Our Research Dollars In Action – Update From Grant Recipient Dr. David Askew

Dear Friends,

We are gratified to provide an update from Grant Recipient Dr. David Askew (Research Accomplishments for 2012-2013).  Dr. Askew is a member of the Huang Lab at Case Medical School (http://www.huanglab.com/ ). Pediatric, Adolescent and Young Adult  (PAYA) Cancer Research is costly and very time consuming. A dedicated PAYA Cancer Researcher, like Dr. Askew, often makes great sacrifices monetarily and personally. The SGAYA Cancer Research Fund is committed to assist our Researchers to find a better way to treat and cure PAYA Cancer!

Below please find Dr. Askew’s Report:

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Thanks to the support of the Steven G. AYA Cancer Research Grant, I have been able to successfully transition from Dr. Kenneth Cooke’s laboratory into Dr. Alex Huang’s laboratory in the Division of Pediatric Hematology-Oncology at Case Western Reserve University School of Medicine since November 2012. Below is a summary of my research activities since joining Dr. Huang’s laboratory during year 1 of the Steven G. AYA Cancer Research Grant funding period.
Project 1: Promoting the development of memory T cells in cancer vaccines.
While immune therapy has been used to fight certain cancers and has shown early promise, there is often a failure to maintain the response against the cancer. This suggests that there is an inability to establish memory T cells that keep an immune response active over a period of time. In previous studies from our laboratory, we identified an important role for a protein called CCR5 in T cells that leads to the development of memory T cells. I am currently identifying the mechanisms that regulate the expression of CCR5 in T cells in order to enhance the development of memory T cells.
Project 2: Preventing the relapse of T cell leukemia.
One major problem with T cell leukemia is the presence of a few cancer cells that remain in the brain (central nervous system; CNS) or bone marrow (BM) after treatment. The presence of these cancer cells can lead to the return of the cancer (relapse). Using a model of T cell leukemia that was developed in our lab, I am characterizing the ability of these tumor cells to move into the CNS and BM. The goal is to eventually identify new targets for intervention that may reduce cancer relapse.
For many proteins to be turned on or off functionally in the cell, they need to be modified chemically. When there is a failure in the chemical modification, the proteins become overly active and cancer can develop as a result. In collaboration with Dr. Gutham Narla at the Harrington Institute at Case Western Reserve University, I am examining the effects of a novel class of drugs that promotes this chemical modification. These drugs are derived from FDA approved medications that are not currently being used to fight cancer. I have shown that one of these compounds can suppress the growth of T cell leukemia and promote death of these tumor cells. We are testing this drug in animal models to look at its ability to limit relapse of leukemia.
When standard treatment for leukemia fails, patients are given very high doses of chemotherapy and/or radiation to kill cancer cells. One result of the treatment is that the patient’s bone marrow, a source of blood cells, is also destroyed and must be replaced. This is known as a stem cell or bone marrow transplant (BMT). Two major complications of this treatment is that the cancer returns or there is a failure of the new bone marrow cells to function in the patient. In collaboration with Dr. John Letterio, I am examining the effects of a new class of anti-inflammatory drugs known as the triterpenoids in preventing leukemia relapse and enhancing stem cell engraftment after BMT. We believe that, when provided as a dietary supplement after BMT, the triterpenoids can improve survival in patients that receive BMT for the treatment of leukemia.
Project 3: Relieving graft-versus-host disease (GVHD).
Another complication that can occur after BMT is a situation in which T cells from the donor bone marrow attach the recipient/patient’s body. This is known as graft-versus-host disease (GVHD) and can be a significant source of illness and death in patients who have received BMT. In collaboration with Dr. John Letterio, we are examining how a protein known as Cdk5 can affect donor T cells function shortly after BMT. In previous work, I showed that Cdk5 dramatically influences the ability of T cells to travel to the lymph node where these T cells become overly active to attach patient’s tissues. I am examining how Cdk5 affects the ability of donor T cells to cause GVHD with a goal to establish Cdk5 is a potential new target in BMT to minimize the risk of developing GVHD.
Summary:
Through the support of the Steven G AYA Research Grant, my ultimate goal as a researcher is to understand the interaction between tumor cells and the immune system to identify novel strategies that will result in better treatments. While tumor cells exhibit several mechanisms to subvert or hide from the immune system, we are increasing our ability to understand these mechanisms with the goal of enhancing the power of the patient’s immune system to eliminate the tumor. Support from the Steven G AYA Research Grant has given me this tremendous opportunity to work with Dr. Huang and the lab environment that he has created, which is the BEST environment possible to achieve these goals.

Poster Presentations
Askew D, Su CA, Barkauskas D, Myers J, Liou R, Chang N, and Huang AY. 2013. Dynamic regulation of CCR5 expression in naïve T cells within inflamed lymph nodes is essential for memory CD8 T cells. Case ShowCase

Askew D, Othman Y, Durand D, Barkauskas D, Myers J, Wang G, Zhou L, and Huang AY. 2013. Identification and characterization of CD8+ and CD4+CD8+ T cell acute lymphoblastic leukemia cells generated through constitutive expression of intracellular NOTCH1. Case Cancer Center Retreat
Askew D, Othman Y, Durand D, Barkauskas D, Myers J, Wang G, Zhou L, and Huang AY. 2013. Identification and characterization of CD8+ and CD4+CD8+ T cell acute lymphoblastic leukemia cells generated through constitutive expression of intracellular NOTCH1. Case Immunology Training Program (Selected as 1 of 3 Best posters)
Askew D, Othman Y, Durand D, Barkauskas D, Myers J, Wang G, Zhou L, and Huang AY. 2013. Identification and characterization of CD8+ and CD4+CD8+ T cell acute lymphoblastic leukemia cells generated through constitutive expression of intracellular NOTCH1. Critical Mass: The Young Adult Cancer Alliance
Manuscripts (In Press)
Scrimieri, F, Askew D, Corn DJ, Eid S, Bobanga ID, Bjelac JA, Tsao ML, Othman YS, Wang SG, Huang AY. Murine Leukemia Virus Envelope Gp70 is a Shared Biomarker for High-sensitivity Detection and Quantification of Murine Tumors. OncoImmunology 2013 (In Press).

Manuscripts in Preparation
1. Askew D, Pareek T, Eid S, Myers J, Keller M, Guirdo-Wolff R, Huang AY, Letterio JJ and Cooke KR. A novel role for lymphocyte expression of cyclin-dependent kinase 5 (Cdk5) in the generation of allogeneic T cell responses after BMT.
2. Askew D, Su CA, Nthale J, Liou R, Barkauskas D, Myers J, and Huang AY. Transient surface CCR5 expression in naïve T cells within inflamed lymph nodes is dependent on LFA-1 and augments helper T-cell dependent memory response
3. Askew D, Eid S, Keller M, Guirdo-Wolff R, and Cooke KR. Conventional splenic dendritic cell subsets direct development of graft-versus-host disease.

Research Support

Current
1. NIH R01 – HL111682 – Novel Mechanism of immune activation following allogeneic hematopoietic stem cell transplant. P.I. John Letterio
2. Steven G. AYA Cancer Research Grant (2012-2013; $15,000)
Pending
NIH R21 –NCI. Role of triterpenoids in regulating relapse and engraftment after stem cell transplant. P.I. – David Askew

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