Expert Anticipates Additional Benefits From RANKL Inhibition

Eva González-Suárez, PhD

Eva González-Suárez, PhD, focuses her research on understanding the mechanisms leading to cell transformation, the metastatic capability of epithelial cells, and the disruption of signaling pathways in cancer, including the role of the RANK pathway in the regulation of tumor-stroma crosstalk and as a novel therapeutic target in cancer.

OncLive: How is RANK pathway dysregulated in cancer cells?

She is principal investigator of the Transformation and Metastasis Group at the Bellvitge Institute for Biomedical Research in Barcelona, Spain.González-Suárez: Multiple myeloma, prostate, and breast cancer have the highest rates of bone metastases. Tumor cells manipulate the bone microenvironment to activate RANK signaling in osteoclasts, leading to bone resorption and metastatic colonization. This osteoclast-dependent process is very well characterized and it is exploited therapeutically.

The RANK pathway is the main mediator of the protumorigenic role of progestins in the mouse mammary gland during tumor initiation. RANKL also acts as a paracrine mediator of progesterone in the human mammary epithelia.

This provides a mechanistic explanation for the deleterious effect of combined hormone replacement therapy on breast cancer. Moreover, it supports the use of RANKL inhibitors to prevent or decrease the incidence of breast cancer in high-risk groups.

However, the therapeutic potential of RANKL inhibitors to “treat” patients with breast cancer remains to be addressed. In breast cancer cell lines, overactivation of RANK signaling increases tumor growth and metastasis. Our recent results in mouse models are encouraging as they demonstrate that RANK blockage induces differentiation of tumor cells, and decreases the cancer stem cell population.

How are drugs targeting this pathway currently used in cancer?

Thus, inhibition of the RANK pathway in patients with breast cancer may reduce recurrence, metastasis, and resistance to chemotherapy. Ongoing experiments using more clinically relevant models, such as patient-derived xenografts, are essential before these results can be translated to patients.The unique role of RANK signaling in the control of osteoclast function and its deregulation during pathological conditions such as osteoporosis and bone metastasis led to the generation and approval of a monoclonal antibody against RANKL (denosumab), which is highly efficient for the management of skeletal- related events derived from these pathologies.

What is the potential for targeting the RANK pathway to prevent certain types of cancer?

In the context of cancer, denosumab is approved for the treatment of bone metastasis of different types of cancer and for the treatment of giant cell tumor of the bone. Ongoing clinical trials aim to demonstrate whether denosumab can prevent bone metastasis.Recent data demonstrate that RANK and RANKL are key molecules involved in the initiation of BRCA1-associated breast cancer, based on its role as a paracrine mediator of progesterone.

What are the most significant unanswered questions and challenges in understanding and targeting the RANK pathway?

Thus, anti-RANKL therapy could be a feasible preventive strategy for women carrying BRCA1 mutations and, by extension, for other women with a high-risk of breast cancer. Again, putative applications of RANKL inhibitors for cancer treatment of BRCA1-positive tumors and other subtypes deserves further investigation.Accumulating evidence highlights the pivotal role of the RANK signaling pathway during all stages of tumor progression from initial transformation to metastasis based on its osteoclast- and cancer cell-dependent roles.

RANK enhances the hallmark capabilities of tumor cells, mostly described in mammary epithelia, increasing proliferation and “stemness” in the early steps of mammary tumorigenesis and enhancing survival and migration in neoplastic cells.

It remains to be proven whether these findings can be extrapolated to other epithelia, and whether therapeutic inhibition of the RANK pathway in human breast cancer and other tumors has benefits beyond the management of bone metastasis.

Further investigation is urgently required to clarify the complex scenario of RANK signaling in tumorigenesis. It will be of paramount importance to dissect the pleiotropic roles of RANK in tumor and stroma cells, and how their crosstalk influences the different stages of tumor progression.

Denosumab has been shown to be highly efficient for the treatment of skeletal-related events, but, considering the multiple effects of RANK signaling in tumor and immune cells, additional benefits and therapeutic applications are anticipated.

We and others have also found that the RANK pathway directly promotes mammary tumor initiation based on its role in the mammary epithelia.