Associate Professor Dong-Joo (Ellen) Cheon | Knowledge is Power: Improving Outcomes in Ovarian Cancer

Ovarian cancer is the second most common gynecological cancer and has the highest mortality rate of all female reproductive cancers in the United States. A lack of early detection, typically aggressive progression, and rapid development of resistance to chemotherapy are key contributing factors to the mortality rate. Dr. Dong-Joo (Ellen) Cheon and her team at Albany Medical College are working to determine the role of key players in the resistance to chemotherapy treatments and examining how best we can target these therapeutically to improve survival.

The Knowledge Gap in Ovarian Cancer

Each year, over 19,000 women are diagnosed with ovarian cancer in the United States. Of these, only 35% will go on to survive beyond the 10-year mark despite research advances. Unfortunately, there are several reasons why ovarian cancer remains such a serious threat.

Ovarian cancer is an aggressive disease that is further complicated by the same symptoms appearing as part of other gynecological issues. As a result, it is often not diagnosed until patients are at the later stages of the disease, when the tumor has spread to other organs. Treatment options include surgery and chemotherapy, either alone or in combination.

Chemotherapy is one of the key treatments for patients at all stages of ovarian cancer, with 54% of patients undergoing curative or palliative chemotherapy as part of their primary cancer treatment. Platinum-based drugs (cisplatin, carboplatin) are the most commonly used chemotherapy for ovarian cancer treatment. They work by causing damage to the DNA in cells and subsequently inducing cell death. Although patients are initially sensitive to platinum chemotherapy, about 70% of patients experience cancer recurrence, and many develop resistance to platinum therapy. As such, uncovering mechanisms that allow patients to become resistant to platinum therapy is a key area of research in the mission to improve survival outcomes for patients, particularly those with more advanced disease.

Dr. Dong-Joo (Ellen) Cheon is an Associate Professor of Regenerative and Cancer Cell Biology at Albany Medical College in New York. Her team’s research focuses on understanding how patients can develop resistance to platinum chemotherapy over time. Conducting detailed analysis of clinical samples and validating their findings in a pre-clinical setting, they work to highlight key genes and pathways that are involved in promoting platinum resistance. These key genes are then explored as targets for the development of therapies and can help clinicians create a more personalized approach to treatment.

Plugging the Gaps

As the genetic expression found in a cell dictates its protein expression and therefore, its function, examining the gene expression profiles of patient tumors can give researchers an insight into changes that are driving the cells to become more cancerous and resistant to therapies. The genetic profile of different cancer types can also tell us a lot about how a patient may respond to treatment and how the tumor growth will progress over time.

With an increased understanding of a patient’s genetic profile comes the opportunity to tailor treatment plans to be most effective against the key therapeutic targets for that tumor. As such, much of the work in cancer research in recent years has moved towards improving our understanding of what drives the growth of tumors and their resistance to therapies. This involves an in-depth look into both the genetic and protein expression that occurs in different cancer types and in different patient groups, e.g., responders to treatments vs those who do not respond efficiently.

Currently, there is no fully validated or clinically applied test to guide treatment decisions in ovarian cancer. Although several research groups have used gene expression data to develop signatures that predict clinical outcomes in ovarian cancer, the different gene signatures described to date exhibit little overlap and lack the correlation to poor outcomes. Consequently, there is not only a critical need for markers that can assess the risk of poor survival in patients with ovarian cancer, but also for a better understanding of the mechanisms that are involved in tumor progression which can be targeted with novel treatment strategies.

Noting this important gap in the research literature, Dr. Cheon and her team set about analyzing patient genetic data from three different datasets (the Cancer Genome Atlas, GSE26712 dataset, and GSE51088 dataset) to identify common gene expression patterns across ovarian cancer patients. Their results showed 61 genes that were present in at least two out of three of the datasets, of which ten genes were expressed across all three. This group of ten genes was then taken as their ‘genetic signature’ for poor prognosis as they found high expression of these genes indicated worse overall survival. Interestingly, the team found that most of the ten genes are known to produce stiff collagen matrices around cancer cells, highlighting the impact of the structural properties of cancer cells on patient survival.

Collagen Type XI Alpha 1 (COL11A1) was found to be the most significantly expressed gene out of the ten highlighted by the researchers. COL11A1 is mostly expressed by a subset of cancer-associated fibroblast cells adjacent to tumor cells, and a small number of cancer cells as well. COL11A1 has previously been shown to have increased expression in several other cancer types, including lung, pancreas, and colorectal cancers, with its high expression often being associated with poor survival, resistance to chemotherapy, and recurrence of the tumor.

Based on the results of their genetic analysis and previous work done in other cancer types, Dr. Cheon and her colleagues set out to validate that COL11A1 played a significant role in tumor progression. They found that removal of COL11A1 expression via genetic modification of cancer cells reduced tumor growth and decreased cell migration, invasion, and tumor progression, supporting the idea of its importance in tumor development. The team also discovered that COL11A1 makes cancer cells more resistant to cisplatin, supporting the clinical observation that COL11A1 is one of the top upregulated genes among patients who are resistant to platinum therapy than those who are sensitive. With these results, the team concluded that the role of COL11A1 made it a promising marker to target therapeutically but they wanted to understand in more detail what made COL11A1 so key for these processes in the tumor.

Delving Deeper into Discovery

Dr. Cheon and her team particularly examined the question of how COL11A1 makes ovarian cancer cells more resistant to platinum therapy. They analyzed proteins upregulated by COL11A1 and discovered that several key proteins of fatty acid oxidation (FAO) are upregulated by COL11A1. FAO is the metabolic process by which fatty acids enter the cell and are broken down to produce energy, reducing power, and biomolecules. This form of metabolism is common in cancers as rapidly proliferating cells rely on large amounts of fatty acids to support various biological processes including membrane formation and signaling. However, it is not fully understood which signals are produced by COL11A1 to regulate this metabolic switching, despite aberrant fatty acid metabolism being implicated in driving malignancy and chemotherapy resistance in several cancers. Therefore, Dr. Cheon and her team set about uncovering the pathways that lead from COL11A1 to metabolic switching and how this is linked to cisplatin resistance.

The team discovered that COL11A1 binds to the cell surface molecule and activates downstream signaling to increase FAO in ovarian cancer cells, making them more resistant to cisplatin. To try and work out the underlying mechanisms, they examined the activation of proteins downstream of COL11A1 and found that heat shock protein 27 (HSP27) activation correlated with levels of COL11A1 expression, suggesting a link between the two. Interestingly, HSP27 is a protein that has previously been implicated in cancer cell survival and resistance to chemotherapies across many cancer types. In ovarian cancer, several studies have established a relationship between this protein and poor patient survival.

In 2021, Dr. Cheon and her team investigated if there is a link between COL11A1/HSP27 expression and platinum resistance. They confirmed that COL11A1 increases HSP27 expression, and inhibiting the function of HSP27 caused re-sensitization of cells to cisplatin, suggesting that HSP27 mediates COL11A1-induced cisplatin resistance in ovarian cancer cells. The team also found that when HSP27 function is inhibited cancer cells upregulate FAO to survive during chemotherapy treatment without HSP27. When both HSP27 and FAO are inhibited, cancer cells show dramatic cell death after cisplatin treatment, suggesting that COL11A1 activates two parallel pathways-FAO and HSP27- to make cancer cells resistant to cisplatin. However, how exactly HSP27 inhibition upregulates FAO and how effective dual inhibition of HSP27 and FAO is in pre-clinical models remain to be determined.

Looking to the future

The work of Dr. Cheon has led to the important discovery that ovarian cancer patients who express high levels of the protein COL11A1 show poor survival outcomes and have a higher risk of developing chemotherapy resistance. Delving deeper into the reasons behind this, she has shown that COL11A1 promotes cisplatin resistance by increasing FAO in ovarian cancer cells. Using inhibitors to target this process, Dr. Cheon has shown that COL11A1^high cisplatin-resistant ovarian cancer cells can be effectively killed by FAO inhibitors in combination with HSP27 inhibitors. As such, these results provide a novel biomarker-guided targeted therapy for cisplatin-resistant ovarian cancer.

Although the link between COL11A1, HSP27, and cancer cell chemotherapy resistance has now been clearly established, understanding the full picture of how this occurs is a challenge that Dr. Cheon now faces. A key area of research will be improving our understanding of metabolism, in particular the metabolism of fats, within cancer cells and the environment surrounding the tumor. A particular interest is in the area of lipid droplets, a type of organelle made up of fats and proteins that help to regulate fat-based metabolism within ovarian cancer cells. Understanding how these organelles are formed and the proteins found within them will help the team pick apart the metabolic processes that allow ovarian cancer cells to aggressively grow. Dr. Cheon hopes that this will lead to a greater understanding of the regulation of platinum resistance within ovarian cancer cells and provide potential targets for the future development of therapies.