Joyce F. Liu, MD, MPH, discusses the role of Wee1 in cell cycle regulation and the rationale for targeting this protein in ovarian cancer.

Dr Liu on the Rationale for Targeting Wee1 in Ovarian Cancer 

Joyce F. Liu, MD, MPH, associate chief and director of clinical research, Division of Gynecologic Oncology, associate clinical research officer, Dana-Farber Cancer Institute; associate professor of medicine at Harvard Medical School, discusses the role of Wee1 in cell cycle regulation and the rationale for developing therapies that inhibit this protein in ovarian cancer.

Ovarian cancer is now recognized as a heterogeneous disease encompassing various subtypes, each with distinct molecular characteristics. One notable feature observed in certain ovarian cancer subtypes is the overexpression of cyclin E, a protein that plays a crucial role in regulating the cell cycle, Liu states. Cyclin E overexpression accelerates cell progression through the G1/S checkpoint, resulting in heightened replication stress within the cells, she expands.

The cell cycle is highly controlled to ensure proper cell division, and one key regulatory checkpoint is the G2/M checkpoint, which is negatively regulated by the protein Wee1, Liu explains. Cells transitioning from G1 to the S phase and then towards mitosis encounter the G2/M checkpoint, where cells with DNA damage are prevented from entering the M phase. In cases of cyclin E amplification or high replication stress, cells become reliant on the G2/M checkpoint for proper division, Liu states. Wee1 inhibitors disrupt this regulatory checkpoint, allowing cells to bypass the G2/M arrest prematurely and enter mitosis, she says. However, cells that are not adequately prepared for division may undergo mitotic catastrophe, a form of cell death triggered by aberrant mitosis, Liu notes.

Ovarian cancers characterized by high cyclin E levels, often due to 

gene amplification or other mechanisms, may be particularly vulnerable to therapies targeting the G2/M checkpoint, Liu emphasizes. By targeting the function of Wee1, these therapies can exploit the dependency of cyclin E-overexpressing cancer cells on the G2/M checkpoint, inducing mitotic catastrophe and potentially inhibiting tumor growth, Liu explains.

Understanding the molecular underpinnings of ovarian cancer subtypes, such as those exhibiting cyclin E dysregulation, enables the development of targeted therapies aimed at exploiting specific vulnerabilities within ovarian cancer cells. This personalized approach holds promise for improving treatment outcomes and advancing precision medicine in ovarian cancer management.

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Joyce F. Liu, MD, MPH, an assistant professor of medicine at Harvard Medical School and director of clinical research for gynecologic oncology at Dana-Farber Cancer Institute, discusses the results of cediranib (Recentin) in combination with olaparib (Lynparza) in a phase 3 trial in patients with recurrent platinum-sensitive ovarian cancer.

In the study, patients were randomized 1:1:1 to receive either standard of care, olaparib, or cediranib/olaparib. The results of the study did not meet the primary end point of the trial; however, at the same time, activity was observed with the combination arm, says Liu. However, it’s important to be cognizant of the toxicity associated with the approach. It is possible that with better mitigation strategies or different dosing techniques, toxicities could be mitigated and allow for a higher degree of activity that is more similar to what was seen in the original phase 2 study.

Beyond that, the other interesting aspect of the study were the results from the preplanned subset analyses among patients who did or did not have a germline 

 mutation. Notably, in those who had a germline 

 mutation, the activity of both the olaparib monotherapy and the combination therapy had quite robust response rates ranging from 89% to 90%. The progression-free survival in both of those arms, although not statistically compared, was numerically longer than what was seen in the chemotherapy arm, concludes Liu.

Joyce F. Liu, MD, MPH, discusses the results of cediranib in combination with olaparib in a phase 3 trial in patients with recurrent platinum-sensitive ovarian cancer.


Dr. Liu on Cediranib/Olaparib in Recurrent Ovarian Cancer

Joyce F. Liu, MD, MPH, assistant professor of medicine, Harvard Medical School, and director of clinical research for gynecologic oncology at Dana-Farber Cancer Institute, discusses findings from a phase 2 study with the Wee1 inhibitor adavosertib in patients with recurrent uterine serous carcinoma.

The study enrolled 35 patients, 34 of which were evaluable for response, says Liu.

In order to be eligible for the study, patients had to have had at least 1 prior platinum-based chemotherapy regimen. Patients in the study had received a median of 3 prior lines of therapy.

Among these 34 patients, the overall response rate was 29.4% (95% CI, 15.1-47.5), says Liu. Additionally, the median progression-free survival was 6.1 months, and the median duration of response was 9.0 months.

Regarding safety, the adverse effects (AEs) were consistent with previously reported data with adavosertib in this patient population, explains Liu. Common grade 3 or higher AEs included neutropenia, anemia, and fatigue.

Additionally, 2 patients discontinued treatment due to AEs; however, dose modifications and dose adjustments allowed the regimen to be well tolerated by most women, concludes Liu.

Joyce F. Liu, MD, MPH, discusses findings from a phase 2 study with the Wee1 inhibitor adavosertib in patients with recurrent uterine serous carcinoma.

Dr. Liu on Phase 2 Study Results of Adavosertib in Recurrent Uterine Serous Carcinoma

Joyce F. Liu, MD, MPH, assistant professor of medicine, Harvard Medical School, and director of clinical research for gynecologic oncology at Dana-Farber Cancer Institute, discusses the use of PARP inhibitors in patients with recurrent ovarian cancer.

All 3 PARP inhibitors—olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca)&mdash;are FDA-approved for use as maintenance therapy in patients with recurrent platinum-sensitive ovarian cancer. Although these agents show benefit across all women with ovarian cancer, their effect is most pronounced in women with 

The only trial to show a benefit with a PARP inhibitor in the upfront maintenance setting is the phase III SOLO-1 trial, in which investigators examined olaparib in women with 

-mutated ovarian cancer. Notably, the study restricted treatment to 2 years in the absence of residual disease, says Liu; however, the benefit seems to extend well beyond that. Although the study showed a profound benefit in terms of progression-free survival with olaparib versus placebo, more mature data are needed to discern the agent’s impact on overall survival.

Dr. Liu on PARP Inhibitors in Recurrent Ovarian Cancer

Joyce F. Liu, MD, MPH, assistant professor of medicine and director of clinical research for gynecologic oncology at Dana-Farber Cancer Institute, discusses the use of bevacizumab (Avastin) in the treatment of patients with newly diagnosed advanced ovarian cancer.

In June 2018, the FDA approved bevacizumab (Avastin) for use in combination with carboplatin and paclitaxel, followed by bevacizumab monotherapy for women with advanced ovarian cancer following initial surgical resection.

Bevacizumab has been studied since 2011 and has shown a consistent progression-free survival benefit of around 2 to 4 months, says Liu. However, it is important to consider how bevacizumab might benefit patients, as it has yet to demonstrate an overall survival benefit, she adds.

Subset analyses from the ICON7 and GOG218 trials suggest that patients with high-risk disease may benefit from bevacizumab. Because it is not yet clear which patient subset, if any, derives the greatest benefit from bevacizumab, physicians are looking for molecular markers that may indicate who these patients are. Although bevacizumab was approved by the FDA, physicians should exercise caution in deciding who should receive it, says Liu.

Joyce F. Liu, MD, MPH

Articles

Dr Liu on the Rationale for Targeting Wee1 in Ovarian Cancer

Dr. Liu on Cediranib/Olaparib in Recurrent Ovarian Cancer

Dr. Liu on Phase 2 Study Results of Adavosertib in Recurrent Uterine Serous Carcinoma

Dr. Liu on PARP Inhibitors in Recurrent Ovarian Cancer

Dr. Liu on the Use of Bevacizumab in Newly Diagnosed Advanced Ovarian Cancer