Full Circle: From Watching the ESPYS to Researching Cancer in the Lab
Read moreState: North Carolina
Carolyn Sartor, M.D.
Funded by the Jimmy V Women’s Basketball Classic
Christopher Counter, Ph.D.
Andrew Futreal, Ph.D.
Andrew Krivoshik, M.D., Ph.D.
Funded by the Jimmy V Celebrity Junior Golf Classic
The Jim Valvano Post-Doctoral Fellowship
in Pediatric Cancer Research
Victoria Seewaldt, M.D.
Funded by the Jimmy V Women’s Basketball Classic
Gerold Bepler, M.D., Ph.D.
Corinne Linardic, M.D., Ph.D.
Funded by the Apple Gold Group
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer of childhood. Because RMS has features of skeletal muscle, we and others have been trying to understand how muscle development pathways inside the tumor cells have gone awry. This project will study the role of a protein called SFRP3, which although it takes part in normal muscle formation, is co-opted to support RMS tumor formation. We aim to understand in more detail how SFRP3 works in RMS, and how to block it. Our goal is to someday use SFRP3 blockade as a therapeutic intervention.
Daniel Wechsler, M.D.
Funded by the Apple Gold Group
The CALM-AF10 chromosomal abnormality is seen in aggressive pediatric and adult acute leukemias that have a poor prognosis. Our lab has discovered that CALM-AF10 interacts with CRM1, a protein that helps transport other proteins from the nucleus to the cytoplasm. This interaction is required to activate HOXA genes, which play a critical role in both CALM-AF10 and other leukemias. This discovery suggests that CRM1 may be important in other leukemias as well, as is significant because a new class of drugs that inhibit interaction with CRM1 (SINEs-Selective Inhibitors of Nuclear Export) has recently been developed. These drugs are effective in a number of human tumor types, and are currently in clinical trials for adult leukemias. Our studies indicate that SINEs may block cancer cells through an unappreciated and novel mechanism-inhibiting CRM1 involvement in activating HOXA genes. In this proposal, we will examine the molecular mechanisms by which CRM1 activates HOXA genes. We will then identify additional CRM1 target genes that are involved in causing leukemias. Studying this previously unrecognized role for CRM1 will enhance our understanding of how SINEs work, and provide preclinical support for their use in pediatric leukemia clinical trials. Since HOXA genes are involved in many hematopoietic malignancies (including MLL-fusion leukemias that are seen in 80% of infant leukemias), these studies may have broad implications for leukemogenesis.
Qing Zhang, Ph.D
Triple Negative Breast Cancer (TNBC) accounts for 15-25% of breast cancers. TNBC is well known for its aggressive clinical behavior and early peak of recurrence. Due to the lack of good therapeutic targets, TNBC represents the specific subtype of breast cancer with worst prognosis. Therefore, there remains the urgent question to be addressed: Can we identity important biological features that serve as high value targets for the development of novel treatment modalities for TNBC? This line of research carries significant social and economic importance. Hypoxia is a characteristic of solid tumor, which contributes to radiation and chemotherapy resistance. One important feature of tumor cells is that they sense the oxygen tension and rewire their signaling pathway to survive under harsh living conditions. EglN2 prolyl hydroxylase serves as an important oxygen sensor. In this proposal, we presented some preliminary data in the TNBC cell lines that getting rid of EglN2 could decrease TNBC tumor growth and invasion. We propose to obtain primary tumors from TNBC patients, implant them into mice and treat them with siRNA nanoparticles that deplete EglN2, which will be used to test the efficacy of targeting EglN2 in a patient relevant system. In addition, we will study mechanistically how EglN2 protein stability is regulated by FBW7 E3 ligase complex. Furthermore, we will implement a novel screening for EglN2 specific inhibitors, which will motivate testing the effect of these potential inhibitors on TNBC tumorigenesis. Successful completion of proposed research will open new therapeutic avenues in treating TNBC.
