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Organoids have immense potential as ex vivo disease models for drug discovery and personalized drug screening. Dynamic changes in individual organoid morphology, number, and size can indicate important drug responses. However, these metrics are difficult and labor-intensive to obtain for high-throughput image datasets. Here, we present OrganoID, a robust image analysis platform that automatically recognizes, labels, and tracks single organoids, pixel-by-pixel, in brightfield and phase-contrast microscopy experiments. The platform was trained on images of pancreatic cancer organoids and validated on separate images of pancreatic, lung, colon, and adenoid cystic carcinoma organoids, which showed excellent agreement with manual measurements of organoid count (95%) and size (97%) without any parameter adjustments. Single-organoid tracking accuracy remained above 89% over a four-day time-lapse microscopy study. Automated single-organoid morphology analysis of a chemotherapy dose-response experiment identified strong dose effect sizes on organoid circularity, solidity, and eccentricity. OrganoID enables straightforward, detailed, and accurate image analysis to accelerate the use of organoids in high-throughput, data-intensive biomedical applications.
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Aprendizaje Profundo , Organoides , Colon , Descubrimiento de Drogas , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
NSD1, NSD2, and NSD3 constitute the nuclear receptor-binding SET Domain (NSD) family of histone 3 lysine 36 (H3K36) methyltransferases. These structurally similar enzymes mono- and di-methylate H3K36, which contribute to the maintenance of chromatin integrity and regulate the expression of genes that control cell division, apoptosis, DNA repair, and epithelial-mesenchymal transition (EMT). Aberrant expression or mutation of members of the NSD family is associated with developmental defects and the occurrence of some types of cancer. In this review, we discuss the effect of alterations in NSDs on cancer patient's prognosis and response to treatment. We summarize the current understanding of the biological functions of NSD proteins, focusing on their activities and the role in the formation and progression in solid tumors biology, as well as how it depends on tumor etiologies. This review also discusses ongoing efforts to develop NSD inhibitors as a promising new class of cancer therapeutic agents.
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N-Metiltransferasa de Histona-Lisina , Neoplasias , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Oral cavity squamous cell carcinoma (OSCC) affects more than 30 000 individuals in the United States annually, with smoking and alcohol consumption being the main risk factors. Management of early-stage tumors usually includes surgical resection followed by postoperative radiotherapy in certain cases. The cervical lymph nodes (LNs) are the most common site for local metastasis, and elective neck dissection is usually performed if the primary tumor thickness is greater than 3.5 mm. However, postoperative histological examination often reveals that many patients with early-stage disease are negative for neck nodal metastasis, posing a pressing need for improved risk stratification to either avoid overtreatment or prevent the disease progression. To this end, we aimed to identify a primary tumor gene signature that can accurately predict cervical LN metastasis in patients with early-stage OSCC. Using gene expression profiles from 189 samples, we trained K-top scoring pairs models and identified six gene pairs that can distinguish primary tumors with nodal metastasis from those without metastasis. The signature was further validated on an independent cohort of 35 patients using real-time polymerase chain reaction (PCR) in which it achieved an area under the receiver operating characteristic (ROC) curve and accuracy of 90% and 91%, respectively. These results indicate that such signature holds promise as a quick and cost effective method for detecting patients at high risk of developing cervical LN metastasis, and may be potentially used to guide the neck treatment regimen in early-stage OSCC.
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Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/genética , Invasividad Neoplásica , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , TranscriptomaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is a molecularly heterogeneous disease, with a 5-year survival rate that still hovers at ~60% despite recent advancements. The advanced stage upon diagnosis, limited success with effective targeted therapy and lack of reliable biomarkers are among the key factors underlying the marginally improved survival rates over the decades. Prevention, early detection and biomarker-driven treatment adaptation are crucial for timely interventions and improved clinical outcomes. Liquid biopsy, analysis of tumour-specific biomarkers circulating in bodily fluids, is a rapidly evolving field that may play a striking role in optimising patient care. In recent years, significant progress has been made towards advancing liquid biopsies for non-invasive early cancer detection, prognosis, treatment adaptation, monitoring of residual disease and surveillance of recurrence. While these emerging technologies have immense potential to improve patient survival, numerous methodological and biological limitations must be overcome before their implementation into clinical practice. This review outlines the current state of knowledge on various types of liquid biopsies in HNSCC, and their potential applications for diagnosis, prognosis, grading treatment response and post-treatment surveillance. It also discusses challenges associated with the clinical applicability of liquid biopsies and prospects of the optimised approaches in the management of HNSCC.
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Biomarcadores de Tumor/análisis , Detección Precoz del Cáncer/métodos , Neoplasias de Cabeza y Cuello/diagnóstico , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/patología , Animales , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , HumanosRESUMEN
BACKGROUND: Recurrent head and neck squamous cell carcinoma (HNSCC) is associated with poor overall survival (OS). Prior studies suggested incorporation of nab-paclitaxel (A) may improve outcomes in recurrent HNSCC. METHODS: This Phase I study evaluated induction with carboplatin and A followed by concomitant FHX (infusional 5-fluorouracil, hydroxyurea and twice-daily radiation therapy administered every other week) plus A with cohort dose escalation ranging from 10-100 mg/m2 in recurrent HNSCC. The primary endpoint was maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) of A when given in combination with FHX (AFHX). RESULTS: Forty-eight eligible pts started induction; 28 pts started AFHX and were evaluable for toxicity. Two DLTs occurred (both Grade 4 mucositis) at a dose level 20 mg/m2. No further DLTs were observed with subsequent dose escalation. The MTD and recommended Phase II dose (RP2D) of A was 100 mg/m2. CONCLUSIONS: In this Phase I study, the RP2D of A with FHX is 100 mg/m2 (AFHX). The role of re-irradiation with immunotherapy warrants further investigation. CLINICAL TRIAL INFORMATION: This clinical trial was registered with ClinicalTrials.gov identifier: NCT01847326.
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Carcinoma , Neoplasias de Cabeza y Cuello , Reirradiación , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Carcinoma/tratamiento farmacológico , Fluorouracilo/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Hidroxiurea , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Paclitaxel , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapiaRESUMEN
BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC. METHODS: Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, [Formula: see text] 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response. DISCUSSION: A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100 .
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Ácidos Nucleicos Libres de Células/sangre , ADN Viral/sangre , Monitoreo de Drogas/métodos , Neoplasias Orofaríngeas/tratamiento farmacológico , Papillomaviridae/genética , Infecciones por Papillomavirus/sangre , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , Carboplatino/administración & dosificación , Quimioradioterapia , Cisplatino/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/sangre , Neoplasias Orofaríngeas/virología , Paclitaxel/administración & dosificación , Infecciones por Papillomavirus/virología , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in December 2019 in Wuhan, China. It was quickly established that both the symptoms and the disease severity may vary from one case to another and several strains of SARS-CoV-2 have been identified. To gain a better understanding of the wide variety of SARS-CoV-2 strains and their associated symptoms, thousands of SARS-CoV-2 genomes have been sequenced in dozens of countries. In this article, we introduce COVIDomic, a multi-omics online platform designed to facilitate the analysis and interpretation of the large amount of health data collected from patients with COVID-19. The COVIDomic platform provides a comprehensive set of bioinformatic tools for the multi-modal metatranscriptomic data analysis of COVID-19 patients to determine the origin of the coronavirus strain and the expected severity of the disease. An integrative analytical workflow, which includes microbial pathogens community analysis, COVID-19 genetic epidemiology and patient stratification, allows to analyze the presence of the most common microbial organisms, their antibiotic resistance, the severity of the infection and the set of the most probable geographical locations from which the studied strain could have originated. The online platform integrates a user friendly interface which allows easy visualization of the results. We envision this tool will not only have immediate implications for management of the ongoing COVID-19 pandemic, but will also improve our readiness to respond to other infectious outbreaks.
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COVID-19/epidemiología , Nube Computacional , Biología Computacional/métodos , Interfaz Usuario-Computador , COVID-19/genética , COVID-19/fisiopatología , COVID-19/virología , Humanos , Factores de Riesgo , SARS-CoV-2/genética , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck malignancy. Although the survival rate of patients with advanced-stage disease remains approximately 20% to 60%, when detected at an early stage, the survival rate approaches 80%, posing a pressing need for a well validated profiling method to assess patients who have a high risk of developing OCSCC. Tumor DNA detection in saliva may provide a robust biomarker platform that overcomes the limitations of current diagnostic tests. However, there is no routine saliva-based screening method for patients with OCSCC. METHODS: The authors designed a custom next-generation sequencing panel with unique molecular identifiers that covers coding regions of 7 frequently mutated genes in OCSCC and applied it on DNA extracted from 121 treatment-naive OCSCC tumors and matched preoperative saliva specimens. RESULTS: By using stringent variant-calling criteria, mutations were detected in 106 tumors, consistent with a predicted detection rate ≥88%. Moreover, mutations identified in primary malignancies were also detected in 93% of saliva samples. To ensure that variants are not errors resulting in false-positive calls, a multistep analytical validation of this approach was performed: 1) re-sequencing of 46 saliva samples confirmed 88% of somatic variants; 2) no functionally relevant mutations were detected in saliva samples from 11 healthy individuals without a history of tobacco or alcohol; and 3) using a panel of 7 synthetic loci across 8 sequencing runs, it was confirmed that the platform developed is reproducible and provides sensitivity on par with droplet digital polymerase chain reaction. CONCLUSIONS: The current data highlight the feasibility of somatic mutation identification in driver genes in saliva collected at the time of OCSCC diagnosis.
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Carcinoma de Células Escamosas , ADN de Neoplasias , Neoplasias de la Boca , Saliva , Biomarcadores de Tumor , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Humanos , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/genética , MutaciónRESUMEN
BACKGROUND: Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted next-generation sequencing-based approaches offer promising diagnostic capabilities, there are still limitations. There is a pressing clinical need for a well-validated, rapid, cost-effective mutation profiling system in patient specimens. Given their speed and cost-effectiveness, quantitative PCR mutation detection techniques are well suited for the clinical environment. The qBiomarker mutation PCR array has high sensitivity and shorter turnaround times compared with other methods. However, a direct comparison with existing viable alternatives are required to assess its true potential and limitations. METHODS: In this study, we evaluated a panel of 117 patient-derived tumour xenografts by the qBiomarker array and compared with other methods for mutation detection, including Ion AmpliSeq sequencing, whole-exome sequencing and droplet digital PCR. RESULTS: Our broad analysis demonstrates that the qBiomarker's performance is on par with that of other labour-intensive and expensive methods of cancer mutation detection of frequently altered cancer-associated genes, and provides a foundation for supporting its consideration as an option for molecular diagnostics. CONCLUSIONS: This large-scale direct comparison and validation of currently available mutation detection approaches is extremely relevant for the current scenario of precision medicine and will lead to informed choice of screening methodologies, especially in lower budget conditions or time frame limitations.
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Análisis Mutacional de ADN/métodos , Xenoinjertos , Neoplasias/genética , Animales , Xenoinjertos/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Ratones , Trasplante de Neoplasias , Neoplasias/patología , Reacción en Cadena de la Polimerasa/métodos , Reproducibilidad de los Resultados , Células Tumorales CultivadasRESUMEN
The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient's tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.
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Importance: Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus-positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity. Objective: To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC. Design, Setting, and Participants: This phase 2 nonrandomized controlled trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023. Interventions: Addition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV. Main Outcomes and Measures: Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated. Results: The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS. Conclusions and Relevance: This phase 2 nonrandomized controlled trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection. Trial Registration: ClinicalTrials.gov Identifier: NCT03107182.
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Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadyuvante , Nivolumab , Neoplasias Orofaríngeas , Humanos , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virología , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/mortalidad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Infecciones por Papillomavirus/complicaciones , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversosRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy worldwide, with a significant proportion of patients developing recurrent and/or metastatic (R/M) disease. Despite recent advances in therapy, the prognosis for patients with advanced HNSCC remains poor. Here, we present the case of a patient with recurrent metastatic HNSCC harboring an HRAS G12S mutation who achieved a durable response to treatment with tipifarnib, a selective inhibitor of farnesyltransferase. The patient was a 48-year-old woman who had previously received multiple lines of therapy with no significant clinical response. However, treatment with tipifarnib resulted in a durable partial response that lasted 8 months. Serial genomic and transcriptomic analyses demonstrated upregulation of YAP1 and AXL in metastatic lesions compared with the primary tumor, the evolution of the tumor microenvironment from an immune-enriched to a fibrotic subtype with increased angiogenesis, and activation of the PI3K/AKT/mTOR pathway in tipifarnib treatment. Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.
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Neoplasias de Cabeza y Cuello , Proteínas Proto-Oncogénicas c-akt , Quinolonas , Femenino , Humanos , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Línea Celular Tumoral , Microambiente Tumoral , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.
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Nasopharyngeal carcinoma is an uncommon head and neck malignancy in most parts of the world but is endemic in Southeast Asia and North Africa.1 Over 130,000 new cases were recorded globally and 80,000 patients succumbed to nasopharyngeal carcinoma in 2020.2 Owing to relatively mild symptoms during early stages, most patients are diagnosed with clinically advanced disease, and the 5-year overall survival for these patients remains approximately 50%.3 Hence, early detection when the disease is most treatable may improve clinical outcomes.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Herpesvirus Humano 4/genética , Infecciones por Virus de Epstein-Barr/diagnóstico , Detección Precoz del Cáncer , ADN ViralRESUMEN
OBJECTIVE: To examine the oral microbiome in the context of oral cavity squamous cell carcinoma. STUDY DESIGN: Basic science research. SETTING: Academic medical center. METHODS: Oral swabs were collected from patients presenting to the operating room for management of oral cavity squamous cell carcinoma and from age- and sex-matched control patients receiving surgery for unrelated benign conditions. 16S ribosomal RNA (rRNA) sequencing was performed on genetic material obtained from swabs. A bacterial rRNA gene library was created and sequence reads were sorted into taxonomic units. RESULTS: Thirty-one control patients (17 males) and 35 cancer patients (21 males) were enrolled. Ages ranged from 23 to 89 (median 63) for control patients and 35 to 86 (median 66) for cancer patients. Sixty-one percent of control patients and 63% of cancer patients were smokers. 16S analyses demonstrated a significant decrease in Streptococcus genera in oral cancer patients (34.11% vs 21.74% of the population, p = .04). Increases in Fusobacterium, Peptostreptococcus, Parvimonas, and Neisseria were also found. The abundance of these bacteria correlated with tumor T-stage. CONCLUSION: 16S rRNA sequencing demonstrated changes in bacterial populations in oral cavity cancer and its progression compared to noncancer controls. We found increases in bacteria genera that correspond with tumor stage-Fusobacteria, Peptostreptococcus, Parvimonas, Neisseria, and Treponema. These data suggest that oral cancer creates an environment to facilitate foreign bacterial growth, rather than implicating a specific bacterial species in carcinogenesis. These bacteria can be employed as a potential marker for tumor progression or interrogated to better characterize the tumor microenvironment.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , Masculino , Bacterias , Carcinoma de Células Escamosas/microbiología , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca/microbiología , ARN Ribosómico 16S/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente TumoralRESUMEN
As aging and tumorigenesis are tightly interconnected biological processes, targeting their common underlying driving pathways may induce dual-purpose anti-aging and anti-cancer effects. Our transcriptomic analyses of 16,740 healthy samples demonstrated tissue-specific age-associated gene expression, with most tumor suppressor genes downregulated during aging. Furthermore, a large-scale pan-cancer analysis of 11 solid tumor types (11,303 cases and 4431 control samples) revealed that many cellular processes, such as protein localization, DNA replication, DNA repair, cell cycle, and RNA metabolism, were upregulated in cancer but downregulated in healthy aging tissues, whereas pathways regulating cellular senescence were upregulated in both aging and cancer. Common cancer targets were identified by the AI-driven target discovery platform-PandaOmics. Age-associated cancer targets were selected and further classified into four groups based on their reported roles in lifespan. Among the 51 identified age-associated cancer targets with anti-aging experimental evidence, 22 were proposed as dual-purpose targets for anti-aging and anti-cancer treatment with the same therapeutic direction. Among age-associated cancer targets without known lifespan-regulating activity, 23 genes were selected based on predicted dual-purpose properties. Knockdown of histone demethylase KDM1A, one of these unexplored candidates, significantly extended lifespan in Caenorhabditis elegans. Given KDM1A's anti-cancer activities reported in both preclinical and clinical studies, our findings propose KDM1A as a promising dual-purpose target. This is the first study utilizing an innovative AI-driven approach to identify dual-purpose target candidates for anti-aging and anti-cancer treatment, supporting the value of AI-assisted target identification for drug discovery.
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Proteínas de Caenorhabditis elegans , Neoplasias , Animales , Humanos , Envejecimiento/genética , Longevidad/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Inteligencia Artificial , Histona Demetilasas/metabolismoRESUMEN
Oral cavity squamous cell carcinoma (OCSCC) is one of the most common head and neck cancers worldwide. It is well known that risk factors for OCSCC include tobacco and excess alcohol consumption. However, in recent years, OCSCC incidence has been increasing in patients without these traditional risk factors. The cause of this increase is unclear and various genetic, environmental, and infectious factors have been hypothesized to play a role. Additionally, there are expert opinions that oral cancer in non-smoking, non-drinking (NSND) patients have a distinct phenotype resulting in more aggressive disease presentation and poorer prognosis. In this review, we summarize the current state of knowledge for oral cavity cancer in patients without traditional risk factors.
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Multiple cancer types have limited targeted therapeutic options, in part due to incomplete understanding of the molecular processes underlying tumorigenesis and significant intra- and inter-tumor heterogeneity. Identification of novel molecular biomarkers stratifying cancer patients with different survival outcomes may provide new opportunities for target discovery and subsequent development of tailored therapies. Here, we applied the artificial intelligence-driven PandaOmics platform ( https://pandaomics.com/ ) to explore gene expression changes in rare DNA repair-deficient disorders and identify novel cancer targets. Our analysis revealed that CEP135, a scaffolding protein associated with early centriole biogenesis, is commonly downregulated in DNA repair diseases with high cancer predisposition. Further screening of survival data in 33 cancers available at TCGA database identified sarcoma as a cancer type where lower survival was significantly associated with high CEP135 expression. Stratification of cancer patients based on CEP135 expression enabled us to examine therapeutic targets that could be used for the improvement of existing therapies against sarcoma. The latter was based on application of the PandaOmics target-ID algorithm coupled with in vitro studies that revealed polo-like kinase 1 (PLK1) as a potential therapeutic candidate in sarcoma patients with high CEP135 levels and poor survival. While further target validation is required, this study demonstrated the potential of in silico-based studies for a rapid biomarker discovery and target characterization.
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Inteligencia Artificial , Sarcoma , Humanos , Centriolos/genética , Carcinogénesis/metabolismo , Sarcoma/metabolismo , Reparación del ADN/genéticaRESUMEN
Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.
Asunto(s)
Inteligencia Artificial , Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , ProteínasRESUMEN
Importance: Clinical practice regarding posttreatment radiologic surveillance for patients with oropharyngeal carcinoma (OPC) is neither adapted to individual patient risk nor fully evidence based. Objectives: To construct a microsimulation model for posttreatment OPC progression and use it to optimize surveillance strategies while accounting for both tumor stage and human papillomavirus (HPV) status. Design, Setting, and Participants: In this decision analytical modeling study, a Markov model of 3-year posttreatment patient trajectories was created. The training data source was the American College of Surgeon's National Cancer Database from 2010 to 2015. The external validation data set was the 2016 International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S) study. Training data comprised 2159 patients with OPC treated with primary radiotherapy who had known HPV status and disease staging information. Patients with American Joint Committee on Cancer, 7th edition stage III to IVB disease and those with clinical metastases during the time of primary treatment were included. Data were analyzed from August 1 to October 31, 2020. Main Outcomes and Measures: Main outcomes included disease stage and HPV status, specific disease transition probabilities, and latency of surveillance regimens, defined as time between recurrence incidence and disease discovery. Results: Training data consisted of 2159 total patients (1708 men [79.1%]; median age, 59.6 years [range, 40-90 years]; 401 with stage III disease, 1415 with stage IVA disease, and 343 with stage IVB disease). Cohorts predominantly had HPV-negative disease (1606 [74.4%]). With model-optimized regimens, recurrent disease was discovered a mean of 0.6 months (95% CI, 0.5-0.8 months) earlier than with a standard surveillance regimen based on current clinical guidelines. Recurrent disease was discovered using the optimized regimens without significant reduction in sensitivity. Compared with strategies based on reimbursement guidelines, the model-optimized regimens found disease a mean of 1.8 months (95% CI, 1.3-2.3 months) earlier. Conclusions and Relevance: Optimized, risk-stratified surveillance regimens consistently outperformed nonoptimized strategies. These gains were obtained without requiring any additional imaging studies. This approach to risk-stratified surveillance optimization is generalizable to a broad range of tumor types and risk factors.