Children's Healthcare of Atlanta, Inc. Archives - Page 2 of 2

2017

Scholar Grant

Dr. Christopher C. Porter

Atlanta, GA

Despite dramatic improvements in survival rates, current treatment regimens have short andlong term side effects, and leukemia remains a leading cause of illness-related death in children. Thus, safer and more effective treatment strategies are urgently needed. While exploiting the immune system for cancer treatment is being pursued for many cancers, including leukemia, much is still unknown about how leukemia cells avoid the immune system and how to best re-engage it. We have found a novel mechanism of immune evasionduring leukemia development that we propose to target to treat leukemia. We have found that leukemia cells depend on an enzyme called calcineurin to avoid destruction by the T cells of the immune system. As T cells also rely on calcineurin, we have worked to identify downstream effectors of calcineurin mediated immune evasion that could be targeted. In so doing, we have identified a cell surface protein (CSP) regulated by calcineurin that leukemiacells rely on during leukemia development. Thus, the goals of this project are to 1) determine whether this CSP is responsible for immune evasion during leukemia development and 2) determine whether this CSP is expressed on human leukemia cells.

We will take advantage of a leukemia model with intact and impaired immune systems, as well as the robust leukemia bio-banking program at the Aflac Cancer and Blood Disorders Center to achieve these goals.

Successful completion of this project could lead to the identification of a novel therapeutic target for childhood acute lymphoblastic leukemia, which could be inhibited using a monoclonal antibody, for example.

2017

Young Investigator

Dr. Sunil S. Raikar

Atlanta, GA

Antigen Receptors for the Treatment of T-cell Malignancies

Acute lymphoblastic leukemia (ALL) is the most common blood cancer in children. T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL that can be harder to cure and has a higher chance of relapse compared to B-cell acute lymphoblastic leukemia (B-ALL). T-Lymphoblastic lymphoma (T-LLy) is a lymph node cancer that behaves like T-ALL and is treated similarly. Relapsed T-ALL/T-LLy is very aggressive and difficult to treat with chemotherapy alone. The only effective treatment for relapsed disease is a bone marrow transplant. Unfortunately, preparation for a bone marrow transplant can take several months and many patients are unable to survive that duration. Thus, there is a need to develop newer therapies targeting T-ALL/T-LLy to help patients proceed to transplant. In my project, I am studying the use of our own immune cells to target and kill cancerous T-cells. The type of immune cells we are using are called natural killer cells. Natural killer cells are an important part of our immune system and have the ability to recognize and kill cells infected with viruses and bacteria. By genetically modifying these immune cells, we are able to specifically direct them towards cancerous T-cells resulting in cancer cell death. We hope that our research will provide the foundation to develop a clinical trial in the future to more effectively treat relapsed T-cell disease.

The goals for my project are as follows:

To genetically modify natural killer cells to direct them towards cancerous T-cells
To test the killing ability of these natural killer cells against T-ALL cell lines
To assess the treatment efficacy of these modified immune cells in T-ALL mouse models created using leukemia cell lines as well as patient samples

2014

Scholar Grant

Dr. Muxiang Zhou

Atlanta, GA

Our early studies found that ALL cells from pediatric patients with drug resistance show an overexpression of MDM2. Our recent drug discovery studies identified a small-molecular compound called AQ-126 that can target MDM2 for degradation, resulting in inhibition of XIAP and activation of p53, which induces potent apoptosis of ALL cells in vitro. Initial animal studies in a human ALL/SCID mouse model indicate AQ-126 effected a cure at about 150 days, after only 2 weeks of AQ-126 treatment, while all the untreated control mice died within 45 days. Interestingly, AQ-126 showed no or much less inhibitory effect on normal human hematopoiesis and it has no mouse heart, liver and kidney toxicity, even when administered at 10-fold the treatment dose. The overall goals of this proposal are: (a) to elucidate the mechanism(s) of action of AQ-126, identified via HTS and developed by chemical modeling, as targeting MDM2 for ALL cell apoptosis; and (b) to further develop this AQ compound as a viable anti-cancer drug for ALL patients, by performing structure-activity relationship (SAR) studies and further refining its structure, to optimize its pro-drug and pharmacological properties. We hope that during the 2-year period of Hyundai Hope on Wheels support, we will be able to develop 1 or 2 leads to be ready to undergo IND-directed pharmacology and toxicology, prior to Phase 1 clinical testing in pediatric ALL through the National Cancer Institute’s NExT program.