Targeting CCAAT/enhancer binding proteins CEBPB and CEBPD in neuroblastoma
Transcription factors are proteins that help to regulate genes. Our goal is to develop an entirely new treatment for neuroblastoma that is directed towards novel transcription factor targets and that uses an innovative strategy to do so. Our studies show that the transcription factors ATF5, CEBPB and CEBPD are required by neuroblastoma cells for their survival. Conventional thought is that targeting such factors clinically is not feasible.
However, we have designed novel peptides that can penetrate into cells and disable these factors, promoting disease death in a wide variety of cancer types, including neuroblastoma. Work on our first such drug, CP-d/n-ATF5 (ST101), has led to a clinical trial in adults with advanced solid tumors. This trial strongly supports the idea that novel peptides of the type we have developed can be translated to safe treatments for childhood cancers. This proposal will evaluate our newest peptides Bpep and Dpep, which target ATF5, CEBPB and CEBPD, and are effective at lower concentrations then our first drug. We will test these peptides against neuroblastoma cells lines both in tissue culture and in mice. The celerity with which our work on CP-dn-ATF5 has moved towards the clinic indicates that our novel approach and peptides have a strong potential to lead to therapy for high-risk neuroblastoma and other childhood tumors.
The work in this proposal is aimed at assessing and substantiating this potential in cellular and animal models so that we can move forward to the clinic.
Project Goals:
Our goals are to demonstrate that the novel peptides Bpep and Dpep can 1) inhibit the growth and metastasis of neuroblastoma tumors, 2) act synergistically with chemotherapy and radiation therapy to inhibit neuroblastoma tumor growth, and 3) increase the immune response to neuroblastoma. Our long term goal is to bring these novel peptides to the clinic.
Project Update 2024:
Our research has shown that the transcription factors ATF5, CEBPB and CEBPD are required by neuroblastoma cells to survive. Conventional thought is that targeting such factors clinically is not feasible. However, we have designed novel peptides that can penetrate cells and disable these factors. We have evaluated our newest peptides Bpep and Dpep and found that there are effective against neuroblastoma cell lines in tissue culture. We have found that Dpep can inhibit the growth of neuroblastoma tumors and decreases metastasis to the bone marrow and liver. We have also demonstrated that Dpep works additively with radiation to markedly inhibit growth of a murine model of neuroblastoma. Our results suggest that targeting the ATF5, CEBPB, and CEBPD, with Bpep/Dpep, is a potential therapy for neuroblastoma.
