The WHG Weekly Brief: Issue 4

Stay informed. Stay ahead. Weekly clinical insights.

July 14, 2025 • Estimated Reading Time: 6 minutes

🌟 Editor's Note

Hello!

Ovarian cancer remains one of the most lethal cancers affecting women, in part because it often returns — even after an initial response to chemotherapy. In this issue, we highlight new research that’s beginning to reframe how we understand and treat chemoresistant ovarian cancer — not just by targeting genes, but the shape of DNA itself.

From G-quadruplex structures to novel drug combinations, researchers are uncovering vulnerabilities in tumors that were once thought untouchable. It’s an exciting time in the science — and a hopeful one for patients.

— The WHG Team

Corcept Therapeutics has submitted a new drug application (NDA) to the FDA for relacorilant, a selective cortisol modulator, in combination with nab-paclitaxel for the treatment of platinum-resistant ovarian cancer.

The submission is based on results from the phase 3 ROSELLA trial, which enrolled women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. All had previously received bevacizumab and had progression within 6 months of platinum therapy.

🔬 Key findings (relacorilant + nab-paclitaxel vs nab-paclitaxel alone):

  • Progression-Free Survival (PFS): 6.5 vs 5.5 months (HR 0.70, p = .0076)

  • Overall Survival (OS): 16.0 vs 11.5 months (HR 0.69, p = .0121)

  • Objective Response Rate (ORR): 37% vs 30%

  • Clinical Benefit Rate (CBR): 51% vs 39%

Relacorilant showed consistent benefit across endpoints, though higher rates of grade ≥3 adverse events were reported (74.5% vs 59.5%).

📌 Clinical takeaway: If approved, relacorilant could become a new treatment option for patients with limited choices in the platinum-resistant setting—marking a meaningful step forward in ovarian cancer care.

✅ In a breakthrough study from Imperial College London, researchers uncovered how G-quadruplexes — rare, four-stranded DNA structures — may contribute to chemotherapy resistance in ovarian cancer. While 70% of patients respond initially to chemotherapy, most eventually relapse, and treatment becomes less effective over time.

The team, led by PhD researchers Gem Flint and Dr. Jenna Robinson, found that drug-resistant ovarian cancer cells accumulate G-quadruplex structures in new regions of the genome. These structures appear to help tumors turn on genes that protect against chemotherapy.

🔬 Key finding: When researchers targeted G-quadruplexes with specialized drugs, they were able to re-sensitize resistant cancer cells, restoring their vulnerability to standard treatments.

This is the first time these DNA structures have been functionally linked to chemoresistance — opening the door to novel treatment strategies for relapsed ovarian cancer.

📌 Clinical takeaway: Targeting the shape of DNA, not just its sequence, could represent a new frontier in overcoming drug resistance across multiple cancer types.

🧠 What’s new in research?

June 2025

GEN1, a gene involved in DNA damage repair, has been included in many breast cancer genetic testing panels. But a new study in Polish women with hereditary breast cancer challenges its role as a high-risk gene.

Researchers sequenced GEN1 in 617 hereditary breast cancer patients and 300 cancer-free controls, focusing on protein-truncating variants. Their key finding:

GEN1 variants—specifically p.Lys645Cysfs*29—were rare and not significantly associated with breast cancer risk (OR = 1.40, p = 0.49).

Tumor characteristics, survival rates, and family history of cancer were similar between variant carriers and non-carriers. Based on these results, the authors conclude that GEN1 is unlikely to be a high- or moderate-risk breast cancer gene, and that GEN1 variants should be reclassified as variants of uncertain significance (VUS) in clinical testing panels.

📌 Clinical takeaway: When GEN1 is flagged on NGS panels, it may not warrant heightened concern — a shift that could influence genetic counseling and risk interpretation.

June 2025

In a new study of 58 ovarian cancer patients, researchers evaluated the expression of two immune checkpoint proteins—LAG-3 and TIM-3—across high-grade serous (HGSOC) and non-HGSOC tumor types.

Using immunohistochemistry, they found that both proteins were commonly expressed in ovarian cancer tissue, with varying intensity.

Key findings:

  • LAG-3 expression was linked to BMI in non-HGSOC patients

  • TIM-3 expression showed an association with age across all ovarian cancers

  • LAG-3 and TIM-3 expression were correlated in both HGSOC and non-HGSOC groups

📌 Clinical takeaway: These markers may play a role in the tumor immune environment and could aid in further stratifying ovarian cancer subtypes in future research.

🧬 Gene of the week: MLH1

Colorectal Cancer + Endometrial + Ovarian (Lynch Syndrome)

MLH1 (MutL Homolog 1) is a DNA mismatch repair (MMR) gene that plays a critical role in maintaining genomic stability. Inherited pathogenic variants in MLH1 are a major cause of Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC), a condition that significantly increases the risk of several cancers, most notably colorectal, endometrial, and ovarian.

Women with MLH1 mutations often present with endometrial or ovarian cancer before age 50, sometimes before any colorectal cancer symptoms. This makes gynecologic cancers a potential first signal of Lynch syndrome in women.

MLH1-related cancers typically exhibit microsatellite instability (MSI) and loss of MLH1 protein expression on immunohistochemistry. Identifying MLH1 mutations can guide not only treatment (e.g., immune checkpoint inhibitors for MSI-H tumors) but also risk-reducing strategies for patients and their families.

Because of its implications across multiple organs, MLH1 is a core gene on all major hereditary cancer panels.

Absolute risk:
Women with a pathogenic MLH1 variant have up to a 40–60% lifetime risk of colorectal cancer, and a 25–40% risk of endometrial cancer. Ovarian cancer risk is lower but elevated (up to 9–12%), often presenting at a younger age than in the general population.

Till next time,

The WHG Team