The AACR-Amgen Inc. Fellowships in Clinical/Translational Cancer Research are open to postdoctoral and clinical research fellows working at an academic, medical or research institution who will be in the first five years of their postdoctoral training at the start of the grant term. Proposed research projects may be in any area of clinical and/or translational cancer research.
2011 GRANTEES
Takashi Kobayashi, M.D., Ph.D.Postdoctoral Research Scientist, Columbia University Medical Center, New York, NY
Novel Therapeutic Targets in Invasive Bladder Cancer
“Treatment of muscle-invasive bladder cancer is still one of the major clinical challenges in urological oncology. Our general lack of understanding reflects a lack of appropriate disease models on which hypothetical disease mechanisms or novel treatment methods can be tested.
Recently we have established a novel mouse model of invasive bladder cancer that recapitulates the human disease by deleting two important tumor suppressor genes, namely p53 and Pten, in bladder urothelial cells. We have also found that expression of another gene, namely p19Arf, is increased in the mouse bladder tumors. Although ARF is well known as an important tumor suppressor through stabilizing p53, it is recently proposed that ARF has multifunctional roles in human cancers, some of which are p53-independent. Here we will investigate the functional relevance of ARF upregulation and its mechanism of function in the tumorigenesis of invasive bladder cancer, which can be a therapeutic target in the treatment of this clinically aggressive disease.
It is a great honor for me to be awarded by the AACR-Amgen Inc. Fellowship in Clinical/Translational Cancer Research for the support of this challenging and exhilarating project. This bestowment will be a strong help for pursuing my career as a urologist-scientist dedicated to bridging basic research and clinical science. I would like to thank my mentor Dr. Cory Abate-Shen for her guidance on this project and AACR for their support.”
Top of Page
Kun Wang, Ph.D.Postdoctoral Fellow, University of Kansas Medical Center, Overland Park, KS
Inhibition of RalA as a Novel Strategy for Targeting Ovarian Cancer
“The Ral (Ras like) GTPase guanyl nucleotide-binding proteins, RalA and RalB are direct effectors of proto-oncogene Ras. RalA and RalB are implicated in tumorigenesis and play distinct roles in mediating carcinogenesis. Our laboratory and others revealed that over-activation of Ral proteins is detected in various human tumors including malignant peripheral nerve sheath tumor, pancreatic, bladder cancers and melanomas. The critical role of RalA in the initiation and progression of ovarian cancer is entirely unclear. Our long-term goal is to understand how Ral proteins and its downstream effectors initiate ovarian cancers and how we can block Ral protein signals for therapeutic purposes. The objective of this application is to determine how RalA is abnormally regulated in human ovarian cancers and evaluate the potential of targeting RalA as therapeutic strategy for ovarian cancer. We will test our central hypothesis: RalA is constitutively over-activated in human ovarian cancers and confers ovarian cancer tumorigenesis.
Our preliminary data revealed that RalA was constitutively activated in human ovarian cancer cells and human ovarian cancer tissues. shRNA-mediated knockdown of RalA inhibited ovarian cancer cell growth. Reducing RalA activation by interfering its post-translational modification suppressed RalA activation and decreased ovarian cancer cell growth in both in vitro and in vivo models. Therefore, RalA is a key player in the biology and dispersal of ovarian cancer cells and is a promising target for development of novel therapeutics. We will develop novel cell penetrable peptides (CPPs) to interfere the interaction between RalA and Ral-binding protein 1 (RalBP-1) and block RalA signaling transduction. The effects of CPPs will be examined. The outcome of the proposed investigation is significant because it is expected to provide novel and promising drug therapy strategies.
I am grateful to AACR-Amgen Inc. for Fellowships in Clinical/Translational Cancer Research. This achievement was made possible by Dr. Faris Farassati who provides mentorship for my research and career development.”
2010 GRANTEES
Sophia Adamia, Ph.D.Postdoctoral Fellow, Dana-Farber Cancer Institute, Boston, MA
Genome-wide Alternative Splicing in AML-Novel Targets for Antibody Therapy
"The development of more effective treatments for AML requires a better understanding of the molecular complexity underlying this disease. Analysis of genome-wide alternative splicing can address this critical gap in our understanding of AML. My study will explore alternative splicing, an epigenetic phenomenon, at the single malignant cell level and further advance the development of highly targeted antibody-based therapies for AML. I am honored and thankful to receive the AACR-Amgen Inc. Fellowship in Clinical/Translational Cancer Research, which will provide valuable support for this project."
Top of Page
Abdel Kareem Azab, Ph.D.Dana-Farber Cancer Institute, Boston, MA
The Role of Hypoxia in the Dissemination of Multiple Myeloma
"Multiple myeloma (MM) is a cancer of plasma cells and the second most prevalent blood cancer. MM progresses in the bone marrow (BM) and the spread of MM involves a process in which cells leave one site of the BM and enter new sites in the BM. The mechanisms that cells use to leave and enter were studied extensively by our group, as well as others, however, the driving force for this process is not well understood. We hypothesize that the rapid and uncontrolled growth of MM cells leads to a low blood and oxygen supply (hypoxia) for the MM cells. We further hypothesize that hypoxia (asphyxiation) will stress the MM cells and drive them to leave the hypoxic-site and travel to new sites with normal oxygen levels.
"Our preliminary data shows that MM cells are hypoxic compared to normal plasma cells in the BM. Additionally, hypoxia decreased MM proliferation, reduced adhesion of MM cells to BM components, and enhanced the ability of MM cells to enter BM sites with normal oxygen levels. These results provide a proof of concept that hypoxia is involved in MM tumor progression and regulates the process of MM spread. In this proposal, we will study the effect of hypoxia on the MM dissemination process in vitro and in vivo and assess the cellular and molecular mechanisms behind this effect. The outcomes of this study will open new windows for discovery of new molecular targets involved in the dissemination of MM, and will help to rationally design and develop new therapeutic agents to prevent the progression and dissemination of MM. Moreover, it will provide the basis for future clinical trials using the new therapeutic agents. This may lead to a paradigm shift in MM therapy, in which prevention of tumor response to hypoxia will decrease spread and increase sensitivity to drugs. The outcomes of this study may also be applied to other hematological malignancies and to metastasis in solid tumors.
"It is a great honor to be awarded by the AACR-Amgen Inc. Fellowship in Clinical/Translational Cancer Research for the support of this challenging and exhilarating project. This bestowment is a turning point in my career as a scientist and pharmacist dedicated to translating basic research into clinical applications. With the munificent support of this fellowship, along with the superb mentorship of Dr. Irene Ghobrial, I greatly look forward to conducting this study."
Top of Page