The AACR Basic Cancer Research Fellowships are open to postdoctoral and clinical research fellows working at an academic, medical or research institution who will be in the first, second or third year of their postdoctoral training at the start of the grant term. Proposed research projects may be in any area of basic cancer research.
2011 GRANTEE
Caroline Kumsta, Ph.D.Postdoctoral Fellow, Stanford-Burnham Medical Research Institute, La Jolla, CA
Translational Control of Tumor Formation in C. Elegans
"The major risk factor for cancer development is increased age. With age, the likelihood of tumor formation and cancer incidence increases in many organisms, including humans. Recently, the nematode Caenorhabditis elegans was employed as a model system for tumor formation, and mutations that increase lifespan, e.g., in the insulin/IGF-1 receptor (InR), decrease tumor growth in this model, suggesting that aging and tumor progression are linked mechanistically. This link creates the opportunity to identify longevity modulators that have effects on tumor formation in C. elegans.
Similarly to inhibition of InR, the reduction of components of the mRNA translation initiation complex was recently found to increase longevity in C. elegans (e.g., Hansen et al., Aging Cell, 2007). Conversely, increased function of translation initiation factors has been observed in many human cancers, yet the precise mechanisms by which these factors affect tumor formation are unclear. This proposal aims to address the hypothesis that reduced translation initiation could constitute a tumor suppressor mechanism in C. elegans.
Specifically, I propose to study the oncogenic function of the translation initiation machinery on the C. elegans tumor model. These tumors arise due to increased Notch signaling in the C. elegans germline, which leads to the massive overproliferation of germ cells and their subsequent break out of the gonad, causing the animals to die prematurely. Notably, I have found that the reduction of specific components of the translation initiation machinery rescues tumor growth and the premature death in C. elegans. These findings, indeed, suggest that impairment of the translation initiation complex has tumor-suppressive effects in C. elegans. To investigate the possible underlying mechanisms by which the translation initiation complex affects tumor formation, I will utilize various molecular approaches, including cellular assays to measure apoptosis and cell proliferation, as well as the powerful genetics of the worm to identify novel downstream effectors. One attractive hypothesis is that the reduction of components of the translation initiation machinery leads to the differential translation of a subset of mRNAs that are involved in tumor-suppression. To investigate this possibility, I will, therefore, screen previously identified differentially translated target genes in worms with reduced mRNA translation for their influence on tumor formation.
This study, which is rapidly carried out in C. elegans due to its tractable genetics and short lifespan, has the potential to identify novel tumor-suppressor and oncogenes that might influence tumor formation also in mammalian systems.
I feel truly honored to be awarded the 2011 AACR-Astellas Pharma Global Development Inc. Fellowship in Basic Cancer Research, which will help me to further an independent career in cancer biology. Of great importance to me in the future is the opportunity to combine basic cancer research with translational research to test novel tumor suppressor genes for roles in clinical tumor biology. I would also like to express my gratitude to my mentor Dr. Malene Hansen for her support and scientific inspiration."
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2010 GRANTEES
AACR-Astellas USA Foundation Fellowship in Basic Cancer Research
Jae Park, M.D.Fellow in Medical Oncology and Hematology,Memorial Sloan-Kettering Cancer Center, New York, New York
Modulating Tumor Microenvironment with Genetically Modified T Cells
"B-cell hematologic malignancies are susceptible to the immunotherapeutic approaches including antibody-based therapy and allogeneic hematopoietic stem cell transplantation. Although targeted therapy using T cells is a more potent approach than antibody therapy, treatment with allogeneic T cells is largely limited by the availability of compatible donors and risk of graft-versus-host disease (GvHD). For these reasons, there is a need for the development of more specific and less-toxic forms of immune-based cellular therapies.
To this end, we have previously developed an artificial T cell receptor called a chimeric antigen receptor (CAR) designed to modify a patient’s own T cells to target CD19 expressed on most B-cell malignancies. This novel approach allows for the rapid generation of tumor-targeted T cells, overcomes the requirement of identifying a suitable HLA-matched donor, and eliminates the risk of GvHD. Our laboratory has previously demonstrated a complete tumor eradication with CD19-targeted modified T cells in SCID Beige mice, and we are currently conducting a phase I clinical trial for patients with relapsed CLL based on this preclinical data. However, we anticipate the clinical effect of the modified T cells may be limited due to a hostile tumor microenvironment containing several inhibitors against the adoptively transferred T cells.
Therefore, we have created a unique clinically relevant syngeneic immune-competent mouse model bearing CD19+ B-cell tumors. Using this well-established mouse model, I propose to better define the tumor microenvironment, and investigate the effect of combining cyclophosphamide and a targeted delivery of IL-12 on the tumor microenvironment and on the in vivo antitumor efficacy. I hypothesize that the combination regimen of cyclophosphamide preconditioning and a targeted IL-12 delivery to the tumor site will overcome the deleterious tumor microenvironment and enhance the cytotoxicity of the T cells. We anticipate that the proposed studies will have direct implications on the generation and design of future clinical trials of genetically modified T cells in patients with B cell malignancies.
Lastly, I am truly honored to receive the 2010 AACR-Astellas USA Foundation Fellowship in Basic Cancer Research. This award will be invaluable for the development of my career as a translational clinical researcher in the field of hematologic malignancies. I am extremely grateful to my mentor, Dr. Renier Brentjens, for his continuous support and mentorship and the leukemia service at MSKCC for their support."
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AACR-Astellas USA Foundation Fellowship in Basic Cancer Research
Karen Vrijens, Ph.D.Postdoctoral Fellow, St. Jude Children's Hospital, Memphis, TN
Small Molecule BMP Agonists as Therapeutic Agents for Brain Tumors
"Medulloblastoma (MB) is the most common malignant pediatric brain cancer. It develops in the cerebellum, the inferior dorsal part of the brain that controls movement, balance and posture. MB can spread to other areas of the brain and spinal cord, which confers an even poorer prognosis. Current therapies have induced survival rates of about 70 percent, but lead to severe side effects. Therefore, it is important to identify new therapeutic approaches. Glioblastoma, on the other hand, is the most common brain tumor in the adult with many cases in the pediatric population with very poor prognosis and limited survival.
"Our laboratory recently showed that bone morphogenetic proteins (BMPs) 2,4,7 potently inhibit the proliferation of granule neuron progenitors and of medulloblastoma-tumor cells and induce their irreversible differentiation in tissue culture and in mice. In contrast, BMP4 does not affect post-mitotic neurons. Similarly, BMP4 stops the proliferation and induces the differentiation of tumor-initiating precursors of glioblastoma multiforme in vitro and in vivo. Therefore, activation of the BMP signaling pathway might prove beneficial in treating both types of brain tumors.
"Because several drawbacks hamper the use of BMPs as therapeutic agents, I aim to identify small molecule BMP agonists that have the potential to be used as chemical surrogates. This goal will be achieved by a cell-based screen of a large (~525,000 compounds) library of small molecules in collaboration with members of the Department of Chemical Biology of St. Jude Children’s Research Hospital. I will characterize compounds with BMP agonist/activator activity using a combination of in vitro and in vivo approaches, and I will study the effects of these small molecule agonists on zebrafish embryonic development. After the necessary PK/PD studies, these small molecules will ultimately be tested in mouse models of brain cancers which have been developed in our laboratory.
"This AACR-Astellas Fellowship will allow me to pursue my scientific goals to identify novel small molecules that act as BMP agonists/activators. My hope is that these small molecules will be used in the future as therapeutic agents to treat medulloblastoma and glioblastoma.
"I feel truly honored to be awarded the AACR-Astellas Fellowship to help me accomplish my research goals. I would like to express my gratitude to my current mentor, Dr. Martine Roussel, for her continued support and inspiration which are helping me to build my scientific career in cancer research."
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