Nationwide Children's Hospital Archives - Page 2 of 3

2017

Scholar Grant

Dr. Timothy Cripe

Columbus, OH

Oncolytic viruses are emerging as treatment options with the potential to attack cancer in ways that have not previously been possible. We have tested an oncolytic herpes simplex virus (oHSV) called Seprehvir (aka HSV1716), in mouse preclinical models and in pediatric cancer patients in a phase I clinical trial. In mice, the virus causes tumor shrinkage in most tumor models and even cures some animals, making it a promising therapeutic. in children, we found the virus is safe to administer both by intratumoral and intravenous routes. In some patients the virus induced transient inflammatory reactions in tumors and caused tumor necrosis. Our aim with this project is to garner sufficient preclinical data to guide us in how best to increase the effectiveness of Seprehvir virotherapy in our next clinical trial. We will study four models of rhabdomyosarcoma: two patient-derived xenograft models in aim 1, and two immunocompetent models in aim 2.

Specific Aim 1. Determine if simultaneous proteasome, HDAC and STAT1 inhibition is superior to each mono- or bi-therapy to increase lytic efficacy of Seprehvir.
1.0 Identify suitable patient-derived xenograft models that are poorly or moderately responsive to Seprhvir virotherapy as mono-therapy (i.e., there is room for improvement).
1.1 Compare Seprehvir virotherapy combined with a proteasome and a histone deacetylase inhibitor each and together.
1.2 Determine if STAT1 inhibition further increases potency of the virus.
1.3 Determine if inhibition of innate immunity with a pre-dose of cyclophosphamide further increases killing potency of the virus.

Specific Aim 2. Compare HDAC, PD1 and TGFE1 inhibition alone and in combination for enhancing immunologic efficacy of Seprehvir.
– 2.1 Compare two drugs known to release the breaks on immunity for their effects on enabling virus-induced cancer immunity.
– 2.2 Determine if a histone deacetylase inhibitor further increases the immunologic effects of virus

Significance: This translational Hyundai project will provide us with important information to help us design and launch the next generation clinical trial of herpes virotherapy for childhood cancer.

2014

Scholar Grant

Dr. Hakan Cam

Columbus, OH

Pediatric sarcomas are among the most aggressive cancers that strike children and teens. The most important factor influencing the survival of children with sarcomas is metastasis – the spread of cancer to other parts of the body. A child diagnosed with a sarcoma has a 70-80% chance of cure, provided they have not developed metastasis. If the tumor has spread, however, that same child will have a 70-80% chance of dying, even with aggressive therapy. Despite the importance of metastasis to outcomes in these cancers, we understand very little about why or how they spread.
Our research has identified changes within the cells of childhood sarcomas-osteosarcoma, Ewing’s Sarcoma, and rhabdomyosarcoma – that drive aggressive behaviors associated with metastasis. We have found that these tumor cells can change the way they express a group of genes from the p53 gene family. The alternatively expressed forms of these genes, called delta-N isoforms, activate pathways within the tumor cells that make them behave aggressively. This grant will allow us to test the ultimate importance delta-N isoforms to the development of metastasis. We will use engineered viruses to manipulate the expression of these genes within the tumor cells then measure the effects of those manipulations on metastasis in our mouse models of pediatric sarcomas.
Even though each tumor type expresses a different delta-N isoform, they all trigger a common final pathway by activating a molecule called STAT3. Our research suggests that blocking STAT3 could suppress the aggressive behaviors that delta-N isoforms elicit. This may interrupt critical steps in the metastatic process and prevent metastases from forming. With this grant, we will test whether drugs that block STAT3 can prevent metastasis and enhance survival. These strategies could translate directly into treatments that would save lives by preventing metastasis in children with pediatric sarcomas.