bims-tumhet 2023-07-30 papers

Issue of 2023–07–30
three papers selected by
Sergio Marchini, Humanitas Research

Transl Res. 2023 Jul 25. pii: S1931-5244(23)00126-3. [Epub ahead of print]

Noninvasive early differential diagnosis and progression monitoring of ovarian cancer using the copy number alterations of plasma cell-free DNA.

Lu Chen, Rong Ma, Chang Luo, Qin Xie, Xin Ning, Kaidi Sun, Fanling Meng, Meng Zhou, Jie Sun.

Ovarian cancer (OV) is the most lethal gynecological malignancy and requires improved early detection methods and more effective intervention to achieve a better prognosis. The lack of sensitive and noninvasive biomarkers with clinical utility remains a challenge. Here, we conducted a genome-wide copy number variation (CNV) profiling analysis using low-coverage whole genome sequencing (LC-WGS) of plasma cfDNA in patients with non-malignant and malignant ovarian tumors, and identified 10 malignancy-specific and 12 late-stage-specific CNV markers from plasma cfDNA LC-WGS data. Concordance analysis indicated a significant correlation of identified CNV markers between CNV profiles of plasma cfDNA and tissue DNA (Pearson's r=0.64, p=0.006 for the TCGA cohort and r=0.51, p=0.04 for the Dariush cohort). By leveraging these specific CNV markers and machine learning algorithms, we developed robust predictive models showing excellent performance in distinguishing between malignant and non-malignant ovarian tumors with F1-scores of 0.90 and ranging from 0.75-0.99, and prediction accuracy of 0.89 and ranging from 0.66-0.98, respectively, as well as between early- and late-stage ovarian tumors with F1-scores of 0.84 and ranging from 0.61-1.00, and prediction accuracy of 0.82 and ranging from 0.63-0.96 in our institute cohort and other external validation cohorts. Furthermore, we also discovered and validated certain CNV features associated with survival outcomes and platinum-based chemotherapy response in multicenter cohorts. In conclusion, our study demonstrated the clinical utility of CNV profiling in plasma cfDNA using LC-WGS as a cost-effective and accessible liquid biopsy for OV.

Keywords: low-coverage whole-genome sequencing; noninvasive diagnosis; ovarian cancer; plasma cell-free DNA; progression monitoring

DOI: https://doi.org/10.1016/j.trsl.2023.07.005

Clin Med Insights Oncol. 2023 ;17 11795549231178173

Pleural Mesothelioma in the Era of Immunotherapy.

Mathieu Chevallier, Floryane Kim, Alex Friedlaender, Alfredo Addeo.

Over the course of the last decade, immunotherapy has revolutionised the management of a great number of cancer types. The treatment of pleural mesothelioma, a rare and highly aggressive cancer, is also being transformed by immunotherapy. The recent combination of ipilimumab and nivolumab improved overall survival compared with platinum-based chemotherapy, irrespective of the histology, establishing immunotherapy as a front-line standard of care in advanced pleural mesothelioma. Yet, most patients do not derive long-term benefit from any of the available therapies, and we note a significant lack of predictive and prognostic biomarkers. After progressing on first-line therapy, patients have limited therapeutic options, and data are scarce about optimal sequencing. In this perspective, we discuss the current management of pleural mesothelioma, defining what we consider to be the therapeutic sequence based on performance status and tumour histology. We also highlight promising ongoing trials that could further shape the management of this rare disease.

Keywords: Mesothelioma; chemotherapy; immunotherapy; palliative treatment; trials

DOI: https://doi.org/10.1177/11795549231178173

Nature. 2023 Jul 26.

Rewiring cancer drivers to activate apoptosis.

Sai Gourisankar, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H Kim, Zhengnian Li, Wendy Wenderski, Juste M Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R Green, Nathanael S Gray, Gerald R Crabtree.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

DOI: https://doi.org/10.1038/s41586-023-06348-2