$5.5 Million

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Terrie Flatt, DO, MA
Hematology/Oncology/BMT, Director of the Spanish Language Clinic
Children’s Mercy Kansas City
Along with Andrew Godwin, PhD, University of Kansas Medical Center

Advancing New Treatment Options to Improve Outcomes of Children and Young Adults Diagnosed with Ewing Sarcoma

Dr. Flatt and Dr. Godwin’s project, “Advancing New Treatment Options to Improve Outcomes of Children and Young Adults Diagnosed with Ewing Sarcoma,” will work to find drugs that destroy and prevent Ewing sarcoma (EWS) cancer cells from growing back.

The team will use their knowledge of the biology of this type of tumor to rationally combine drugs with like properties.

Based on the team’s findings, they will work with expert cancer physicians at Children’s Mercy and the KU Cancer Center to develop a clinical study to treat children and young adults with EWS that are not cured by standard chemotherapies.

The study will test multiple novel agents to develop treatments for EWS patients.

“We accepted this challenge, given no new therapies have been offered to children and young adults with EWS for nearly two decades,” the investigators wrote in their application. “This study will have a potential to offer new treatment options not typically afforded to patients with very rare tumors such as Ewing sarcoma.”

Co-investigators include Joy Fulbright, MD, Hematology/Oncology/BMT, and Joaquina Baranda, MD, Leonidas Bantis, PhD, and Vikalp Vishwakarma, PhD, all of the University of Kansas Medical Center.

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Jay Vivian, PhD
Clinical Genetics, Director of the Rare Disease Model Research Program
Children’s Mercy Kansas City

Induced pluripotent stem cell models for pediatric KMT2A-r leukemia development and discovery of targeted therapies.

Dr. Vivian’s project, “Induced pluripotent stem cell models for pediatric KMT2A-r leukemia development and discovery of targeted therapies,” focuses on advancing therapies for children with leukemia in which the KMT2A gene is rearranged.

The team will investigate the cellular and molecular changes in novel engineered stem cell models of pediatric leukemia subtypes and assess the response of three different KMT2A rearrangements to standard chemotherapy and novel agents.

“This study is the first of its kind, and we anticipate it will generate fundamental, mechanistic insight that can be shared with other researchers and will become widely used to study new treatments for leukemia involving KMT2A, in both children and adults,” Dr. Vivian wrote.

Co-investigators include John Perry, PhD, Hematology/Oncology/BMT, Children’s Mercy Kansas City.

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Tomoo Iwakuma, MD, PhD
Hematology/Oncology/BMT, Director of Translational Laboratory Oncology Research
Children’s Mercy Kansas City

Identifying compounds that target vulnerabilities imposed by EWS haploin sufficiency to discover novel treatments for EWSR1 fusion-positive childhood sarcomas.

Dr. Iwakuma’s project, “Identifying compounds that target vulnerabilities imposed by EWS haploin sufficiency to discover novel treatments for EWSR1 fusion-positive childhood sarcomas,” will investigate if a lesser amount of Ewing sarcoma (EWS) proteins caused by EWS-fusion sarcomas commonly carrying only one EWS gene contributes to disease progression.

Based on the results of previous research the team has done, they hypothesize that the loss of a single EWS gene in human cancer cells increases yet unappreciated cancer promoting signaling that is crucial for the survival of cancer cells with a single EWS gene.

The goal of this study is to find drugs that specifically kill cancer cells with low EWS protein levels in EWS-fusion sarcomas while sparing normal tissues and to understand the underlying mechanism. They will screen drug libraries to identify drugs/compounds that specifically kills cells with one EWS gene without killing cells with two EWS genes. They will investigate how the identified drugs affect cell death, cell cycle progression, DNA copy numbers, and molecular changes in the cell. Finally, they will investigate how the identified drugs inhibit cancer progression following transplantation of Ewing sarcoma cells with one EWS gene into immunocompromised mice.

“Significance of this study is the new concept in which the drugs can specifically kill sarcoma cells with low EWS protein levels (with one EWS gene) while sparing normal cells with two EWS genes,” Dr. Iwakuma wrote. “Innovation of this study is that the drug will change the paradigm by reducing the side effects in the patients with EWS-fusion sarcomas.”

The ultimate goal is to increase the survival rate of patients with EWS-fusion sarcomas.

Co-investigators include Mizuki Azuma, PhD, the University of Kansas.

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Midhat Farooqi, M.D., Ph.D.
Director, Molecular Oncology
Children’s Mercy Genome Center

Targeting solid tumors with multi-antigen specific T cells by identifying the genetic and epigenetic determinants of therapeutic response

T cells, a type of immune cell, circulate in our bodies and scan for microbes as well as abnormal cells. In the laboratory, exposing T cells to small fragments of proteins (“antigens”) expressed on the surface of tumor cells trains these T cells to recognize cancer cells and eradicate them. This finding led to the recent development of ‘multi-antigen specific T cells’ (MAS T cells), a safe and novel form of targeted therapy for a range of pediatric solid tumors including neuroblastoma, Ewing Sarcoma and Wilms tumor. Dr. Farooqi’s team seeks to understand whether a tumor’s genetic profile affects its response to MAS T cell infusion. With funding from Braden’s Hope, his team is performing comprehensive genetic sequencing of patient tumor samples pre- and post-therapy. The project involves patients and tumor samples from Children’s National Medical Center in Washington, D.C.; Children’s Health in Dallas, Texas, and Cook Children’s in Fort Worth, Texas, with plans in the near future to include samples from the Instituto Nacional de Pediatria in Mexico City, Mexico.

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John M. Perry, Ph.D.
Research Faculty, Children’s Mercy Research Institute
Hematology/Oncology/BMT

Overcoming therapeutic resistance by repurposing a classic chemotherapeutic drug as a targeted therapy to reactivate anti-cancer immunity

Our immune systems normally recognize potentially cancerous cells early enough to prevent tumor development. However, cancer stem cells, which are resistant to most therapies and cause cancer relapse, are especially good at evading and resisting the immune system. Dr. Perry’s team found that a long-used chemotherapy drug, doxorubicin, could be used in a more targeted manner to stimulate the immune system and replenish normal stem cells, while inhibiting cancer stem cell’s immune evasion. Dr. Perry is now focused on developing a new drug, with similar properties as doxorubicin but with more potent and specific effects. With support from Braden’s Hope, Dr. Perry’s long-term goal is to eliminate cancer stem cells and provoke an immune response that will effectively vaccinate patients against relapse.

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Tomoo Iwakuma, M.D., Ph.D.
Director, Translational Laboratory Oncology Research Program, Children’s Research Institute
Volunteer faculty of Department of Cancer Biology, KUMC
Co-leader of Cancer Biology Program, KU Cancer Center

Capitalizing on p53 loss/mutations in osteosarcoma by novel compounds

Dr. Iwakuma’s team has identified a new compound that kills only cancer cells lacking a key cancer-preventive protein called “tumor suppressor p53.” Since over 50% of human cancers and specifically about 80% of osteosarcoma cases lose the p53 activity, and because normal tissues have intact p53 activity, Dr. Iwakuma’s compound has the potential to only kill cancer cells with minimal side effects to healthy cells. With support from Braden’s Hope, Dr. Iwakuma’s team recently discovered that this compound also blocks one of the key DNA damage repair machineries in cells that lose p53 activity and inhibits osteosarcoma tumor growth in mouse models. The team is modifying the chemical structure of this compound so that it can be suited for clinical use in pediatric patients. Dr. Iwakuma is quick to point out that without Braden’s Hope, his research would not have progressed as far as it has in less than three years.

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We funded a two-year, $200,000 study to Dr. Andrew Godwin and Dr. Glenson Samuel at KU Medical Center for Ewings Sarcoma research. The study is “Exosome miRNAs as biomarkers and targets for chemoresistance in Ewing Sarcoma”.

We also funded a two-year, $300,000 study to Dr. Shrikant Anant from KU Medical Center and Dr. Kathleen Chastain from Children’s Mercy Hospital for “Sarcoma in a Dish: a novel approach for precision medicine”. This study seeks to find answers for Rhabdomyosarcoma cancers in children.

We funded a third study which was a one-year $100,000 study to Dr. Yael Mosse, titled “Immunotherapeutic Strategies to Target ALK on the Cell Surface of High Risk Neuroblastoma”. This study addresses high risk neuroblastoma and is a precision medicine approach to treating this deadly disease.

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Two grants were awarded this year. One was to Dr. Kathleen Chastain from Children’s Mercy Hospital in conjunction with Dr. Shrikant Anant at KU Medical Center for rhabdomyosarcoma research. The amount of that grant was $193,700.

The second grant totaling $100,000 was awarded to Dr. Andrew Godwin from KU Medical Center in conjunction with Dr. Kathleen Chastain of Children’s Mercy Hospital for work in the area of Ewings Sarcoma.

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We awarded two grants in 2014. One was to Dr. Kathleen Neville at Children’s Mercy Hospital in conjunction with Dr. Giselle Sholler from Helen deVos Hospital in Grand Rapids, Michigan. This was a Phase One research trial with two targeted treatment drugs called DFMO and Velcade which are given to patients who have gone through neuroblastoma treatments in an attempt to keep them in remission as a high percentage of neuroblastoma patients relapse.

The second grant was awarded in 2014 was to Dr. Doug Myers from Children’s Mercy Hospital in partnership with Dr. Thomas Yankee at KU Medical Center. Their research focuses on all solid mass tumors and the grant title was Next generation chimeric antigen receptors for personalized anti-tumor therapy.  Their work focuses on infusing donor cells from a relative that are “supercharged” into a childhood cancer patient. Those cells then target cancer cells to destroy them and teach the child’s own immune system to recognize the invading cancer cells and destroy them. This is the second phase of their work and the preliminary results from the first phase of their work were extremely promising.

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Our first grant was awarded to Dr. Jason Shohet at Texas Children’s Hospital to find a specific stem cell that is believed to be an activator of neuroblastoma cancers. His work was designed to find that cell, learn what activates it, and then develop a treatment that would shut that cell activator down.