bims-tumhet 2026-04-19 papers

Nat Rev Cancer. 2026 Apr 13.

Rethinking ovarian cancer III: the past decade and future directions.

Approximately 80% of deaths from ovarian cancer are due to high-grade serous carcinoma (HGSC), which has the highest proportion of BRCA1 or BRCA2 (BRCA1/BRCA2) mutations of any cancer type and is a highly chromosomally unstable disease. Despite the introduction of targeted therapies benefitting some patients with HGSC as well as surgical advances, only 50% of patients will survive more than 5 years, and just 30% of patients who present with advanced disease without BRCA1/BRCA2 mutations will survive this long. This Expert Recommendation is based on discussions among emerging and leading ovarian cancer researchers at the 15th Helene Harris Memorial Trust International Forum on ovarian cancer hosted by Ovarian Cancer Action in October 2024. The meeting considered advances in HGSC research and treatment made over the last decade, current challenges, emerging technologies in prevention, early detection, and treatment, and research priorities for the years ahead.

DOI: https://doi.org/10.1038/s41568-026-00916-0

Lancet. 2026 Apr 10. pii: S0140-6736(26)00462-9. [Epub ahead of print]

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial.

BACKGROUND: Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here.
METHODS: In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing.
FINDINGS: Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6-25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51-0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0-18·3] vs 11·9 months [10·0-13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis.
INTERPRETATION: The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer.
FUNDING: Corcept Therapeutics.

DOI: https://doi.org/10.1016/S0140-6736(26)00462-9

Cell. 2026 Apr 16. pii: S0092-8674(26)00334-X. [Epub ahead of print]189(8): 2195-2196

The Hallmarks of Cancer: 25 years guiding discovery and therapy.

Cell Editorial Team

Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding of cancer, guided drug development, and evolved to incorporate new discoveries and address emerging challenges.

DOI: https://doi.org/10.1016/j.cell.2026.03.033

Nat Commun. 2026 Apr 15.

The genetic basis for DNA methylation variation across tissues and development.

Jonathan Rosenski, Ofra Sabag, Eitan Marcus, Netanel Loyfer, Yuval Dor, Howard Cedar, Tommy Kaplan.

The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.

DOI: https://doi.org/10.1038/s41467-026-71693-5

Cell. 2026 Apr 16. pii: S0092-8674(26)00286-2. [Epub ahead of print]189(8): 2232-2253

Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers.

Mengyao Shi, Gary J Patti, Marc J Gunter, Ramaswamy Govindan, Iris Lansdorp-Vogelaar, Ting Wang, Jeffrey P Townsend, Graham A Colditz, Yasmine Belkaid, Yin Cao.

Cancer in younger adults is rising globally, with notable birth-cohort effects. This epidemiological shift underscores the urgent need to accelerate the identification of novel causes and underlying biological networks, with the aim of translating these insights into prevention and interception strategies. In this perspective, we revisit the major milestones in the discovery of cancer causes and outline challenges that hinder progress. To address these challenges, we advocate closer integration of epidemiologic and mechanistic studies and propose three interconnected frameworks that extend current epidemiologic approaches: a tissue ecosystem-anchored framework for cancer cause discovery, a biological state-based framework for precision cancer risk assessment, and a dynamic framework to characterize cancer preventability. This roadmap aims to stimulate conceptual, resource, and methodological advances to accelerate cancer etiology research and prevention in the era of rising early-onset cancers.

DOI: https://doi.org/10.1016/j.cell.2026.03.019

Cell. 2026 Apr 16. pii: S0092-8674(26)00336-3. [Epub ahead of print]189(8): 2278-2306

Targeting genomic instability in cancer.

Timothy A Yap, H Charles Manning, Puja Sapra, Gordon B Mills, Mark J O'Connor.

Genomic instability is a defining feature of cancer, which arises when the cellular systems that maintain DNA integrity falter, enabling the accumulation of genetic and epigenetic alterations that drive malignant transformation. It is both the architect of cancer's evolution and its Achilles' heel. Targeting genomic instability has reshaped oncology: first through systemic chemotherapy and external beam radiation and then with poly(ADP-ribose) polymerase (PARP) inhibitors in homologous recombination repair-deficient tumors and other DNA damage response targets. Recently, tumor-targeted DNA-damaging platforms, namely antibody-drug conjugates (ADCs) and radiopharmaceuticals, have emerged alongside modern precision medicine strategies to optimize patient selection, develop rational combinations, and widen the therapeutic index.

DOI: https://doi.org/10.1016/j.cell.2026.03.035