bims-tumhet 2022-04-17 papers

Ann Oncol. 2022 Apr 07. pii: S0923-7534(22)00681-0. [Epub ahead of print]

Cancer Res. 2022 Apr 15. 82(8): 1646-1657

Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification.

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies.SIGNIFICANCE: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2409

Int J Mol Sci. 2022 Mar 31. pii: 3871. [Epub ahead of print]23(7):

The Interplay between PARP Inhibitors and Immunotherapy in Ovarian Cancer: The Rationale behind a New Combination Therapy.

Brigida Anna Maiorano, Domenica Lorusso, Mauro Francesco Pio Maiorano, Davide Ciardiello, Paola Parrella, Antonio Petracca, Gennaro Cormio, Evaristo Maiello.

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies.

Keywords: BRCA; HRD; ICIs; OC; PARP inhibitors; durvalumab; immune checkpoint inhibitors; niraparib; olaparib; ovarian cancer

DOI: https://doi.org/10.3390/ijms23073871

Cancer Res. 2022 Apr 15. 82(8): 1461-1463

Early Insights into Cancer Epigenetics: Gene Promoter Hypermethylation Emerges as a Potential Biomarker for Cancer Detection.

Susan J Clark, Peter L Molloy.

DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it plays an essential role in core biologic processes by assuring the proper regulation of gene expression and stable gene silencing. In cancer cells, genome-wide DNA methylation patterns are altered and often represent an early and fundamental step in neoplastic transformation. The landmark study from Esteller and colleagues, published in Cancer Research in 2001, was the first to reveal high frequency promoter methylation across multiple cancer types. They highlighted that widespread alterations in DNA methylation may be a key characteristic of oncogenesis and proposed aberrant DNA methylation of gene promoters could provide markers for sensitive detection of nearly all cancer types. The authors used a candidate gene approach to show promoter hypermethylation occurred across 12 cancer-associated genes in DNA from over 600 primary tumor samples, representing 15 major tumor types. The profile of promoter hypermethylation differed in every tumor type, suggesting that alterations in DNA methylation are pervasive, but the genes affected may be tumor-specific and impact multiple signaling pathways. Over the past 20 years since this publication, the cancer epigenetics field has exploded to generate thousands of normal and cancer methylome maps and developed sophisticated informatic tools for genome-wide methylome analyses. These methylomes are providing roadmaps for the study of cancer biology and discovery of DNA methylation biomarkers for early detection and monitoring of cancer. See related article by Esteller and colleagues, Cancer Res 2001;61:3225-29.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0657