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1.
Cell Death Dis ; 13(7): 606, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831273

RESUMO

Renal cell carcinoma (RCC) is a common malignant tumor in the world. Histologically, most of RCC is classified as clear cell renal cell carcinoma (ccRCC), which is the most prevalent subtype. The overall survival of patients with ccRCC is poor, thus it is urgent to further explore its mechanism and target. S-phase kinase-associated protein 2 (SKP2) is overexpressed in a variety of human cancers and is associated with poor prognosis by enhancing tumor progression. However, it is unclear whether or how SKP2 is involved in ccRCC progression. Here, we reported that overexpression of SKP2 enhanced cell proliferation of ccRCC, while SKP2 depletion exhibited the opposite effect. Bioinformatic analyses found that SKP2 was positively correlated with Aurora-A (Aur-A) in ccRCC. The protein and mRNA levels of SKP2 were elevated or reduced by Aur-A overexpression or silencing, respectively. It was further found that Aur-A caused an increase phosphorylation of FOXO3A, which is a negatively transcription factor for SKP2. Interestingly, SKP2 mediated ubiquitylation and degradation of FOXO3A depend on the kinase activity of Aur-A. The combination of Aur-A inhibitor MLN8237 and SKP2 inhibitor SZL P1-41 showed a synergistic tumor growth inhibition in vivo and in vitro of ccRCC models. Thus, our data reveal that Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in ccRCC, and the double inhibition of SKP2 and Aur-A shows significant synergistic effect, which indicates a potential new therapeutic strategy for ccRCC.


Assuntos
Aurora Quinase A , Carcinoma de Células Renais , Neoplasias Renais , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/metabolismo , Azepinas/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Transdução de Sinais
2.
Curr Opin Oncol ; 34(4): 403-411, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35837710

RESUMO

PURPOSE OF REVIEW: To summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials. RECENT FINDINGS: For the first time since gemcitabine-cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine-cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600E mutations or KRASG12C mutations. SUMMARY: In this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.


Assuntos
Neoplasias do Sistema Biliar , Cisplatino , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/genética , Humanos , Imunoterapia , Terapia de Alvo Molecular , Medicina de Precisão , Receptores de Fatores de Crescimento de Fibroblastos
3.
J Ethnopharmacol ; 296: 115521, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35809757

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: During the treatment of diseases, histone deacetylases (HDAC) may have side effects such as strong immune inhibition and drug resistance, which may lead to damage of heart, liver and kidney. Traditional Chinese medicine (TCM) is a valuable and unique resource in China, which has good efficacy and safety. At present, it has been found that Chinese herbal compounds and active ingredients can effectively inhibit the expression of HDAC. Moreover, pharmacological studies have shown that these TCMs have shown therapeutic effects in the treatment of cancer, cardiovascular and cerebrovascular diseases, orthopedic diseases and skin diseases. AIM OF THE REVIEW: This article reviews the mechanism of action of HDAC, and introduces the epigenetic correlation between TCM and HDAC. We expounded the histone deacetylase inhibitor (HDACi)-like inhibitory effect and clinical application of natural drugs, and summarized the research progress of TCM on HDAC in recent years. MATERIALS AND METHODS: We collected relevant information published before March 2022 by searching the literature in various online databases such as PubMed, CNKI, Wanfang Database, Elsevier, Web of Science and China Biomedical Database. Search terms include "HDAC" or "HDACi", as well as "herb" or "herbal ingredient". RESULTS: A large number of studies have proved that many TCMs and their chemical components have the effect of inhibiting HDAC activity, which is highly selective, acts on different HDAC subtypes, and plays a certain therapeutic effect in cancer, cardiovascular and cerebrovascular diseases, orthopedic diseases, skin diseases and other diseases by inhibiting the process of HDAC. DISCUSSION AND CONCLUSIONS: The review of this paper is helpful to understand and excavate the active components of TCM, further explore the role of plant drugs with HDACi-like effect in diseases, and provide ideas for the development of new HDACi.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Medicina Tradicional Chinesa , Terapia de Alvo Molecular , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico
4.
Med Oncol ; 39(10): 149, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834030

RESUMO

Breast cancer is categorized at the molecular level according to the status of certain hormone and growth factor receptors, and this classification forms the basis of current diagnosis and treatment. The development of resistance to treatment and recurrence of the disease have led researchers to develop new therapies. In recent years, most of the research in the field of oncology has focused on the development of targeted therapies, which are treatment methods developed directly against molecular abnormalities. Promising advances have been made in clinical trials investigating the effect of these new treatment modalities and their combinations with existing therapeutic treatments in the treatment of breast cancer. Monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates, PI3K/Akt/mTOR pathway inhibitors, cyclin-dependent kinase 4/6 inhibitors, anti-angiogenic drugs, PARP inhibitors are among the targeted therapies used in breast cancer treatment. In this review, we aim to present a molecular view of recently approved target agents used in breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo
5.
Med Oncol ; 39(10): 147, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834033

RESUMO

Lung cancer is the prime cause of cancer-related deaths globally, with a contribution of 85% from non-small cell lung cancer. Before a few decades back, conventional chemotherapy was the most chosen treatment option for NSCLC but with side effects. Now, the treatment approaches have shifted to a new trend, targeted therapy, and a better treatment strategy with minimal side effects compared to chemotherapy. Advances in technologies and understanding the pathways lead to the discovery of new targets and through which it is possible to improve treatment outcomes and patient compliance. Unlike chemotherapy, targeted therapy focuses on the tumor cells and does not produce toxicity to healthy cells. The last two decades were very crucial in the development of many small molecules with the capability to target-specific proteins or genes in the disease progression pathway. Although the targeted therapy approach was a gemstone with many successful drugs for the treatment of NSCLC, various resistance mechanisms and activation of bypass signaling pathways put many of these drugs in the trash. In this review, we will discuss the major targeted proteins involved in NSCLC as well as the inhibitor drugs developed to target them for now and along with the future directions.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular
6.
Proc Natl Acad Sci U S A ; 119(30): e2123065119, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35858407

RESUMO

SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.


Assuntos
Antivirais , COVID-19 , Interações Hospedeiro-Patógeno , Terapia de Alvo Molecular , Processamento de Proteína Pós-Traducional , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/virologia , Células CACO-2 , Exorribonucleases/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Sirtuínas/metabolismo , Succinatos/metabolismo , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
7.
J Enzyme Inhib Med Chem ; 37(1): 2004-2016, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35844184

RESUMO

Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.


Assuntos
Chalconas , Fator de Transcrição STAT3 , Neoplasias Gástricas , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/farmacologia , Humanos , Terapia de Alvo Molecular , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico
8.
BMJ Open ; 12(7): e058350, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35820758

RESUMO

OBJECTIVES: Cancer is increasingly classified according to biomarkers that drive tumour growth and therapies developed to target them. In rare biomarker-defined cancers, randomised controlled trials to adequately assess targeted therapies may be infeasible. Extrapolating existing evidence of targeted therapy from common cancers to rare cancers sharing the same biomarker may reduce evidence requirements for regulatory approval in rare cancers. It is unclear whether guidelines exist for extrapolation. We sought to identify methodological guidance for extrapolating evidence from targeted therapies used for common cancers to rare biomarker-defined cancers. DESIGN: Scoping review. DATA SOURCES: Websites of health technology assessment agencies, regulatory bodies, research groups, scientific societies and industry. EBM Reviews-Cochrane Methodology Register and Health Technology Assessment, Embase and MEDLINE databases (1946 to 11 May 2022). ELIGIBILITY CRITERIA: Papers proposing a framework or recommendations for extrapolating evidence for rare cancers, small populations and biomarker-defined cancers. DATA EXTRACTION AND SYNTHESIS: We extracted framework details where available and guidance for components of extrapolation. We used these components to structure and summarise recommendations. RESULTS: We identified 23 papers. One paper provided an extrapolation framework but was not cancer specific. Extrapolation recommendations addressed six distinct components: strategies for grouping cancers as the same biomarker-defined disease; analytical validation requirements of a biomarker test to use across cancer types; strategies to generate control data when a randomised concurrent control arm is infeasible; sources to inform biomarker clinical utility assessment in the absence of prospective clinical evidence; requirements for surrogate endpoints chosen for the rare cancer; and assessing and augmenting safety data in the rare cancer. CONCLUSIONS: In the absence of an established framework, our recommendations for components of extrapolation can be used to guide discussions about interpreting evidence to support extrapolation. The review can inform the development of an extrapolation framework for biomarker-targeted therapies in rare cancers.


Assuntos
Terapia de Alvo Molecular , Neoplasias , Biomarcadores , Humanos , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Avaliação da Tecnologia Biomédica
9.
Zhongguo Fei Ai Za Zhi ; 25(7): 506-510, 2022 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-35899449

RESUMO

As lung cancer targeted therapy and immunotherapy drugs are the current hot spot in the research and development area of new anti-tumor drugs, the amount of clinical trial in this area is increasing year by year. On the basis of combing the on-site inspections of drug registration clinical trials from 2019 to 2021, combined with the characteristics of lung cancer targeted therapy and immunotherapy drugs, this paper discusses the focus of on-site inspection of clinical trials of such drugs, and puts forward suggestions for the compliant implementation of lung cancer clinical trials.
.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular
10.
Proc Natl Acad Sci U S A ; 119(29): e2113180119, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858356

RESUMO

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia de Alvo Molecular , Oligonucleotídeos Antissenso , Proteínas Proto-Oncogênicas p21(ras) , Animais , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/terapia , Camundongos , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/uso terapêutico , Polietilenoglicóis , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Curr Oncol ; 29(7): 5054-5076, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35877260

RESUMO

Prostate cancer remains one of the leading causes of cancer death in men worldwide. In the past decade, several new treatments for advanced prostate cancer have been approved. With a wide variety of available drugs, including cytotoxic agents, androgen receptor axis-targeted therapies, and alpha-emitting radiation therapy, identifying their optimal sequencing remains a challenge. Progress in the understanding of the biology of prostate cancer has provided an opportunity for a more refined and personalized treatment selection process. With the advancement of molecular sequencing techniques, genomic precision through the identification of potential treatment targets and predictive biomarkers has been rapidly evolving. In this review, we discussed biomarker-driven treatments for advanced prostate cancer. First, we presented predictive biomarkers for established, global standard treatments for advanced diseases, such as chemotherapy and androgen receptor axis-targeted agents. We also discussed targeted agents with recent approval for special populations, such as poly ADP ribose polymerase (PARP) inhibitors in patients with metastatic castrate-resistant prostate cancer with homologous recombination repair-deficient tumors, pembrolizumab in patients with high levels of microsatellite instability or high tumor mutational burden, and prostate-specific membrane antigen (PSMA) directed radioligand theragnostic treatment for PSMA expressing tumors. Additionally, we discussed evolving treatments, such as cancer vaccines, chimeric antigen receptor T-cells (CAR-T), Bispecific T-cell engagers (BiTEs), other targeted agents such as AKT inhibitors, and various combination treatments. In summary, advances in molecular genetics have begun to propel personalized medicine forward in the management of advanced prostate cancer, allowing for a more precise, biomarker-driven treatment selection with the goal of improving overall efficacy.


Assuntos
Antineoplásicos , Neoplasias da Próstata , Antineoplásicos/uso terapêutico , Biomarcadores , Humanos , Masculino , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Receptores Androgênicos/uso terapêutico
12.
Biol Pharm Bull ; 45(7): 814-823, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35786588

RESUMO

Oral multi-kinase inhibitors have transformed the treatment landscape for various cancer types and provided significant improvements in clinical outcomes. These agents are mainly approved at fixed doses, but the large inter-individual variability in pharmacokinetics and pharmacodynamics (efficacy and safety) has been an unsolved clinical issue. For example, certain patients treated with oral multi-kinase inhibitors at standard doses have severe adverse effects and require dose reduction and discontinuation, yet other patients have a suboptimal response to these drugs. Consequently, optimizing the dosing of oral multi-kinase inhibitors is important to prevent over-dosing or under-dosing. To date, multiple studies on the exposure-efficacy/toxicity relationship of molecular targeted therapy have been attempted for the implementation of therapeutic drug monitoring (TDM) strategies. In this milieu, we recently conducted research on several multi-kinase inhibitors, such as sunitinib, pazopanib, sorafenib, and lenvatinib, with the aim to optimize their treatment efficacy using a pharmacokinetic/pharmacodynamic approach. Among them, sunitinib use is an example of successful TDM implementation. Sunitinib demonstrated a significant correlation between drug exposure and treatment efficacy or toxicities. As a result, TDM services for sunitinib has been covered by the National Health Insurance program in Japan since April 2018. Additionally, other multi-kinase targeted anticancer drugs have promising data regarding the exposure-efficacy/toxicity relationship, suggesting the possibility of personalization of drug dosage. In this review, we provide a comprehensive summary of the clinical evidence for dose individualization of multi-kinase inhibitors and discuss the utility of TDM of multi-kinase inhibitors, especially sunitinib, pazopanib, sorafenib, and lenvatinib.


Assuntos
Antineoplásicos , Monitoramento de Medicamentos , Antineoplásicos/efeitos adversos , Humanos , Terapia de Alvo Molecular , Sorafenibe , Sunitinibe
13.
Int J Mol Sci ; 23(14)2022 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-35887235

RESUMO

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually associated with tobacco and/or alcohol use, whereas human papillomavirus (HPV) infection, particularly HPV16 infection, is increasingly recognized as a cause of oropharyngeal HNSCC. Despite clinical, histologic, and molecular differences between HPV-positive and HPV-negative HNSCCs, current treatment approaches are the same. For recurrent disease, these strategies include chemotherapy, immunotherapy with PD-1-inhibitors, or a monoclonal antibody, cetuximab, that targets epidermal growth factor; these therapies can be administered either as single agents or in combination. However, these treatment strategies carry a high risk of toxic side effects; therefore, more effective and less toxic treatments are needed. The landscape of HNSCC therapy is changing significantly; numerous clinical trials are underway to test novel therapeutic options like adaptive cellular therapy, antibody-drug conjugates, new targeted therapy agents, novel immunotherapy combinations, and therapeutic vaccines. This review helps in understanding the various developments in HNSCC therapy and sheds light on the path ahead in terms of further research in this field.


Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imunoterapia , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
14.
Clin. transl. oncol. (Print) ; 24(7): 1262-1273, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203827

RESUMO

Solid tumors including skin, lung, breast, colon, and prostate cancers comprise the most diagnosed cancers worldwide. Treatment of such cancers is still challenging specially in the advanced/metastatic setting. The growing understanding of the tumor microenvironment has revolutionized the cancer therapy paradigms. Targeting programmed death-1 (PD-1)/PD-L1 immune checkpoint has been extensively studied over this decade as a new trend in the management of hard-to-treat cancers by harnessing the power of the immune system to eradicate the tumors. Yet, low response rate and resistance were observed when immunotherapies were tested as monotherapy. This urged the need to develop combinatorial regimens of immunotherapy with other immune modulatory agents to enhance its therapeutic potential and help in reverting the resistance. Epigenetic modifiers such as histone deacetylase inhibitors (HDACIs) showed favorable effects on modulating the tumor microenvironment along with the host immune cells. This qualified HDACIs as an attractive candidate class to be tested in combination with immunotherapy. In this review we cover the ongoing clinical trials that investigate the safety and/or the efficacy of HDACI/immunotherapy combinations in solid tumors including skin cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and recapitulates areas for future research.


Assuntos
Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Imunoterapia , Microambiente Tumoral
15.
Oncol Rep ; 48(2)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35775375

RESUMO

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer­specific biomarkers. The application of three membrane­bound receptors, namely urokinase­type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)­positive and 48 HPV­negative groups, the IHC­determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow­up data, overall survival (OS) and recurrence­free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log­rank test following Kaplan­Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor­specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92­4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor­specific expression pattern.


Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores Tumorais/biossíntese , Receptores ErbB/biossíntese , Humanos , Imagem Molecular , Terapia de Alvo Molecular , Neoplasias Orofaríngeas/diagnóstico por imagem , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Infecções por Papillomavirus/diagnóstico por imagem , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Prognóstico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Tromboplastina/biossíntese
16.
Nature ; 606(7916): 976-983, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35705807

RESUMO

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.


Assuntos
Instabilidade Cromossômica , Neoplasias , Instabilidade Cromossômica/genética , Recombinação Homóloga/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
17.
Cancer ; 128(16): 3019-3026, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35726525

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy arising from precursor dendritic cells. BPDCN cells characteristically express several markers on their cell surfaces including CD123, CD4, and CD56. Because of its rarity and challenging clinical presentation, there was no standard of care in managing BPDCN for decades and its prognosis overall was poor. However, as understanding of this rare neoplasm has increased, so have treatment options. The conventional cytotoxic chemotherapy regimens once used in the treatment of BPDCN were modest in their impact on disease relapse until paired with hematopoietic stem cell transplant. Although recent data suggest that there still remains a role for chemotherapeutic agents, targeted modalities have expanded the overall BPDCN treatment landscape. The CD123-targeted agent, tagraxofusp, was the first Food and Drug Administration-approved monotherapy in the treatment of BPDCN. Since its inception, several CD123-targeted and other cell-surface agents have been investigated, with many agents still in the preclinical stages. Although relapsed/refractory disease and central nervous system disease both remain formidable areas of research, there are several promising therapeutic approaches that could have a significant impact on the trajectory of treatment. This review will provide detailed insight on the novel drugs currently in use and those being explored in the management of BPDCN.


Assuntos
Antineoplásicos , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Doença Aguda , Antineoplásicos/uso terapêutico , Células Dendríticas/metabolismo , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-3/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Cutâneas/patologia
18.
Proc Natl Acad Sci U S A ; 119(24): e2200200119, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35675429

RESUMO

The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 µg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 µg/teat). MCF7 tumor-bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.


Assuntos
ADP Ribose Transferases , Toxinas Bacterianas , Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Exotoxinas , Imunotoxinas , Terapia de Alvo Molecular , Receptores da Transferrina , Fatores de Virulência , ADP Ribose Transferases/administração & dosagem , ADP Ribose Transferases/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Toxinas Bacterianas/administração & dosagem , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Exotoxinas/administração & dosagem , Feminino , Humanos , Imunotoxinas/administração & dosagem , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores da Transferrina/metabolismo , Fatores de Virulência/administração & dosagem
19.
Pharmacol Ther ; 236: 108234, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35732246

RESUMO

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno , Terapia de Alvo Molecular , Mutação , Oximas/farmacologia , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/uso terapêutico
20.
Comput Biol Med ; 147: 105739, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35763932

RESUMO

BACKGROUND: Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the main components of turmeric that commonly used to treat neuropathic pain (NP). However, the mechanism of the therapy is not sufficiently clarified. Herein, network pharmacology, molecular docking and molecular dynamics (MD) approaches were used to investigate the mechanism of curcuminoids for NP treatment. METHODS: Active targets of curcuminoids were obtained from the Swiss Target database, and NP-related targets were retrieved from GeneCards, OMIM, Drugbank and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. Furthermore, DAVID was used for GO and KEGG pathway enrichment analyses. Interactions between potential targets and curcuminoids were assessed by molecular docking and the MD simulations were run for 100ns to validate the docking results on the top six complexes. RESULTS: CUR, DMC, and BDMC had 100, 99 and 100 targets respectively. After overlapping with NP there were 33, 33 and 31 targets respectively. PPI network analysis of TOP 10 core targets, TNF, GSK3ß were common targets of curcuminoids. Molecular docking and MD results indicated that curcuminoids bind strongly with the core targets. The GO and KEGG showed that curcuminoids regulated nitrogen metabolism, the serotonergic synapse and ErbB signaling pathway to alleviate NP. Furthermore, specific targets in these three compounds were also analysed at the same time. CONCLUSIONS: This study systematically explored and compared the anti-NP mechanism of curcuminoids, providing a novel perspective for their utilization.


Assuntos
Curcuma , Curcumina , Diarileptanoides , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia , Curcuma/química , Curcumina/química , Curcumina/farmacologia , Bases de Dados Factuais , Diarileptanoides/química , Diarileptanoides/farmacologia , Receptores ErbB/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Nitrogênio/metabolismo , Serotonina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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