Molecular Oncology and Experimental Therapeutics

Personalized cancer therapy entails targeting and optimizing treatments to the patient. This includes clinical pharmacology of anti-cancer drugs, genetic assessment of each patient’s ability to tolerate treatment and identification of genetic biomarkers in DNA and proteins that predict therapy response.

Researchers in the Pediatric Molecular Oncology and Experimental Therapeutics research program are working on developing and optimizing new drugs to treat patients with cancer.

The Fishel and Kelley labs have worked on the development of APE1/Ref-1 (AP endonuclease1 / Redox effector factor-1) inhibitors based on its role in response to stress, inflammation, and chemoresistance. These studies are built on the structure-affinity relationship (SAR) analysis on parent compound, APX3330 which has completed phase I clinical trials in solid tumors in adults.

Active studies on a number of sarcomas have a focus on relapsed osteosarcoma and Ewing’s sarcoma. These highly aggressive tumors are in the bones or in tissue around the bones. Novel tumor models are being developed directly from tumor samples donated by young patients at Riley Hospital for Children at IU Health.

Ongoing research in the molecular oncology program involved subsets such as malignant peripheral nerve sheath tumor (MPNST). The collaborative group from the Herman B Wells Center discovered that a protein with DNA repair and transcriptional regulatory activity (APE1/Ref-1) increases as NF1 tumors progress to MPNST. Efforts are ongoing to develop and test new inhibitors of this protein in mouse models in order to inhibit the growth of these tumors. The program's interrogation of public and internal MPNST gene expression data resulted in the identification of genes that are upregulated specifically in MPNST and can then be downregulated with inhibition of APE1/Ref-1 in MPNST cells.

Glioblastoma multiforme (GBM) is a cancer with no known cure. In pediatric patients 15 years of age or younger, malignant brain tumors represent approximately one-quarter of all pediatric cancers and are associated with the most significant cancer morbidity. Researchers at the Wells Center are focused on understanding the complex mechanisms involved in GBM progression and finding therapeutic agents that interfere with these complex processes.

Investigators are working to identify cellular defects that lead to the toxicity of cancer treatments. In many people who survive cancer, treatment-related damage can result in lifelong issues such as neuropathy (pain, numbness, hearing loss). This is a major concern for children who survive cancer treatments.

Human papillomavirus (HPV) is a common infection that affects more than 75 percent of the adult population and is typically acquired during adolescence and early adulthood. Nearly 5 percent of cancers worldwide are caused by HPV. Based on their association with cancer, different types of HPV are categorized as high-risk or low-risk. The molecular oncology research group studies the protein partnerships that drive cancer development and progression in certain high-risk HPV viral oncogenes.