Melanoma treatment method using estrogen modulating small molecules

Unmet Need

Metastatic melanoma, skin cancer that has spread, is an incredibly deadly cancer, with a median survivorship of 6-9 months. For patients with melanoma, a frequently used therapy is immune checkpoint blockade (ICB). These drugs correct the immune system’s response to target melanoma cells, as the cancerous cells can use these checkpoints to avoid being detected and attacked. However, new and acquired resistance to these therapies is a big hurdle during therapy such that the treatment is currently effective in only about 20% of patients and puts a limitation on its clinical useability. There is a need for treatment strategies that have greater efficacy, reliability, and decrease the toxicities linked to ICB to combat aggressive melanoma and other cancer cells.

Technology

Duke inventors have developed a combinatorial treatment method with increased therapeutic effectiveness for patients with metastatic melanoma. Specifically, this treatment method uses estrogen modulating drugs, both selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs), in combination with immune checkpoint blockage (ICBs) therapies. Together, these drugs reduce tumor growth by preventing estrogen from targeting and decreasing important immune responses that identify cancerous cells. In vitro, the inventors showed that cells treated with estrogen had an increased ability to suppress T cell proliferation and overall elevated an immune-suppressive microenvironment. However, these effects were reversed with fulvestrant, a clinically available SERD. In vivo, the impact of fulvestrant in combination with ICBs was shown in mice, in which fulvestrant increased the effectiveness of ICBs, specifically α-PD1 and α-CTLA4. Fulvestrant together with the ICB suppressed tumor growth and boosted adaptive immunity. This combinatorial treatment also worked in mice models that were unresponsive to ICB and showcase the treatment method’s potential for helping the approximately 80% of patients who do not respond to ICB therapy alone.

Other Applications

This technology could also be used in patients with lung and colon cancer.

Advantages

• Provides a treatment option for patients that do not respond or have diminishing responses to immune checkpoint inhibitor therapy (80% of patients)
• In vivo data showing significant tumor size difference, approximately 100% reduction, in group treated with combinatorial treatment compared to group treated with fulvestrant alone
• In vivo data showing the effectiveness of combinatorial treatment in models unresponsive to ICBs alone
• in vitro data highlighting the role of estrogen modulating drugs in reversing the suppressive effects of estrogen on T cell proliferation and immune response
• Many candidate estrogen modulating drugs SERDs (12 in clinical development) and SERMs available