Targeted Treatments Offer New Hope for Ovarian Cancer Patients

Our bodies are amazing machines. That doesn’t mean they don’t occasionally turn on us. An allergic reaction is nothing more than an overactive immune system. With Type 1 diabetes, our immune system attacks insulin-producing cells in the pancreas; with the autoimmune disease lupus, people’s own cells attack their skin, lungs, and kidneys. With cancer, researchers have discovered infection-fighting T-cells within tumors –– rendered powerless and inactive by the disease. Now researchers are examining the role of certain genes and how they go into overdrive with some cancer patients. In a pair of studies, they have identified those genes and discovered how to “reawaken” infection-fighting cells in the battle against cancer. Here’s what they learned and what it means for patients coping with chemo-resistant ovarian cancer.

Ovarian Cancer Risks

Cancer is the result of out-of-control, abnormal cell growth. Instead of dying, these genetically damaged cells keep dividing and multiplying. Although the word “cancer” inspires anxiety for most people, the truth is that most cancers are survivable and the prognosis for patients in 2022 is better than it has ever been. That doesn’t mean all cancers respond well to treatment. Ovarian cancer, for example, is often deadly. The disease metastasizes or spreads quickly ––– usually with few symptoms. It often takes less than a year for it to progress from early to advanced stages. Most women with ovarian cancer are diagnosed with malignant epithelial carcinoma which can metastasize in just weeks.

Treatment can be challenging. Although early-stage ovarian cancer has a five-year survival rate of 90%, after it invades both of the two almond-sized ovaries that make up part of the female reproductive system (responsible for producing the hormones estrogen and progesterone along with eggs), treatment usually requires surgery and chemotherapy –– which has significant side effects. At later stages, many ovarian cancers are chemo-resistant. Fewer than one out of every five women with Stage Four ovarian cancer are still alive five years after diagnosis. Recently, researchers have discovered ways to improve those odds. 

Two Promising Studies Provide Hope

Earlier research revealed that more than half of women with ovarian clear cell carcinomas that don’t respond to treatment have mutations in the ARID1A gene. Part of the SWI/SNF protein complexes responsible for regulating gene activity, one of ARID1A’s functions is as a tumor suppressor –– working to keep damaged cells from dividing or spreading. The mutation meant the gene was no longer doing its job of suppressing tumor growth. In recent research conducted at The Wistar Institute Cancer Center, professor and lead author of the study, Rugang Zhang, Ph.D., explained, “The goal of our research is to uncover the molecular changes caused by ARID1A loss so that we can target them specifically to achieve effective therapies for this devastating disease; we focused on a stress response mechanism that tumors resort to for survival and found a link that offers a therapeutic opportunity.”

Researchers looked at a cellular structure called the endoplasmic reticulum (ER), which is in charge of protein production and stress response. Unfortunately, this response becomes hyperactive when cancer cells are present –– which actually aids their survival. Shutting down this stress response could also shut down cancer cell production. Because the response is carried along a signaling pathway that is usually regulated by the ARID1A gene, when the gene is mutated the stress response travels without inhibition and encourages cell development. 

As Zhang points out, “…the mechanisms cancer cells exploit to their advantage also make them vulnerable because they become dependent on certain pathways. If we can find ways to block those pathways, we may be able to use them as weak spots for killing cancer.” So far several drugs have affected the pathway –– offering promise to patients with late-stage, chemo resistant ovarian cancer. 

Another study has offered a different target for women with a similar prognosis. For years, the DOT1L protein has been examined in connection with cancer patients because of its role in both normal cellular processes and in tumor development. Recently researchers at the University of Alabama at Birmingham demonstrated how the protein encourages ovarian cancer tumor growth and prevents abnormal cell death. Comparing healthy subjects to those with ovarian cancer, researchers discovered that not only was DOT1L expression higher in the patients with cancer but the higher the expression the faster the spread and the lower their overall survival rate. 

Testing EPZ-5676, a DOT1L inhibitor previously deployed against leukemia cells, researchers soon discovered that when it was used against ovarian cancer cells it blocked their growth. Although research is ongoing and human trials not yet set, both studies provide promising news for fighting a deadly, fast-spreading cancer for which treatment options have been few and far between.

References

• Why Immune Cells Sometimes Fail to Fight Cancer (and What to Do about It)
• What Is Cancer?
• Facts & Figures 2020 Reports Largest One-year Drop in Cancer Mortality
• Stages of Ovarian Cancer
• Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers
• DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment
• Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis