Ann & Robert H Lurie Children's Hospital of Chicago Archives

2017

Scholar Grant

Dr. Oren Josh Becher

Chicago, IL

Diffuse Intrinsic Pontine Glioma {DIPG) tumors account for 10-15% of all brain tumors in children. Unlike many other pediatric cancers, there has been little progress in improving treatments and survival rates for DIPG over the last few decades. These aggressive tumors typically result in death within two years of diagnosis. The current standard-of-care is conventional radiation therapy {RT), although this provides only temporary relief from symptoms and does not represent a cure. Moreover, while numerous clinical trials of new therapies have been performed, no chemotherapeutic agent has demonstrated significant efficacy. This lack of efficacy is likely the result of early studies using adult glioma as a pre-clinical model. Research has revealed that DIPG is biologically distinct from adult glioma. Therefore, pre-clinical trials using DIPG-specific models to test novel therapies are needed to improve outcomes for children.

We have developed a genetically engineered mouse model of DIPG that faithfully replicates the human disease in children and represents a novel platform with which to study the biology and treatment of DIPG. Using this model, we propose to conduct a pre-clinical study of the drug AZ59 to examine its ability to improve the efficacy of RT. We hypothesize thatAZ59 will inhibit the protein A TM (Ataxia telangiectasia mutated), which plays a central role in cell division and DNA repair, and, by doing so, will sensitize this DIPG model to RT. We expect this to result in slowed tumor growth and a prolonged lifespan for treated animals with brainstem tumors.

Specific aims include:
-Determining whether the ATM inhibitor, AZ59, can increase the cytotoxic effect of radiation in a DIPG mouse model -Investigating the ability of ATM inhibition to sensitize DIPG to RT and increase survival oftumor-bearing mice.

This project could yield urgently needed treatment strategies for children impacted by this incurable brain cancer.

2014

Scholar Grant

Dr. James Labelle

Chicago, IL

A paramount obstacle to personalized cancer therapy is effective modulation of the anti-tumor immune response. Accordingly, the ultimate goal of this proposal is to develop an immunomodulatory therapeutic strategy against pediatric solid tumors such as rhabdomyosarcoma, Ewing sarcoma, and desmoplastic small round cell tumors. Although these tumors have recently been shown to be recognized by the immune system, clinically effective anti-tumor responses in pediatric patients with refractory or relapsed disease are rare. This immune unresponsiveness is, in large part, secondary to an otherwise normal immune cell called a regulatory T cell (Treg). Unlike other immune cells, Tregs are exquisitely dependent upon the transcriptional protein FOXP3. If Tregs are experimentally removed either in culture or in cancer patients, the suppressive “veil” inhibiting an effective immune response can be lifted. The therapeutic challenge is that these regulatory T cells are difficult to target in patients without affecting other immune cells necessary for normal immunological defense against infection. This becomes an even greater issue in patients already immunosuppressed because of conventional chemotherapy. Using new FOXP3 structural information, we aim to develop a novel therapy specifically directed towards inhibition of Tregs. Cutting-edge chemical biology will be used to transform natural protein segments of FOXP3 into molecular tools that can identify and potentially neutralize FOXP3 in Tregs in an effort to help break cancer’s survival advantage in patients with relapsed or refractory disease. To achieve the goals of this project, I aim to take a multidisciplinary approach spanning synthetic chemistry, biochemistry, and molecular biology. The inclusion of leaders in the field of peptide therapeutics greatly enhances the translational power of this approach and extrapolation to a host of other cancer treatment strategies.