bims-tumhet 2023-07-23 papers

Issue of 2023–07–23
six papers selected by
Sergio Marchini, Humanitas Research

Nat Commun. 2023 Jul 20. 14(1): 4387

The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma.

BriTROC Investigators

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

DOI: https://doi.org/10.1038/s41467-023-39867-7

Cancer Drug Resist. 2023 ;6(2): 358-377

Immune checkpoint inhibitors in ovarian cancer: where do we go from here?

Won-Hee Yoon, Anna DeFazio, Lawrence Kasherman.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.

Keywords: Ovarian cancer; drug development; immunotherapy; tumour microenvironment

DOI: https://doi.org/10.20517/cdr.2023.13

Cancer Drug Resist. 2023 ;6(2): 345-357

The evolving role of DNA damage response in overcoming therapeutic resistance in ovarian cancer.

Sara Bouberhan, Liron Bar-Peled, Yusuke Matoba, Varvara Mazina, Lauren Philp, Bo R Rueda.

Epithelial ovarian cancer (EOC) is treated in the first-line setting with combined platinum and taxane chemotherapy, often followed by a maintenance poly (ADP-ribose) polymerase inhibitor (PARPi). Responses to first-line treatment are frequent. For many patients, however, responses are suboptimal or short-lived. Over the last several years, multiple new classes of agents targeting DNA damage response (DDR) mechanisms have advanced through clinical development. In this review, we explore the preclinical rationale for the use of ATR inhibitors, CHK1 inhibitors, and WEE1 inhibitors, emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer. We also present an overview of the clinical development of the leading drugs in each of these classes, emphasizing the rationale for monotherapy and combination therapy approaches.

Keywords: DDR; Ovarian cancer; PARPi resistance; platinum resistance

DOI: https://doi.org/10.20517/cdr.2022.146

Mol Cancer. 2023 Jul 17. 22(1): 114

Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy.

F Torricelli, B Donati, F Reggiani, V Manicardi, S Piana, R Valli, F Lococo, Alessia Ciarrocchi.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients' management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place.
METHODS: We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis.
RESULTS: Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability.
CONCLUSIONS: Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.

Keywords: Cancer heterogeneity; Epithelial mesenchymal transition; Inflammation; Malignant pleural mesothelioma; Tumor associated Macrophages; Tumor microenvironment

DOI: https://doi.org/10.1186/s12943-023-01816-9

Nat Rev Cancer. 2023 Jul 21.

Polygenic scores in cancer.

Xin Yang, Siddhartha Kar, Antonis C Antoniou, Paul D P Pharoah.

Since the publication of the first genome-wide association study for cancer in 2007, thousands of common alleles that are associated with the risk of cancer have been identified. The relative risk associated with individual variants is small and of limited clinical significance. However, the combined effect of multiple risk variants as captured by polygenic scores (PGSs) may be much greater and therefore provide risk discrimination that is clinically useful. We review the considerable research efforts over the past 15 years for developing statistical methods for PGSs and their application in large-scale genome-wide association studies to develop PGSs for various cancers. We review the predictive performance of these PGSs and the multiple challenges currently limiting the clinical application of PGSs. Despite this, PGSs are beginning to be incorporated into clinical multifactorial risk prediction models to stratify risk in both clinical trials and clinical implementation studies.

DOI: https://doi.org/10.1038/s41568-023-00599-x