Pub Date : 2024-02-01DOI: 10.1136/bmjonc-2023-000154
Brian M Ortmann
Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF’s dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine.Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.
{"title":"Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity","authors":"Brian M Ortmann","doi":"10.1136/bmjonc-2023-000154","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000154","url":null,"abstract":"Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF’s dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine.Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.","PeriodicalId":505335,"journal":{"name":"BMJ Oncology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139878065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/bmjonc-2023-000073
B. Budnik, Hossein Amirkhani, M. Forouzanfar, A. Afshin
Early detection of cancer is crucial for reducing the global burden of cancer, but effective screening tests for many cancers do not exist. This study aimed to develop a novel proteome-based multi-cancer screening test that can detect early-stage cancers with high accuracy.We collected plasma samples from 440 individuals, healthy and diagnosed with 18 early-stage solid tumours. Using proximity extension assay, we measured more than 3000 high-abundance and low-abundance proteins in each sample. Then, using a multi-step statistical approach, we identified a limited set of sex-specific proteins that could detect early-stage cancers and their tissue of origin with high accuracy.Our sex-specific cancer detection panels consisting of 10 proteins showed high accuracy for both males (area under the curve (AUC): 0.98, 95% CI 0.96, 1) and females (AUC: 0.983, 95% CI 0.95, 1.00). At stage I and at the specificity of 99%, our panels were able to identify 93% (95% CI 79%, 100%) of cancers among males and 84% (95% CI 68%, 100%) of cancers among females. Our sex-specific localisation panels consisted of 150 proteins and were able to identify the tissue of origin of most cancers in more than 80% of cases. The analysis of the plasma concentrations of proteins selected showed that almost all the proteins were in the low-concentration part of the human plasma proteome.The proteome-based screening test showed promising performance compared with other technologies and could be a starting point for developing a new generation of screening tests for the early detection of cancer.
癌症的早期检测对于减轻全球癌症负担至关重要，但目前还没有针对许多癌症的有效筛查测试。本研究旨在开发一种新型的基于蛋白质组的多癌症筛查检测方法，该方法可高精度地检测早期癌症。我们收集了440名健康和确诊为18种早期实体瘤患者的血浆样本。我们收集了 440 名健康和确诊为 18 种早期实体瘤患者的血浆样本，利用近距离延伸测定法，测量了每个样本中 3000 多种高丰度和低丰度蛋白质。然后，我们采用多步骤统计方法，确定了一组有限的性别特异性蛋白质，这些蛋白质可高精度地检测早期癌症及其来源组织。我们的性别特异性癌症检测面板由 10 种蛋白质组成，对男性和女性都显示出很高的准确性（曲线下面积（AUC）：0.98，95% CI）：我们的性别特异性癌症检测面板由 10 种蛋白质组成，对男性（曲线下面积（AUC）：0.98，95% CI 0.96，1）和女性（AUC：0.983，95% CI 0.95，1.00）的准确率都很高。在第一阶段和特异性为 99% 的情况下，我们的面板能够识别 93% （95% CI 79%，100%）的男性癌症和 84% （95% CI 68%，100%）的女性癌症。我们的性别特异性定位面板由 150 种蛋白质组成，能够识别 80% 以上病例中大多数癌症的原发组织。对所选蛋白质血浆浓度的分析表明，几乎所有蛋白质都属于人体血浆蛋白质组的低浓度部分。与其他技术相比，基于蛋白质组的筛查测试显示出良好的性能，可以作为开发新一代癌症早期检测筛查测试的起点。
{"title":"Novel proteomics-based plasma test for early detection of multiple cancers in the general population","authors":"B. Budnik, Hossein Amirkhani, M. Forouzanfar, A. Afshin","doi":"10.1136/bmjonc-2023-000073","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000073","url":null,"abstract":"Early detection of cancer is crucial for reducing the global burden of cancer, but effective screening tests for many cancers do not exist. This study aimed to develop a novel proteome-based multi-cancer screening test that can detect early-stage cancers with high accuracy.We collected plasma samples from 440 individuals, healthy and diagnosed with 18 early-stage solid tumours. Using proximity extension assay, we measured more than 3000 high-abundance and low-abundance proteins in each sample. Then, using a multi-step statistical approach, we identified a limited set of sex-specific proteins that could detect early-stage cancers and their tissue of origin with high accuracy.Our sex-specific cancer detection panels consisting of 10 proteins showed high accuracy for both males (area under the curve (AUC): 0.98, 95% CI 0.96, 1) and females (AUC: 0.983, 95% CI 0.95, 1.00). At stage I and at the specificity of 99%, our panels were able to identify 93% (95% CI 79%, 100%) of cancers among males and 84% (95% CI 68%, 100%) of cancers among females. Our sex-specific localisation panels consisted of 150 proteins and were able to identify the tissue of origin of most cancers in more than 80% of cases. The analysis of the plasma concentrations of proteins selected showed that almost all the proteins were in the low-concentration part of the human plasma proteome.The proteome-based screening test showed promising performance compared with other technologies and could be a starting point for developing a new generation of screening tests for the early detection of cancer.","PeriodicalId":505335,"journal":{"name":"BMJ Oncology","volume":"19 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139455905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/bmjonc-2023-000184
Holli A. Loomans-Kropp
{"title":"Multi-cancer early detection tests: a strategy for improvement","authors":"Holli A. Loomans-Kropp","doi":"10.1136/bmjonc-2023-000184","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000184","url":null,"abstract":"","PeriodicalId":505335,"journal":{"name":"BMJ Oncology","volume":"40 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139454884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1136/bmjonc-2023-000287
Daniel A Goldstein, Leonard B Saltz, Gregory R. Pond, I. F. Tannock
In the field of general medicine, class effects, or therapeutic interchangeability, have been declared for several families of drugs including statins, calcium channel blockers and ACE inhibitors. The existence of such class effects enables healthcare payers to negotiate for substantially lower drug prices, thereby reducing financial toxicity, both at an individual and societal levels. Until now, the existence of class effects in oncology has been considered rare. Here, we review evidence from clinical trials that supports the existence of class effects for several types of anticancer drugs. These class effects in oncology should be exploited to reduce healthcare costs.
{"title":"Pharmacological class effects of anticancer drugs: opportunities for decreasing healthcare spending","authors":"Daniel A Goldstein, Leonard B Saltz, Gregory R. Pond, I. F. Tannock","doi":"10.1136/bmjonc-2023-000287","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000287","url":null,"abstract":"In the field of general medicine, class effects, or therapeutic interchangeability, have been declared for several families of drugs including statins, calcium channel blockers and ACE inhibitors. The existence of such class effects enables healthcare payers to negotiate for substantially lower drug prices, thereby reducing financial toxicity, both at an individual and societal levels. Until now, the existence of class effects in oncology has been considered rare. Here, we review evidence from clinical trials that supports the existence of class effects for several types of anticancer drugs. These class effects in oncology should be exploited to reduce healthcare costs.","PeriodicalId":505335,"journal":{"name":"BMJ Oncology","volume":"64 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140525126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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