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1.
Cancers (Basel) ; 13(20)2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34680377

RESUMO

BACKGROUND: We address novelty regarding metabolomic profiling in renal cell carcinoma (RCC) patients, in an attempt to postulate potential treatment strategies. METHODS: A large-scale literature search in existing scientific websites focusing on the keywords "renal cell carcinoma", "clear cell histology", "papillary histology", "metabolomic profiling", and "therapeutics" was performed. Results: The PI3K/Akt signaling pathway is key in clear cell RCC metabolism and accordingly several drugs are presently available for routine use in clinical practice. Along this line, new treatment combinations against PI3K/Akt family members are currently under clinical investigation. On the other hand, new developed targets such as c-Met tyrosine kinase domain, glutathione (GSH) metabolism, and histone deacetylases enzymes (HDAC), as well as therapeutic strategies targeting them are currently being tested in clinical trials and here discussed. CONCLUSIONS: In RCC patients, the PI3K/Akt signaling is still the most effective targetable pathway. Targeting other metabolic pathways such as c-Met, GSH, and HDAC appears to be a promising approach and deserve further insights.

2.
Expert Opin Pharmacother ; : 1-14, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34405738

RESUMO

Introduction: In the evolving treatment scenario of metastatic renal cell carcinoma, cabozantinib is gaining increasing attention, presenting as a cornerstone therapy, both as a monotherapy and in combination with immune-checkpoint inhibitors.Areas covered: In this review, the authors explore the role of cabozantinib in the treatment of metastatic clear cell and non-clear cell renal cell carcinoma, presenting data from the most recent clinical trials and investigating ongoing studies. They, furthermore, evaluate the pharmacokinetic, pharmacodynamic, and immunomodulatory effect of cabozantinib, as well as underlining the tolerability profile and patients' quality of life.Expert opinion: Cabozantinib's administration as a single agent is restricted to intermediate- and poor-risk patients (according to IMDC criteria). The further advent of anti-VEGF-receptor tyrosine kinase inhibitors combined with immune checkpoint inhibitor regimens (such as pembrolizumab + axitinib) has allowed to expand the use of cabozantinib, leading to its combination with nivolumab. In the next few years, more information is required to look for the application of cabozantinib-based combinations as a later-line approach in metastatic RCC patients, beside their use in the first-line setting.

3.
Target Oncol ; 16(5): 625-632, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34338966

RESUMO

BACKGROUND: Renal cell carcinoma with sarcomatoid differentiation is a highly aggressive form of kidney cancer. OBJECTIVE: We aimed to analyze the outcomes of patients treated with cabozantinib for metastatic renal cell carcinoma with sarcomatoid features. METHODS: We retrospectively collected data from 16 worldwide centers. Overall survival and progression-free survival were analyzed using Kaplan-Meier curves. Cox proportional models were used for univariate and multivariate analyses. RESULTS: We collected data from 66 patients with metastatic sarcomatoid renal cell carcinoma receiving cabozantinib as second-line (51%) or third-line (49%) therapy. The median progression-free survival from the start of cabozantinib was 7.59 months (95% confidence interval [CI] 5.75-17.49) and was longer in male patients (8.81 vs 5.95 months, p = 0.042) and in patients without bone metastases (7.59 vs 5.11 months, p = 0.010); the median overall survival was 9.11 months (95% CI 7.13-23.80). At the multivariate analysis, female sex (hazard ratio = 1.81; 95% CI 1.02-3.37, p = 0.046), bone metastases (hazard ratio = 2.62; 95% CI 1.34-5.10, p = 0.005), and International Metastatic Renal Cell Carcinoma Database Consortium criteria (hazard ratio = 3.04; 95% CI 1.54-5.99, p = 0.001) were significant predictors of worse overall survival. CONCLUSIONS: Our data show that cabozantinib is active in pretreated patients with sarcomatoid renal cell carcinoma. Biomarkers are needed in this field to select patients for multi-kinase inhibitors or other options.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34058953

RESUMO

Introduction: Substantial paradigm shifts have been recently registered in metastatic renal cell carcinoma (mRCC), with combination therapies including immunotherapy showing unprecedented results. We performed number needed to treat (NNT) and number needed to harm (NNH) analyses to evaluate these approaches in mRCC.Areas covered: Clinical data of mRCC patients enrolled in four phase III trials were collected. The rates at 6, 12, 18, and 24 months for overall survival (OS), duration of response (DoR), and progression-free survival (PFS) were considered. At 6 months, the number of patients that should be treated to prevent one death with sunitinib was 20 for both pembrolizumab-lenvatinib or axitinib, 14 for nivolumab-cabozantinib, and 50 for nivolumab-ipilimumab. NNT was 100 (at 6 months) or >100 (at 12 and 18 months) for nivolumab-ipilimumab. The combinations reported peculiar and not superimposable safety profiles at the NNH analysis.Expert opinion: Although our results should be interpreted with caution, the analysis provides useful insight into the increasingly compelling interpretation of clinical trials. Immune combinations present clinically meaningful differences in terms of efficacy, with some treatments reporting different results at the NNT and the NNH analyses.

5.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188547, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33932561

RESUMO

Chimeric antigen receptor (CAR) T cell treatment has provided notable results in hematological tumors. Unfortunately, this evidence has not been translated into improved outcomes in solid malignancies so far, where several reports have suggested that T cells encounter substantial difficulties in penetrating and surviving in the tumor microenvironment (TME). Thus, researchers have recently investigated other immune cell types as CAR platforms, in order to overcome the limitations of CAR T cells. Among them, CAR-macrophages (M) technology has emerged as a novel perspective for cancer patients, on the basis of preclinical studies observing that CAR expression in human macrophages could play a crucial role in enhancing phagocytosis, polarizing M2 to M1 phenotype, and stimulating T cell anti-tumor activity. Herein, we provide an overview of current scenario of CAR-Ms in several solid tumors, also focusing on the biological rationale behind this promising therapeutic approach and future research directions in this setting.


Assuntos
Plasticidade Celular , Terapia Genética , Imunoterapia Adotiva , Macrófagos/transplante , Nanomedicina , Neoplasias/terapia , Receptores de Antígenos Quiméricos/metabolismo , Macrófagos Associados a Tumor/metabolismo , Animais , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Nanopartículas , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/genética , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia
6.
Transl Androl Urol ; 10(3): 1562-1568, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33850790

RESUMO

Prostate cancer represents the most frequent tumor in men, accounting for the 21% of all diagnosed tumors, with 191,930 new cases and 33,330 deaths estimated in 2020. Advanced prostate cancer represents a heterogeneous disease, ranging from hormone naive or hormone sensitive to castration resistant. The therapeutic armamentarium for this disease has been implemented in the last years by novel hormonal therapies and chemotherapies. However, the percentage of patients who achieve complete responses still results negligible. On this scenario, the design of clinical trials investigating new therapeutic approaches represent a dramatic medical need. Predicting cancer incidence may be fundamental to design specific clinical trials, to optimize the allocation of economic resources, and to plan future cancer control programs. ERG, SPOP and DDR genes alterations can act as therapeutic targets in prostate cancer patients and can be tested to identify a gene-selected patient population to enrol in specific trials. According to our predictions, ERG gene fusions will be the most predominant molecular subtype, accounting for 69,050 new cases in 2030. Mutation in SPOP gene will be diagnosed in 16,512 tumors, corresponding to the number of cases associated with alterations in DDR genes (including 7,956 BRCA2 mutated tumors). In this article, we analyzed and discussed the future molecular and clinical profiles of prostate cancer in the United States, aimed to describe a series of distinct subpopulations and to quantify potential clinical trial candidates in the next years.

7.
Pathol Res Pract ; 222: 153440, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33857854

RESUMO

BACKGROUND: The Androgen Receptor Splice Variant 7 (AR-V7) has been associated with poor clinical outcomes in patients with castration-resistant prostate cancer (CRPC). Herein, we performed a meta-analysis aimed at systematically exploring the association between metastatic sites and AR-V7 expression in CRPC patients across prospective clinical trials. METHODS: We retrieved all the relevant prospective clinical trials through PubMed/Medline, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included metastatic sites (lymph node metastases, any site metastases, visceral metastases, and bone metastases) in AR-V7 positive and AR-V7 negative CRPC patients. Odds Ratios (ORs) and 95 % confidence intervals (CI) were calculated. RESULTS: Overall, 14 eligible prospective studies involving a total of 1944 CRPC patients (AR-V7 positive: 467; AR-V7 negative: 1477) were included in the analysis. According to our results, no differences between AR-V7 positive and AR-V7 negative CRPC patients were observed in terms of lymph node (OR 1.01; 95 % CI 0.49-2.09) and visceral metastases (OR 1.23; 95 % CI 0.89-1.71). Conversely, AR-V7 positive CRPC patients presented higher rate of any site metastases (OR 2.22; 95 % CI 1.58-3.12) and bone metastases (OR 2.03; 95 % CI 1.42-2.9) compared to AR-V7 negative subjects. CONCLUSIONS: The results of this meta-analysis, the first in literature to be specifically focused on this topic so far, suggest that AR-V7 positivity may be associated with any site metastases and bone metastases; conversely, no association has been highlighted between AR-V7 expression and lymph node or visceral metastases. Although this meta-analysis should be interpreted with caution due to some limitations, our findings confirm that AR-V7 status could designate a unique and peculiar subtype of PC. Further studies aimed at improving and standardizing AR-V7 detection in clinical trials on CRPC patients are warranted.

8.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557050

RESUMO

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called "antibody-drug conjugates" (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells' surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunoconjugados/farmacologia , Masculino , Terapia de Alvo Molecular , Prognóstico , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etiologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Padrão de Cuidado , Resultado do Tratamento
9.
Expert Opin Investig Drugs ; 30(3): 245-251, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33599169

RESUMO

INTRODUCTION: Signal transducer and activator of transcription 3 (STAT3) is involved in cancer initiation and resistance to chemo-radiation therapies and targeted agents. The role of STAT3 in inflammation and immunity together with its involvement in a variety of diseases including genitourinary, gastrointestinal, lung, ovarian and brain tumors makes STAT3 an ideal candidate for therapeutic strategies. AREAS COVERED: The authors provided an overview on STAT3 inhibitors and examined the most recent results obtained by these agents in cancer patients. The authors discussed the results published since 2015 and the ongoing clinical trials on anti-STAT3 agents in cancer patients. The authors also provide our opinion on the future perspectives of this therapeutic approach in this context. The manuscript includes information from trial databases and scientific literature. EXPERT OPINION: Future challenges include the development of non-peptide small-molecule inhibitors of STAT3 designed to directly inhibit STAT3 activity. In addition, inhibitors of STAT3/STAT3 nuclear translocation or DNA binding activity are also emerging as novel promising therapeutic approaches A better comprehension of the role of STAT3 in modulating immune response together with advances in understanding the mechanisms of STAT3-induced chemo and/or radio-resistance will also help the design of combined strategies in cancer patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Desenvolvimento de Medicamentos , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Fator de Transcrição STAT3/metabolismo
11.
Diagnostics (Basel) ; 11(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477676

RESUMO

We analyzed the clinical and pathological features of renal cell carcinoma (RCC) patients treated with cabozantinib stratified by body mass index (BMI). We retrospectively collected data from 16 worldwide centers involved in the treatment of RCC. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. We collected data from 224 patients with advanced RCC receiving cabozantinib as second- (113, 5%) or third-line (111, 5%) therapy. The median PFS was significantly higher in patients with BMI ≥ 25 (9.9 vs. 7.6 months, p < 0.001). The median OS was higher in the BMI ≥ 25 subgroup (30.7 vs. 11.0 months, p = 0.003). As third-line therapy, both median PFS (9.2 months vs. 3.9 months, p = 0.029) and OS (39.4 months vs. 11.5 months, p = 0.039) were longer in patients with BMI ≥ 25. BMI was a significant predictor for both PFS and OS at multivariate analysis. We showed that a BMI ≥ 25 correlates with longer survival in patients receiving cabozantinib. BMI can be easily assessed and should be included in current prognostic criteria for advanced RCC.

12.
Immunol Lett ; 229: 44-47, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33248167

RESUMO

The interplay between microbiota and nervous system has been associated with a variety of diseases, including stress, anxiety, depression and cognition. The growing body of evidences on the essential role of gut microbiota in modulating acute and chronic pain has opened a new frontier for pain management. Gut microbiota is involved in the development of visceral, inflammatory and neuropathic pain. Bacterial alterations due to chronic opioid administration have been directly related to the development of drug tolerance, which can be potentially restored by the use of probiotics and antibiotics. In this review we describe the mechanisms underlying the brain/gut axis and the relationship between gut microbiota, immunity and pain.

13.
Future Oncol ; 17(2): 159-168, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33305617

RESUMO

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018-2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.


Assuntos
Neoplasias/epidemiologia , História do Século XX , História do Século XXI , Humanos , Incidência , Neoplasias/história , Redes Neurais de Computação , Vigilância em Saúde Pública , Estados Unidos/epidemiologia
14.
Diagnostics (Basel) ; 10(12)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339422

RESUMO

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

16.
BMC Cancer ; 20(1): 1119, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213401

RESUMO

BACKGROUND: Breast cancer (BC) is the second most common type of cancer worldwide. Among targeted therapies for Hormone Receptor-positive (HR+) and Human Epidermal growth factor Receptor 2-negative (HER2-) BC, the Cyclin-Dependent Kinases (CDK4/6) are targeted by inhibitors such as Ribociclib (Rib); however, resistance to CDK4/6 inhibitors frequently develops. The aim of this work is to assess in vitro activity of Rib and Everolimus (Eve) in HR+HER2- MCF-7 and HR-HER2-BT-549 BC cell lines. METHODS: HR+HER2- MCF-7 and HR-HER2- BT-549 BC cell lines were treated with increasing concentration of Rib and Eve (up to 80 µg/mL) for 48-72 h. Subsequently, HR+HER2- MCF-7 cells were silenced for Retinoblastoma (Rb) gene, and thus, the effect of Rib in sequential or concurrent schedule with Eve for the treatment of both Rb wild type or Rb knock-down MCF-7 in vitro was evaluated. Cell viability of HR+HER2- MCF-7cells treated with sequential and concurrent dosing schedule was analyzed by MTT assay. Moreover, cell cycle phases, cell death and senescence were evaluated by cytofluorimetric analysis after treatment with Rib or Eve alone or in combination. RESULTS: The sequential treatment didn't produce a significant increase of cytotoxicity, compared to Rib alone. Instead, the cotreatment synergized to increase the cytotoxicity compared to Rib alone. The cotreatment reduced the percentage of cells in S and G2/M phases and induced apoptosis. Rib triggered senescence and Eve completely reversed this effect in Rb wild type BC cells. Rib also showed Rb-independent effects as shown by results in Rb knock-down MCF-7. CONCLUSION: Overall, the Rib/Eve concurrent therapy augmented the in vitro cytotoxic effect, compared to Rib/Eve sequential therapy or single treatments.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Everolimo/uso terapêutico , Células MCF-7/metabolismo , Purinas/uso terapêutico , Receptor ErbB-2/metabolismo , Aminopiridinas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Everolimo/farmacologia , Feminino , Humanos , Purinas/farmacologia
17.
Ther Adv Med Oncol ; 12: 1758835920968463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224275

RESUMO

Background: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events. Patients and methods: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported. Results: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3-2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5-3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated (p = 0.009, p < 0.0001, p < 0.0001). Overall COVID-19 prevalence was 1.2% for vaccinated (six of 482 cases, all confirmed) and 1.7% for unvaccinated (8 of 473, 3 confirmed COVID-19 and 5 COVID-like), p = 0.52. The difference remained non-significant, considering confirmed COVID-19 only (p = 0.33). Conclusion: COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

18.
Immunotherapy ; 12(17): 1257-1268, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32998603

RESUMO

Immune checkpoint inhibitors have radically changed the treatment approach to metastatic renal cell carcinoma (mRCC). In the present article, we reported and discussed the available data with immunocombinations in mRCC, offering new perspectives in the treatment landscape of these patients. We discussed the main results of pivotal clinical trials of immune checkpoint inhibitors in the treatment of mRCC. Moreover, we discussed novel immuno-based treatments currently under investigation in ongoing clinical trials. Renal cell carcinoma is a particularly immunogenic tumor and immunotherapy is a pivotal treatment approach. A wide series of clinical trials is exploring novel promising immunocombinations in patients with renal cell carcinoma.

19.
Front Oncol ; 10: 1167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983959

RESUMO

Background: We hypothesized that non-small cell lung cancer (NSCLC) patients with a tumor positive for single nucleotide polymorphisms (SNPs) of the Excision Repair Cross Complementation Group 1 (ERCC-1) gene could be more genetically instable and consequently more responsive to a programmed cell death-1 (PD-1) blockade. Methods: We evaluated the T19007C and C8092A ERCC-1 SNPs by pyrosequencing assay, on tumor specimens from two independent cohorts of patients who relapsed after one or more prior systemic treatments for advanced NSCLC and who received nivolumab (3 mg/kg intravenously every 2 weeks) as part of the Italian Expanded Access Program. We aimed to assess the outcome of enrolled subjects according to the ERCC-1 SNPs status, to evaluate the role of these polymorphisms as putative biomarkers associated with a response/clinical benefit to anti-PD-1 therapies. Results: Of the 45 patients included in the final analysis, 21 (47%) and 16 (36%) were positive for the T19007C and C8092A polymorphic genotype (PG), respectively. In univariate analyses, overall survival (OS) and progression free survival (PFS) were shorter in patients with the T19007C PG, but neither difference achieved statistical significance (P = 0.131 and P = 0.717, respectively). The presence of the C8092A PG was associated with a longer OS and PFS, although statistical significance was only reached for PFS (P = 0.112 and P = 0.025, respectively). These results were confirmed by multivariate analyses. The response rate was only significantly higher in patients with the C8092A PG vs. wild type ERCC-1 (62 vs. 7%, P < 0.001). Conclusions: Results from this hypothesis generating pilot study, provided suggestive evidence that a subgroup of NSCLC patients could benefit differently from nivolumab according to the C8092A ERCC-1 SNP status. However, these data warrant further investigation.

20.
Front Genet ; 11: 349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32351542

RESUMO

About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors. A positive feedback loop links mTOR and ER that support each other. We subsequently considered whether a combined or sequential inhibition of CDK4/6 and PI3K/AKT/mTOR could ensure better results. Studies indicate that inhibition of CDK4/6 activates mTOR as an escape mechanism to ensure cell proliferation. In literature, the little evidence dealing with this topic suggests that pre-treatment with mTOR pathway inhibitors could prevent or delay the onset of CDK4/6 inhibitor resistance. Additional studies are needed in order to find biomarkers that can identify patients who will develop this resistance and in whom the sensitivity to CDK4/6 inhibitors can be restored.

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