feline mammary carcinoma treatment through HER2-related immunochemotherapy agents and biomarkers - The feline mammary carcinoma (FMC) is a common tumour, with the HER2-positive and triple-negative being the most aggressive subtypes, as in women. This tumour is usually diagnosed belatedly, with scarce information about its development, and limited therapeutic options beyond mastectomy, presenting the cat a low overall survival time. Thus, this project was developed in order to improve therapeutic options, as well as, to reveal new tumour diagnosis/prognosis biomarkers, related to HER2 protein and taking advantage for the extensive knowledge in protocols used in humans. In order to disclose different therapeutic options for diseased cats, several drugs (TKi – lapatinib and neratinib; mAbs – trastuzumab and pertuzumab; ADC – T-DM1; and mTOR inhibitor – rapamycin, as adjuvant) and combined protocols were tested using FMC cell lines (CAT-M, FMCp and FMCm). These assays revealed promising antiproliferative effects and conserved molecular responses, inducing lower phosphorylation levels of target proteins, when TKi were used, and apoptosis, when mAbs and ADC drugs were evaluated. In parallel, combined protocols presented excellent synergistic responses. Moreover, feline tumour clinical tissue samples were analysed in order to identify her2 mutations as prognosis markers or therapy resistance indicators. The obtained results correlates a her2 mutation, in exon 18 (c.19573 A>T), to larger tumour sizes, a poor prognosis feature. Furthermore, any of the mutations found are described, in woman, as inducing therapeutic resistance. Additionally, considering the close relationship between obesity with increased leptin levels and the development of HER2-positive breast cancer, in woman, and since in cat obesity is a frequent nutritional disorder, the leptin/leptin receptor (ObR) axis was evaluated as possible tumour biomarker. Interestingly, cats with mammary carcinoma presented a decreased free leptin index, being the higher leptin levels associated to poor prognostic features, and serum ObR levels were correlated to an immunosuppressive status. In conclusion, the results obtained support the use of therapeutic drugs targeting the HER2, in order to improve cats’ prognosis, which could contribute for an advance in the veterinary oncology practice. Furthermore, leptin and ObR were suggested as tumour biomarkers, being proposed its use as putative adjuvant therapeutic targets
- HER2-Targeted immunotherapy and combined protocols showed promising antiproliferative effects in feline mammary carcinoma cell-based modelsPublication . Gameiro, Andreia; Nascimento, Catarina; Correia, Jorge Manuel de Jesus; Ferreira, FernandoABSTRACT - Feline mammary carcinoma (FMC) is a highly prevalent tumor, showing aggressive clinicopathological features, with HER2-positive being the most frequent subtype. While, in human breast cancer, the use of anti-HER2 monoclonal antibodies (mAbs) is common, acting by blocking the extracellular domain (ECD) of the HER2 protein and by inducing cell apoptosis, scarce information is available on use these immunoagents in FMC. Thus, the antiproliferative effects of two mAbs (trastuzumab and pertuzumab), of an antibody–drug conjugate compound (T-DM1) and of combined treatments with a tyrosine kinase inhibitor (lapatinib) were evaluated on three FMC cell lines (CATMT, FMCm and FMCp). In parallel, the DNA sequence of the her2 ECD (subdomains II and IV) was analyzed in 40 clinical samples of FMC, in order to identify mutations, which can lead to antibody resistance or be used as prognostic biomarkers. Results obtained revealed a strong antiproliferative effect in all feline cell lines, and a synergistic response was observed when combined therapies were performed. Additionally, the mutations found were not described as inducing resistance to therapy in breast cancer patients. Altogether, our results suggested that anti-HER2 mAbs could become useful in the treatment of FMC, particularly, if combined with lapatinib, since drug-resistance seems to be rare.
- Análise de imagens de tomografia computorizada para determinação da área de superfície corporal em cães (Canis lupus familiaris)Publication . Gameiro, Andreia; Lopes, António Manuel Correia Martinho; Antunes, Lara Filipa Ribeiro (Tutora)Em medicina veterinária, o cálculo das doses de fármacos aplicados em protocolos de quimioterapia está dependente da área de superfície corporal (ASC), considerando esta o peso, como a única variável morfométrica, introduzindo um fator de erro. Assim, este estudo visa determinar a ASC de cães (n=6), através de imagens de tomografia computorizada (TC) e, comparar à fórmula de cálculo em uso (Meeh, 1879) e a determinada por Girens et al., 2019. Foi também objetivo determinar a densidade total do corpo da população em estudo. Os resultados revelaram que a ASC se encontra correlacionada com o peso (p=0,0028), sendo o erro obtido, por comparação à fórmula de Meeh, 1879 e de Girens et al., 2019 não estatisticamente significativo (p=0,9268). A densidade dos animais em estudo apresentou uma mediana de 1023,810kg/m3, mostrando-se que a cavidade abdominal tem uma área de superfície superior (mediana 29,142%) à cavidade torácica (mediana 13,302%). Através da equação obtida para o cálculo da ASC e por aplicação em casos clínicos (n=2), não foram verificadas diferenças estatisticamente significativas entre as doses de fármacos calculadas. O recurso à TC poderá permitir uma reformulação do cálculo da ASC, com impacto na clínica, sendo necessário o estudo de uma população maior e representativa da espécie.