Each year, approximately 200 children and young adults are diagnosed with Ewing sarcoma in the United States. About half of all the diagnoses are in people between the ages of 10 and 20, slightly more males than females develop this cancer, and nearly all cases occur in White and Hispanic people. The presence of metastases is the most adverse prognostic factor in Ewing sarcoma, particularly in bone, tumor hypoxia, and chromosomal instability (CIN). A 3-year event-free survival for those with metastatic diseases is less than 30 percent, and it further decreases to 8-14 percent in patients with osseous dissemination.
The current standard of care for Ewing sarcoma involves systemic cell-killing chemotherapy that can create adverse effects to other cells. Additionally, there are no targeted treatments toward genetic alterations used in routine treatment of this cancer. This dearth of effective therapies suggests a poor understanding of the mechanisms underlying Ewing sarcoma metastasis. Although the etiology and molecular mechanisms of its progression are unclear, growing evidence indicates the role of tumor hypoxia in Ewing sarcoma metastasis.
In new research led by scientists from the Georgetown University Medical Center, a novel biological pathway that drives genomic changes and bone metastasis in Ewing sarcoma was identified (Nat Commun 2022; doi.org/10.1038/s41467-022-29898-x).
In the current study, researchers aimed to test the effect of hypoxia on its dissemination and determine the contribution of the neuropeptide Y (NPY)/Y5 receptor (Y5R) pathway to this process. NPY and its receptors are found in numerous tumors and have multifaceted actions pertinent to cancer biology, including cell proliferation, angiogenesis, survival, motility, differentiation, and invasiveness.
To test the effect of hypoxia on Ewing sarcoma metastatic pattern and uncover mechanisms underlying these effects, the investigators used an in vivo orthotopic Ewing sarcoma xenograft model. It demonstrated that tumor hypoxia selectively exacerbates bone metastasis in this cancer. A Y5R antagonist was administered for only 5 days, during the time when xenografts develop endogenous hypoxia, which leads to RhoA over-activation and cytokinesis failure. These mitotic defects lead to the formation of polyploid Ewing sarcoma cells, the progeny of which present high CIN, an ability to invade and colonize bone, and a resistance to chemotherapy. Blocking Y5R in these tumors successfully reduced hypoxia-induced polyploidization and prevented bone metastasis. Furthermore, the dose of the antagonist had to be limited due to its anti-orexigenic activity.
Corresponding author, Joanna Kitlinska, PhD, connected with Oncology Times to provide additional insights their study and the biological pathways that drive genomic changes and bone metastasis in Ewing sarcoma. She is Associate Professor in the Department of Biochemistry and Molecular & Cellular Biology at Georgetown University Medical Center.
Oncology Times: What are challenges to the standard of care of Ewing sarcoma?
Kitlinska: "The presence of metastases is one of the most adverse prognostic factors in Ewing sarcoma, particularly when the tumors spread to bones. A 3-year event-free survival for patients with metastatic tumors remains below 30 percent and decreases to 8-14 percent in those with osseous dissemination. Thus far, there are no targeted therapies for Ewing sarcoma and no specific treatment for the metastatic disease. As a result, Ewing sarcoma patients with metastatic disease are treated with the same routine therapy as those with localized disease, despite its known lack of efficiency in this patient population. Hence, understanding the mechanisms driving Ewing sarcoma metastases is crucial for designing novel therapies preventing the disease spread and targeting the population of metastatic cells."
Oncology Times: What factors do you consider when designing Y5R-targeted drugs for Ewing sarcoma?
Kitlinska: "Neuropeptide Y (NPY) is known for its central effects in the brain. Most importantly, the NPY/Y5R pathway in CNS is involved in stimulation of food intake and, therefore, became a target for anti-obesity therapies. Consequently, the vast majority of available Y5R antagonists are designed to be active in the brain. Unfortunately, these anti-orexigenic effects can be harmful for cancer patients and limit the dose of Y5R antagonist that can be administered. Hence, creating novel Y5R antagonists that do not cross the blood-brain barrier would increase clinical utility of such therapies."
Oncology Times: What is one of the most compelling aspects of this study? And based on your findings, what do you think is the role of Y5R in Ewing sarcoma dissemination and recurrence?
Kitlinska: "There are two important aspects of our study. 1) NPY/Y5R pathway as a trigger of chromosomal aberrations. Chromosomal instability is a known driver of cancer progression to metastatic and chemoresistant phenotype. There is also mounting evidence indicating that defects in cell division leading to the formation of polyploid cells trigger such chromosomal instability. However, the therapeutic strategies preventing this process are lacking.
"In Ewing sarcoma, in particular, chromosomal instability has been linked with worse prognosis; however, its role in the disease progression was underappreciated and not understood. Our studies identified the hypoxia-inducible pathway leading to chromosomal instability in these tumors and mechanisms linking it with Ewing sarcoma progression. We have found that NPY/Y5R axis activation occurring in hypoxic Ewing sarcoma leads to mitotic failure, resulting in chromosomal instability, while Y5R inhibition averts accumulation of chromosomal abnormalities. Hence, targeting the NPY/Y5R pathway with Y5R antagonists provides a unique opportunity to prevent genomic changes driving cancer progression.
"2) Hypoxia-induced polyploid cells initiate bone metastasis. We have shown that the progeny of polyploid cells arising in hypoxic Ewing sarcoma tumors due to the activation of the NPY/Y5R pathway have high propensity for bone metastasis and increased resistance to chemotherapy. This phenomenon may explain lack of response to routine therapy observed in Ewing sarcoma patients with bone metastases. While blocking Y5R can prevent bone metastasis, identifying unique molecular features of this specific cell population enabling its survival in hypoxic bone environment and resistance to cytotoxic therapies may allow for targeting existing bone metastases."
Oncology Times: What additional questions will you investigate?
Kitlinska: "Our current research focuses on developing the most efficient strategies of blocking NPY metastatic effects and identifying mechanisms underlying osseous dissemination and chemoresistance of the hypoxia-induced polyploid cells. While our studies center on pediatric tumors, Y5R expression has also been shown in common adult malignancies, such as breast, prostate, and liver cancers, all of which metastasize to bone. Hence, we will determine if Y5R signaling is also involved in dissemination of tumors other than Ewing sarcoma."
Dibash Kumar Das is a contributing writer.