• Cancer
• Drugs
• Nuclear stress
• Ribosome biogenesis
• p53
• p53 inhibitors
• p53 mutation

• Humans
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Animals
• Ribosomes/metabolism
• Neoplasms/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neoplasms/genetics
• Cell Nucleus/metabolism
• Stress, Physiological/physiology
• Signal Transduction/physiology

• Angiogenesis
• Cancer
• Inhibitors
• VEGFR

• Humans
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
• Receptors, Vascular Endothelial Growth Factor/metabolism
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/chemistry
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology
• Animals
• Molecular Structure

• cancer
• chemotherapy
• drug targeting
• immunotherapy
• p53
• tumor suppressor

• Humans
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Friends
• Genes, p53
• Mutation
• Neoplasms/genetics
• Neoplasms/therapy
• Tumor Microenvironment

• 82073477 National Natural Science Foundation of China
• 2022JDJQ0051 the Young Talent Project of China National Nuclear Corporation, and Scientific Fund for Distinguished Young Scholars in Sichuan Province
• National Natural Science Foundation of China

• Alzheimer’s disease
• cancer
• drugs
• epigenetics
• metabolism
• molecular mechanisms of pathogenesis
• neurodegenerative diseases
• oxidative stress

• Humans
• Neurodegenerative Diseases/metabolism
• Oxidative Stress/physiology

• 075-15-2022-1128 Ministry of Science and Higher Education of the Russian Federation at FRC Kazan Scientific Center

• Angiogenesis
• ELK3
• Glioma
• HIF-1
• VEGF-A

• Animals
• Mice
• Mice, Nude
• Vascular Endothelial Growth Factor A/metabolism
• Glioma/pathology
• Signal Transduction
• Cell Proliferation
• Hypoxia-Inducible Factor 1/metabolism
• Cell Line, Tumor
• Neovascularization, Pathologic/metabolism

• 2023-YBSF-096 Key R &D Plan Projects in Shaanxi Province
• 81772661 National Natural Science Foundation of China
• 2020JZ-30 Natural Science Basic Research Program of Shaanxi Province of China for Project
• 2023-JC-JQ-68 Shaanxi Outstanding Youth Science Foundation Project

• Anlotinib hydrochloride
• anti-angiogenesis therapy
• case report
• chemotherapy
• elderly patients
• front-line treatment
• non-small cell lung cancer
• tegafur-uracil

• PENAO
• SAHA
• SLC25A5
• neuroblastoma

• Animals
• Mice
• Antineoplastic Agents/pharmacology
• Apoptosis
• Cell Line, Tumor
• Histone Deacetylase Inhibitors/pharmacology
• Histones/metabolism
• Hydroxamic Acids/therapeutic use
• Mitochondria/metabolism
• Neuroblastoma/drug therapy
• Vorinostat/pharmacology
• Adenine Nucleotide Translocator 2/antagonists & inhibitors

• Cancer Council NSW
• Cancer Institute NSW

• clinical trial
• mutant p53
• reactivation
• synthetic lethality
• vulnerability

• R01 CA214916 NCI NIH HHS
• R01 CA214916 NIH HHS

Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure–activity relationships and future directions.

• Antiangiogenesis treatment
• Antitumor drugs
• Dual inhibitor
• VEGFR kinase

Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients’ initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m², presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.

Distant metastasis is the major contributor to the high mortality rate of colorectal cancer (CRC). To overcome the poor prognosis caused by distant metastasis, the mechanisms of CRC metastasis should be further explored. Epigenetic events are the main mediators of gene regulation and further affect tumor progression. Recent studies have found that some epigenetic enzymes are often dysregulated or mutated in multiple tumor types, which prompted us to study the roles of these enzymes in CRC metastasis. In this review, we summarized the alteration of enzymes related to various modifications, including histone modification, nonhistone modification, DNA methylation, and RNA methylation, and their epigenetic mechanisms during the progression of CRC metastasis. Existing data suggest that targeting epigenetic enzymes is a promising strategy for the treatment of CRC metastasis.

• CRC metastasis
• DNA methylation
• Epigenetics
• Histone modification
• RNA methylation

Solitary fibrous tumor (SFT) of the central nervous system is rare. It is predominantly benign and rarely malignant. There is no established standardized treatment regimen for malignant intracranial SFTs.

We present a rare case of SFT in a 9-year-old girl with a space-occupying effect in the frontal-parietal lobes. She underwent craniotomy, and the mass was resected. Immunohistochemistry examination of the specimen showed that Ki-67 proliferation index staining was highly positive in 80% of tumor cells. Whole exome sequencing of the surgical tissue showed 38 somatic gene mutations and 1 gene amplification such as fibroblast growth factor receptor 4 or TP53. At 1.5 mo after surgery, head magnetic resonance imaging revealed that the tumor had recurred. The patient received 60 Gy and 30 fractions of intensity modulated radiotherapy. The patient then received anlotinib 8 mg po qd for 1-14 d of a 21 d cycle. Following this regimen, the patient achieved stable disease for > 17 mo. Magnetic resonance imaging at 1.5 year after surgery showed that the tumor had not progressed.

This is the first reported case of SFT of the central nervous system treated with surgery, radiotherapy and anlotinib. This regimen may be an effective treatment option for malignant intracranial SFT patients.

• Anlotinib
• Biological therapy
• Mutation
• Recurrence
• Sequence analysis
• Case report

HER2 is a member of the ERBB family of receptor tyrosine kinases, and HER2 mutations occur in 1–4% of non-small cell lung cancer (NSCLC) as an oncogenic driver mutation. We found a rare mutation of HER2 p.Asp769Tyr in NSCLC.

We presented a case of a 68-year-old nonsmoking male patient with brain metastasis from lung adenocarcinoma harboring a rare mutation of HER2 p.Asp769Tyr. After multiple lines of treatment, he obtained a durable response (10 months) to afatinib and anlotinib.

We reported for the first time that afatinib and anlotinib have successfully treated lung adenocarcinoma with HER2 p.Asp769Tyr mutation. This finding can provide an insight into the optimal treatment of lung adenocarcinoma patients with novel mutations. Additionally, we summarized the efficacy of targeted therapy for HER2 mutant lung cancer in this article.

The online version contains supplementary material available at 10.1186/s12957-021-02444-7.

• Afatinib
• Anlotinib
• HER2 mutation
• Lung adenocarcinoma
• Targeted therapy

• TP53
• anthracyclines
• biomarker
• prognosis
• sarcoma

The preventive activity of dietary fiber against colorectal cancer (CRC) may be in part mediated by the fermentation product of fiber, butyrate, a histone deacetylase inhibitor (HDACi) that induces CRC cell growth arrest and apoptosis. This action of butyrate, and other HDACis, is in part due to the hyperactivation of the deregulated Wnt activity found in the relevant CRC cell lines. The histone acetylases CBP and p300 interact with beta-catenin; and the relative levels of CBP-Wnt vs. p300-Wnt activity influences CRC cell physiology. It has previously been observed that there are cell type-specific differences in how cotreatment with butyrate and ICG-001, an agent that blocks CBP-Wnt activity allowing for p300-Wnt activity, affects CRC cell physiology. These differences may have clinical significance in dealing with treatment of CRC patients with ICG-001-like agents. Sam68 is a factor differentially expressed in cancer cells, with higher expression in cancer cell lines that have cancer stem cell (CSC)-like properties. Sam68 expression sensitizes cancer cells to ICG-001 treatment, as ICG-001 enhances nuclear localization of Sam68, where binding between Sam68 and CBP diminishes CBP-beta-catenin binding and thus CBP-Wnt activity. Pygo2 is a chromatin effector involved with Wnt signaling that is differentially acetylated by CBP and p300; thus CBP-mediated acetylation localized Pygo2 to the nucleus where it functions in transcriptional activation, while p300-mediated acetylation localizes Pygo2 to the cytoplasm. This paper proposes the hypothesis that Sam68 and Pygo2 are responsible for cell type-specific response of CRC cell lines cotreated with ICG-001 and butyrate as well as other HDACis. Further, experiments are proposed to evaluate this hypothesis and consider possible expected results that could be obtained from such studies.

• CBP
• ICG-001
• Sam68
• Wnt signaling
• butyrate
• colorectal cancer
• p300

The appearance of tyrosine kinase inhibitors (TKIs) has been a major breakthrough in renal cell carcinoma (RCC) therapy. Unfortunately, a portion of patients with TKIs resistance experience disease progression after TKIs therapy. Epigenetic alterations play an important role in the development of TKIs resistance. Current evidence suggests that epigenetic alterations occur frequently in RCC patients with poor response to TKIs therapy, and modulation of them could enhance the cytotoxic effect of antitumor therapy. In this review, we summarize the currently known epigenetic alterations relating to TKIs resistance in RCC, focusing on DNA methylation, non-coding RNAs (ncRNAs), histone modifications, and their interactions with TKIs treatment. In addition, we discuss application of epigenetic alteration analyses in the clinical setting to predict prognosis of patients with TKIs treatment, and the potential use of epigenetics-based therapies to surmount TKIs resistance.

• epigenetics
• histone modification
• long non-coding RNA
• methylation
• microRNA
• renal cell carcinoma
• target therapy
• tyrosine kinase inhibitor

• Adverse events
• Outcomes
• Pazopanib
• Safety
• Soft tissue sarcoma

• Pazopanib
• colorectal cancer
• lymph node metastasis
• lymphangiogenesis
• nude mice
• orthotopic tumor

Multitargeted antiangiogenic drugs have demonstrated significant antitumor activity against a variety of solid tumors. Anlotinib, a novel oral multitargeted antiangiogenic tyrosine kinase inhibitor, was approved as a third-line treatment for advanced NSCLC in China. However, predictive biomarkers are currently insufficient and are urgently required. Herein, we report three pre-treated cases of advanced NSCLC with TP53 mutations, wherein these patients showed partial response to anlotinib. Moreover, the three patients have achieved a progression-free survival of 8, 6.5, and 5 months, respectively. The main toxicities were hypertension, hand-foot syndrome and fatigue. In conclusion, TP53 mutations may represent a biomarker for predicting salutary effects of anlotinib.

• TP53
• angiogenesis
• anlotinib
• non-small cell lung cancer

• Age-related diseases
• Cell death
• Cell survival
• Glioma
• Neurotoxicity
• Redox system

• Brain/metabolism
• Brain/pathology
• Cyclin D/genetics
• Cyclin E/genetics
• Cyclins/genetics
• Disease Progression
• Humans
• NIMA-Interacting Peptidylprolyl Isomerase/genetics
• Neoplasms/genetics
• Neoplasms/pathology
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/pathology
• Protein Phosphatase 2/genetics
• Tumor Microenvironment/genetics
• Tumor Suppressor Protein p53/genetics

• 2018M3C7A1021848 the Original Technology Research Program for Brain Science of the National Research Foundation of Korea

• Cetuximab sensitivity
• Colorectal cancer
• SETDB1

Purpose: The goal of the present study was to determine the efficacy of temozolomide (TEM) and pazopanib (PAZ) combined with FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil) on a colorectal cancer patient-derived orthotopic xenograft (PDOX) mouse model. Materials and Methods: A colorectal cancer tumor from a patient previously established in non-transgenic nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Then labeled tumors were orthotopically implanted into the cecum of nude mice. Mice were randomized into four groups: Group 1, untreated control; group 2, TEM + PAZ; group 3, FOLFOX; group 4, TEM + PAZ plus FOLFOX. Tumor width, length, and mouse body weight were measured weekly. The Fluor Vivo imaging System was used to image the GFP-lableled tumor stromal cells in vivo. H&E staining and immunohistochemical staining were used for histological analysis. Results: All three treatments inhibited tumor growth as compared to the untreated control group. The combination of TEM + PAZ + FOLFOX regressed tumor growth significantly more effectively than TEM + PAZ or FOLFOX. Only the combination of TEM + PAZ + FOLFOX group caused a decrease in body weight. PAZ suppressed lymph vessels density in the colorectal cancer PDOX mouse model suggesting inhibition of lymphangiogenesis. Conclusion: Our results suggest that the combination of TEM + PAZ + FOLFOX has clinical potential for colorectal cancer patient.

We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1–2.3] vs. 3.5 months [95% CI, 1.7–5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8–9.8] vs. 12.7 months [95% CI, 7.1–18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.

• Wnt signaling
• apoptosis
• butyrate
• cell cycle
• colorectal cancer
• histone deacetylase inhibitor
• retinoblastoma protein

• Cancer therapy
• Sarcoma

• Institute of Cancer Research, Royal Cancer Hospital (ICR)
• Sarcoma UK
• Royal Marsden NHS Foundation Trust (Royal Marsden)
• As above

• Breast cancer
• DNA methylation
• epigenetic biomarker
• epigenetic therapy
• histone deacetylation
• metastasis
• microRNA regulations.

• Animals
• Biomarkers, Tumor/genetics
• Breast Neoplasms/diagnosis
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• DNA Methylation
• Epigenesis, Genetic
• Female
• Humans
• Neoplasm Metastasis

• KRAS
• Phase I trial
• TP53
• non-small cell lung cancer
• overall survival

• Adenosine Triphosphate/metabolism
• Administration, Intravenous
• Angiogenesis Inhibitors/chemistry
• Angiogenesis Inhibitors/pharmacology
• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Aorta, Thoracic/drug effects
• Cell Proliferation/drug effects
• Drug Evaluation, Preclinical/methods
• Epigenesis, Genetic/drug effects
• HT29 Cells
• Histone Deacetylase Inhibitors/chemistry
• Histone Deacetylase Inhibitors/pharmacology
• Human Umbilical Vein Endothelial Cells
• Humans
• Indazoles
• Male
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Molecular Targeted Therapy
• Pyrimidines/chemistry
• Rats, Sprague-Dawley
• Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
• Sulfonamides/chemistry
• Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
• Vascular Endothelial Growth Factor Receptor-2/chemistry
• Vascular Endothelial Growth Factor Receptor-2/metabolism
• Xenograft Model Antitumor Assays

Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations.

Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index <30 kg/m², and the absence of lung metastasis was established and validated. Phase I cancer patients in the low-risk group had a median OS of 16.6 months compared with 5.4 months in the high-risk group (p < 0.001). Untreated patients in the low-risk group had a median OS of 6.7 months compared with 3.6 months in the high-risk group (p = 0.033).

We analyzed 163 consecutive patients with advanced KRAS+/TP53+ mutant cancer who were referred to phase I clinical trials, to identify molecular aberrations, clinical characteristics, survivals, and potentially effective treatment regimens.

This study provided preliminary evidence that besides modulation of the proinflammatory state, antiangiogensis and concomitant gene aberration-related therapies may improve the treatment of KRAS+/TP53+ mutant cancer.

• KRAS
• TP53
• chronic inflammation
• gene aberration-related therapy
• phase I trial

Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo. Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.

• Akt
• PUMA
• apoptosis
• colon cancer
• p53

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer. It encodes p53, a DNA-binding transcription factor that regulates multiple genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis, and senescence. TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival. Identifying the discrete TP53 mutations in tumor cells may help direct therapies that are more effective. In this study, we identified the frequency of individual TP53 mutations in patients with colon adenocarcinoma (48%), non–small cell lung carcinoma (NSCLC) (36%), and glioma/glioblastoma (28%) at our institution using next-generation sequencing. We also identified the occurrence of somatic mutations in numerous actionable genes including BRAF, EGFR, KRAS, IDH1, and PIK3CA that occurred concurrently with these TP53 mutations. Of the 480 tumors examined that contained one or more mutations in the TP53 gene, 219 were colon adenocarcinomas, 215 were NSCLCs, and 46 were gliomas/glioblastomas. Among the patients positive for TP53 mutations diagnosed with colon adenocarcinoma, 50% also showed at least one mutation in pathogenic genes of which 14% were BRAF, 33% were KRAS, and 3% were NRAS. Forty-seven percent of NSCLC patients harboring TP53 mutations also had a mutation in at least one actionable pathogenic variant with the following frequencies: BRAF: 4%, EGFR: 10%, KRAS: 28%, and PIK3CA: 4%. Fifty-two percent of patients diagnosed with glioma/glioblastoma with a positive TP53 mutation had at least one concurrent mutation in a known pathogenic gene of which 9% were CDKN2A, 41% were IDH1, and 11% were PIK3CA.

High-grade epithelial ovarian cancer (HG-EOC) is the most lethal gynecologic malignancy worldwide Once patients develop chemoresistance, effective novel strategies are required to improve prognosis We analyzed characteristics and outcomes of 242 consecutive patients with HG-EOC participating in 94 phase I clinical trials at The University of Texas MD Anderson Cancer Center. Baseline lactate dehydrogenase levels, albumin levels, and number of metastatic sites were independent predictors of overall survival (OS). Receiving more than 1 phase I protocol was associated with improved OS (p < 0.001). Regimens including a chemotherapeutic agent plus bevacizumab or Aurora A kinase inhibitor led to a median progression-free survival (PFS) duration of more than 6 months. Although patients receiving bevacizumab-based regimens in the phase I clinical trials had significantly longer PFS than those receiving other anti-angiogenic therapies (p = 0.017), patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) had significantly longer OS (12.2 months) than those not treated with VEGFR-TKIs (8.6 months, p = 0.015).

In conclusion, anti-angiogenic therapy is one of the most important strategies for the treatment of HG-EOC, even in those who have already experienced tumor progression. Therefore, eligible patients with HG-EOC should be encouraged to participate in novel phase I studies of anti-angiogenic therapies, even after disease progression.

• anti-angiogenesis
• epithelial ovarian cancer
• overall survival
• progression-free survival
• tumor progression

• malignant fibrous histiocytoma
• molecular profiling
• next generation sequencing
• soft tissue sarcoma
• undifferentiated pleomorphic sarcoma

• eribulin
• high-grade
• immunotherapy
• metastatic
• olaratumab
• pazopanib
• sarcoma
• soft tissue
• trabectedin

• histone deacetylase inhibitor
• angiogenesis
• clear-cell renal cell carcinoma

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bevacizumab/administration & dosage
• Biomarkers, Tumor/blood
• Carcinoma, Renal Cell/blood
• Carcinoma, Renal Cell/drug therapy
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/pathology
• Cytokines/blood
• Female
• Follow-Up Studies
• Histone Deacetylase Inhibitors/therapeutic use
• Humans
• Hydroxamic Acids/administration & dosage
• Immunoenzyme Techniques
• Kidney Neoplasms/blood
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/genetics
• Kidney Neoplasms/pathology
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Staging
• Prognosis
• Vascular Endothelial Growth Factor A/antagonists & inhibitors
• Vorinostat

• UM1 CA186716 NCI NIH HHS
• P30 CA016056 NCI NIH HHS
• R21 CA121590 NCI NIH HHS
• UM1 CA186691 NCI NIH HHS
• U01 CA062491 NCI NIH HHS
• U01 CA070095 NCI NIH HHS

• Angiogenesis
• chemotherapy
• novel agents
• sarcoma
• targeted therapy

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Humans
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Precision Medicine
• Prognosis
• Sarcoma/drug therapy
• Sarcoma/pathology

• gene aberration-related therapy
• leiomyosarcoma
• overall survival
• phase I clinical trial
• prognostic scoring model

• Academic Medical Centers
• Adult
• Aged
• Clinical Trials as Topic
• Female
• Follow-Up Studies
• Humans
• Kaplan-Meier Estimate
• Leiomyosarcoma/complications
• Leiomyosarcoma/drug therapy
• Leiomyosarcoma/mortality
• Leiomyosarcoma/pathology
• Male
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neoplasm Staging
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Survival Analysis
• Texas
• Treatment Outcome

• UL1 TR000371 NCATS NIH HHS

• Anti-angiogenesis
• Bone sarcoma
• Ewing
• Imatinib
• Non-GIST
• Osteosarcoma
• PDGF
• Pazopanib
• Sarcoma
• Soft tissue sarcoma
• Sorafenib
• Sunitinib
• TKI
• Tyrosine kinase inhibitor
• VEGF

Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify ‘druggable’ targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25–87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6–93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients.

• high resolution melting-polymerase chain reaction
• high-grade serous ovarian carcinoma
• immunohistochemistry
• next generation sequencing
• signaling pathway
• targeted therapy