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Study uncovers target to overcome resistance in ARID1A-mutant cancers

Many ovarian clear cell carcinomas (OCCCs) have mutations that inactivate the ARID1A tumor suppressor and are associated with resistance to standard treatments and poor patient prognoses. To provide insights into the underlying mechanisms, researchers led by , examined ARID1A-mutant OCCC cells. They found that ARID1A mutations create a dependence on the alanine amino acid through regulating alanine transporter proteins including SLC38A2, which acts as a gatekeeper to support rapid cancer growth. Inhibiting SLC38A2 led to reduced alanine, slowed cell growth and tumor shrinkage. Additionally, SLC38A2 inhibition enhanced the activity of immune checkpoint blockade in vivo and chimeric antigen receptor (CAR) T therapy in vitro. These results suggest that targeting alanine transport alone or in combination with immunotherapy is a promising therapeutic strategy for ARID1A-mutant cancers. Learn more in .

New genetic marker linked to improved survival with immunotherapy in ovarian and other cancers

• Ovarian clear cell carcinoma is difficult to treat, and treatment options are limited
• Patients with specific PPP2R1A mutations in their tumors survived significantly longer after immunotherapy treatment
• Targeting PPP2R1A may improve responses even further according to laboratory studies
• PPP2R1A is an important predictive biomarker and possible treatment target for multiple cancer types, study found

HOUSTON, JULY 2, 2025 ¨D Patients with ovarian clear cell carcinoma (OCCC) whose tumors have specific mutations in the PPP2R1A gene were found to have improved survival following immunotherapy compared to patients without these mutations, according to researchers from .

The findings, published today in , suggest PPP2R1A mutations could be a valuable biomarker to help guide treatment for this difficult-to-treat ovarian cancer subtype and may offer a new therapeutic target to further improve outcomes in multiple cancer types.

Results of the study found that patients with PPP2R1A-mutant OCCC had a median overall survival (OS) of more than five years (66.9 months) after immunotherapy treatment, compared to just 9.2 months for patients without this mutation.

¡°Developing effective immunotherapies for ovarian cancer, including rare subtypes like ovarian clear cell carcinoma, remains a significant unmet clinical need,¡± said co-senior author Amir Jazaeri, M.D., professor of Gynecologic Oncology and Reproductive Medicine. ¡°Our study is the first to demonstrate the clinical importance of PPP2R1A mutations, and it opens the door to new strategies that could benefit many more patients.¡±

In a Phase II trial, researchers investigated outcomes in a cohort of 34 patients with treatment-resistant OCCC who had been treated with a combination of immune checkpoint inhibitors ¨C durvalumab and tremelimumab. Based on their findings in OCCC, experts also looked at two additional independent cohorts, one consisting of patients with endometrial cancer and the other including more than 9,000 patients with multiple cancer types who received immunotherapy treatment. Analyses confirmed the improved OS following immunotherapy in those with tumor PPP2R1A mutations.

In parallel, laboratory research showed that targeting PPP2R1A both in vitro and in vivo was also associated with improved response to immunotherapy, suggesting a causal link. This too indicates that therapies targeting PPP2R1A and the associated protein phosphatase 2A (PP2A) molecular pathway could be added to immunotherapy to further boost outcomes.

¡°Not only did we identify a new biomarker in ovarian cancer, but we also confirmed survival benefits in other cancer types,¡± Jazaeri said. ¡°Since PPP2R1A mutations are relatively uncommon, we believe the same benefits may be possible by targeting the PPP2A pathway --using drugs, and we currently are evaluating this in a clinical trial at MD Anderson.¡±

The study represents an ongoing collaboration across multiple disciplines, led by co-senior authors Jazaeri; , associate professor of Genomic Medicine and associate member of the and focus area co-lead with the Institute for Data Science in Oncology; and , chair of Experimental Therapeutics.

This research was co-lead by first authors Yibo Dai and Minghao Dang, Ph.D., of the Wang laboratory; Anne Knisely, M.D., fellow in Gynecologic Oncology and Reproductive Medicine; and Mitsutake Yano, M.D., Ph.D., postdoctoral fellow in the Zhang laboratory. A full list of collaborating authors and their disclosures can be found .

Novel therapeutic target overcomes treatment resistance in triple-negative breast cancer
Many patients with triple-negative breast cancer (TNBC) do not respond to combination treatment with chemotherapy and immunotherapy. Understanding what makes these tumors immunologically ¡°cold,¡± or resistant to therapy, and how to turn them immunologically ¡°hot,¡± could improve patient outcomes. Researchers led by , identified one such mechanism in which cancer cells can evade the immune system via an ancient stress sensor IRE1¦Á activation, which blocks pathways that would normally ignite ¡°cold¡± tumors and initiate an immune response. Using an IRE1¦Á-selective inhibitor, ORIN1001, the researchers reversed these effects and prompted a robust immune response in vivo in combination with taxane-based chemotherapy, effectively converting the immunologically ¡°cold¡± tumors to ¡°hot¡± tumors. These results highlight IRE1¦Á as a potential therapeutic target to overcome treatment resistance in patients with TNBC. Learn more in Cell.

Targeting glycans sensitizes ovarian tumors to immune checkpoint blockade

Cancer cells employ sugar molecule known as glycans on cell surface to evade detection by the immune system. This may also regulate how cancer cells response to therapies that aim to restore anti-tumor immune response. For example, ovarian cancers respond poorly to a class of immunotherapy called immune checkpoint blockade. To understand whether and how sugar coating may help ovarian cancer cells evade detection by the immune system, Rugang Zhang, Ph.D. and colleagues discovered that fucosylation is broadly employed by ovarian cancer cells to evade immune surveillance. Interestingly, another class of sugar molecule called branched N-glycans are specifically associated with immune evasion of ovarian cancer cells expressing genes whose mutation increases ovarian cancer risk such as BRCA1/2. Removing sugar coating from ovarian cancer cells¡¯ surface make them sensitive to immunotherapy, suggesting that glycans are promising therapeutic targets to overcome immune evasion in ovarian cancer. Learn more in .

Normal Risk Ovarian Screening Study: 21-Year Update

Han CY,* Lu KH,* Corrigan G, Perez A, Kohring SD, Celestino J, Bedi D, Bedia E, Bevers T, Boruta D, Carlson,M, Holman L, Leeds L, Mathews C, McCann G, Moore R, Schlumbrecht M, Slomovitz B, Tobias D, Williams-Brown Y, Liu J, Gornet T, Handy BC, Lu Z, Bedia JS, Skates SJ,* Bast, RC Jr*.

One of the major barriers to better outcomes for patients with ovarian cancer is late diagnosis where 65-70% of patients are diagnosed with advanced stage (III/IV) disease. An effective screening strategy remains an unmet medical need. Our article in the Journal of Clinical Oncology reports a 21-year update of the Normal Risk Ovarian Cancer Screening Study (NROSS) where 7,856 women were screened for over >50,000 woman-years with a two-stage strategy. Post-menopausal women at average genetic risk had annual determinations of the blood biomarker CA125 analyzed with the Risk of Ovarian Cancer Algorithm (ROCA). Rising CA125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer in a small fraction of women.

The two-stage screening strategy prompted 34 operations to detect 17 cases of ovarian cancer (15 invasive and two borderline) with 70% in early stage (I/II). In addition, seven cases of endometrial cancer were detected with six in stage I. The overall sensitivity for detecting ovarian cancer was 70%. NROSS screening reduced late-stage (III/IV) disease by 34% compared to UKCTOCS controls and by 30% compared to US SEER values. The positive predictive value (PPV) was 50% for detecting ovarian cancer and 74% for detecting any cancer, far exceeding the minimum acceptable study endpoint of 10%.

While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV and marked stage shift support further development of this strategy. Funded by the NCI Early Detection Research Network we are conducting a second-generation trial (NROSS-2) to measure the specificity and sensitivity of a 4-biomarker algorithm for detecting early-stage ovarian cancer over the next four years at 11 US sites in ~4,500 postmenopausal women. Learn more in the .

TXNRD1 enzyme drives innate immune response in senescent cells, with implications for aging and cancer

Chronic inflammation associated with aging ¡ª called inflammaging ¡ª contributes to cancer development and progression. Cellular senescence, a state in which cells have lost their ability to divide and multiply, also regulates cancer and tissue aging by secreting proinflammatory factors. There is evidence to suggest that TXNRD1, an enzyme regulating cellular redox, is implicated in tissue aging. In a new study, , and colleagues discovered that TXNRD1 drives inflammaging through the cGAS-STING pathway in a senescence-dependent manner that is distinct from its activity as a redox enzyme. Blocking the TXNRD1 interaction with cGAS using a specific inhibitor lowered markers of inflammaging in preclinical models, suggesting that the TXNRD1-cGAS interaction is a potential therapeutic target for both tissue aging and cancer. Learn more in .