FMN2

*仅供医学专业人士阅读参考小细胞肺癌（SCLC）是最致命的癌症之一，5年生存率不足7%。小细胞肺癌有个与众不同的特点，治疗一开始的时候它对标准治疗方案中的铂类药物高度敏感，但随后会迅速复发。遗憾的是，一旦小细胞肺癌复发，其他化疗药物或免疫疗法的后线治疗疗效甚微，患者最终会因病死亡。一直以来，科学家对小细胞肺癌这种“抽风式”临床反应特征背后的机制知之甚少。今天，由德国科隆大学Roman K. Thomas、Martin Peifer和Julie George领衔的研究团队，在顶级期刊《自然》发表重磅研究成果[1]，首次破解了上述谜题。他们分析小细胞肺癌原发灶和转移灶的测序数据，确定了从诊断时到整个化疗或免疫治疗期间肿瘤的系统发育情况。他们发现，未经治疗的小细胞肺癌，在不同的肿瘤部位表现出克隆同质性；而一线铂类化疗，竟会“引爆”小细胞肺癌在基因组层面的肿瘤异质性和空间克隆多样性。更重要的是，他们还摸清楚了小细胞肺癌这种“大变脸”背后的原因，让小细胞肺癌的治疗迈出了决定性一步。论文首页截图George等人共收集了65名小细胞肺癌患者的160份肿瘤样本（包括原发肺肿瘤、肺淋巴结、肝脏、胸膜和脑转移灶），并对样本进行了全外显子组、基因组和转录组测序。所有病例的肿瘤组织学均被证实为小细胞肺癌，大多数患者接受过以铂类为基础的一线化疗，中位无复发间隔为88天。复发后，80%的患者（55例中的44例）接受了其他治疗，包括其他化疗药物或PD-1抑制剂和/或CTLA-4抑制剂。为了保证研究数据的可靠性，他们对每位患者至少两个肿瘤样本进行了分析，这些样本是在整个治疗过程中的单个或多个时间点获得的。此外，为了进行患者间比较，他们重点对患者在整个临床过程中不同情况下获得的肿瘤样本进行了配对研究。患者的基本情况及研究流程基于以上测序数据，George团队重建了65名患者的小细胞肺癌克隆谱系和肿瘤系统发育。他们在不同部位的肿瘤中观察到，未接受治疗患者肿瘤的克隆多样性显著低于接受治疗的患者。因此，肿瘤的基因组异质性，虽然在诊断时是有限的，但是在治疗干预后明显增加。具体来说，在对未接受过治疗的患者样本（包括肺内和肺外不同空间的部位）进行的分析后，George团队发现，这些部位要么没有亚克隆，要么突变差异非常有限，呈线性进化模式。将转移部位的样本相互比较时，会发现它们之间的克隆多样性较低。研究人员认为，在成功建立转移灶后，亚克隆的组成似乎基本没有变化。通过对化疗后的复发肿瘤样本进行分析后，他们发现这些高度异质性的病灶中的相当一部分其实存在一个共同的祖先，这个祖先在复发中发挥了关键作用。基于以上数据，George团队认为，在刚诊断时，一个高度增殖的克隆在肿瘤中占主导地位，一线化疗可以清除这些癌细胞；在肿瘤复发时，新出现的肿瘤是由最近的共同祖先产生的多个亚克隆，进而增加了异质性。随着时间的推移，异质性逐渐增加在后续的研究中，George团队发现，驱动小细胞肺癌异质性/快速复发的创始克隆由TP53和RB1的突变所定义，尤其是二者的损伤性基因突变（产生不完整的蛋白或者不产生蛋白）。对于TP53错义突变的患者而言，CREBBP/EP300、TP73或FMN2的共突变，也会增强小细胞肺癌对化疗的耐药。值得注意的是，George团队在分析一线化疗对后线免疫治疗效果的影响时发现，在免疫治疗先起效后无效（复发）的患者中，肿瘤样本中存在铂类化疗导致的基因组损伤。他们认为，一线化疗造成的基因组损伤，会使后续治疗的疗效和反应持续时间受影响。进化示意图总的来说，George及其同事认为，他们的这一发现，首次从机理上解释了小细胞肺癌最初对一线铂类化疗高度敏感，随后迅速复发的临床现象。他们的研究表明，有效的化疗（铂类化疗）会导致在确诊时主导肿瘤癌细胞群被消灭，随后来自祖先克隆（TP53和RB1突变的亚克隆）的大量亚克隆会扩增。他们认为，原发肿瘤是一个具有持续进化适应性的病灶：在药物引发的压力下，原发肿瘤中已经存在的祖先克隆从共同祖先中产生，并产生有异质性的亚克隆，导致癌症复发。围绕上述研究结果，George团队还提出了三个临床意义。第一，一线治疗方案的筛选很重要，因为它会影响后线治疗；第二，目前正在研发中的新药，虽然在后线治疗中失利，但有可能在一线治疗中起效；第三，围绕异质性癌细胞的祖先克隆，有可能找到治疗小细胞肺癌的突破性新疗法。参考文献：[1].George, J., Maas, L., Abedpour, N. et al. Evolutionary trajectories of small cell lung cancer under therapy. Nature. 2024. doi:10.1038/s41586-024-07177-7本文作者丨BioTalker

Test Has Potential to Revolutionize Cervical Cancer Screening, Leading to Improved Patient Prognoses and Survival Rates Study Published in the International Journal of Cancer HONG KONG, Aug. 22, 2023 /PRNewswire/ -- HKG Epitherapeutics ("HKG" or the "Company"), a commercial-stage biotech company developing novel tools for the early detection of cancer and promoting healthy aging, in collaboration with McGill University, announced today that the International Journal of Cancer has published new data on the ability of the Company's proprietary epiCervix test to detect cervical cancer in patients sooner compared to traditional screening methods, including manual laboratory cell examination from Papanicolaou (Pap) smears and human papillomavirus (HPV) testing. As cervical cancer remains the fourth most common type of cancer among women globally, the World Health Organization calls for women to be screened regularly with a high-performance test. In 2020 alone, there were approximately 604,000 new cases and 342,000 deaths due to cervical cancer. If caught at its earliest stage, patients typically have a 93 percent survival rate; if the disease advances, however, the survival rate decreases to 15 percent. "The problem with existing cervical cancer screenings is that they don't always catch malignant cells, and even if a woman has HPV, it doesn't mean that she has cancer. HKG's test gives doctors and patients a much earlier warning system than what is in use today. The earlier the detection, the greater the chances are for survival," said Prof. Moshe Szyf, HKG Epitherapeutics CEO. "Since HKG's epiCervix test is more sensitive than traditional screens, it can find cancer DNA among cells that look noncancerous, enabling doctors to more accurately identify patients who need further testing for cervical cancer. The results from this study have the potential to transform the global cervical cancer screening market through offering a more effective, less invasive and cost-efficient solution. Through integrating epiCervix into the current screening process, we can make cervical cancer no different for women than needing to get a tooth extracted." HKG's epiCervix test can detect cervical cancer at its earliest stages by looking at changes in four specific genes. Results from the study, which evaluated 800 women in Quebec, demonstrated the test's near-perfect accuracy in identifying women with both premalignant and malignant cells, including those who did not have their cancer detected through traditional screening methods. When cervical cancer is found early, doctors can treat it through immediate surgery, saving women from unnecessary medical procedures, anxiety and costs. "A traditional cytology test involves a cytopathologist observing specific cell types to screen for cancer, which is inherently subjective. In contrast, HKG's DNA methylation approach offers a more objective method by analyzing modifications in four specific genes (CA10, DPP10, FMN2 and HAS1) in cervical cells, leading to more accurate results and, most importantly, early detection," said Eduardo Franco, Professor and Chair, Department of Oncology, at McGill University and Principal Investigator of the study. "For example, epiCervix successfully detected high-grade cervical intraepithelial neoplasia among women who underwent colposcopies because of an abnormal Pap smear. If left untreated, these premalignant lesions can progress to cervical cancer." About HKG Epitherapeutics HKG Epitherapeutics is a commercial-stage biotech company developing novel tools for the early detection of cancer and promoting healthy aging. Through translating its pioneering epigenetic research into innovative medical and consumer-focused tests, HKG provides valuable genetic insights that empower healthcare professionals and individuals to adopt a more personalized, proactive approach to healthcare. For more information, visit . Media Contacts Raquel Cona / Shana Marino KCSA Strategic Communications [email protected] / [email protected] SOURCE HKG Epitherapeutics