Research

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 Xi Chen, Ph.D., identified one such mechanism in which cancer cells can evade the immune system via an ancient stress sensor IRE1α activation, which blocks pathways that would normally ignite “cold” tumors and initiate an immune response. Using an IRE1α-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 IRE1α 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 Nature Communications.

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 Journal of Clinical Oncology.

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

Chronic inflammation associated with aging — called inflammaging — 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, Rugang Zhang, Ph.D., 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 Nature Aging.