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. The research proposed for funding may be in any area of basic cancer research. The fellowships provide one-year grants of $45,000 to support the salary and benefits of the fellow while working on mentored basic cancer research. A partial amount of the funds may be designated for non-personal research expenses, such as equipment and research/laboratory supplies
Camilla L. Oxley, Ph.D.
Postdoctoral Researcher, University of Pennsylvania, Philadelphia, PA
Anaplastic Lymphoma Kinase and its Inhibition in Cancer Therapy
ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase (RTK) recently identified as an oncogenic driver in neuroblastoma, a devastating pediatric cancer of the sympathetic nervous system, and inflammatory breast cancer (IBC), the most aggressive and fatal form of invasive breast cancer. The success of crizotinib for the treatment of ALK-driven non-small cell lung cancer has stimulated recent investigations into the utility of crizotinib in other cancers that might be fueled by aberrant ALK signaling. Crizotinib treatment is showing promise in clinical trials with neuroblastoma patients in which ALK overexpression or mutation is the oncogenic driver and preclinical investigations in mouse xenograft models of IBC show that crizotinib promotes tumor shrinkage. These results suggest that ALK is a tractable therapeutic target in neuroblastoma and IBC – a finding particularly encouraging because few molecular signatures have been identified in IBC.
Unfortunately, as with most tyrosine kinase inhibitors used in cancer therapy, resistance to crizotinib inevitably emerges. Efforts in neuroblastoma have revealed problems with primary resistance for several frequent mutants. As a result, the development of alternative (and complementary) therapeutics is required to reach the full clinical potential of ALK inhibition. Therapeutic antibodies offer an alternative avenue for pharmacological intervention, and we have recently shown that antibody targeting of ALK – especially when combined with crizotinib treatment – induces cytotoxicity of neuroblastoma cell lines. I, therefore, propose studies aimed at selecting, testing and optimizing inhibitory ALK antibodies for the treatment of cancers fueled by aberrant ALK signaling, such as neuroblastoma and IBC.
"To identify the most effective strategy of antibody-based ALK inhibition, we will screen a panel of ALK monoclonal antibodies (mAbs) to: (i) identify the most potent antagonists; (ii) assess their ability to synergize with other ALK-targeted mAbs; and (iii) evaluate their ability to synergistically inhibit neuroblastoma and IBC growth when combined with crizotinib. These in vitro studies will set the stage for in vivo mouse studies and humanization of the primary lead mAb(s) for progression into clinical studies. Thus, our work will be a major step toward ALK-targeted immunotherapy in neuroblastoma and IBC."
"I am extremely grateful to the AACR for awarding me the Anna D. Barker Fellowship in Basic Cancer Research. It will allow us to make significant progress in developing new therapeutic approaches for the treatment of neuroblastomas and inflammatory breast cancers with genetic alterations in ALK. I would like to thank my previous scientific mentors, Drs. Iain Campbell and Jane Endicott, as well as my current mentor, Dr. Mark Lemmon, for their guidance and support."
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Szilvia Solyom, Ph.D.
Postdoctoral Fellow, Kazazian Lab, Johns Hopkins University School of Medicine, Baltimore, MD
The Impact of Human Retrotransposons on Gastrointestinal Cancers
"Transposons (“jumping genes”) are highly abundant mobile genetic elements. Retrotransposons mobilize by a copy-and-paste mechanism via an RNA intermediate. Three types of retrotransposons, long interspersed elements (L1s), Alus and SVAs are active in humans, causing genetic diseases. Evidence is now emerging that new, somatic L1 insertions are ongoing in certain tumor types which presents a novel mutational phenomenon in malignancy. Using high-throughput sequencing on tumor-normal tissue pairs, we detect extensive somatic L1 retrotransposition in colon tumors, where genes with driver functions in tumorigeneses are targets of insertional mutagenesis. The aim of this study is to determine if retrotransposition has an etiological role in gastrointestinal cancers with respect to early tumorigenesis, clonal evolution and metastasis. I will map and characterize L1, Alu, and SVA retrotransposon insertions in a cohort of colorectal and pancreatic cancer cases, including paired normal tissue, adenoma, primary cancer and metastasis from the same patients. I will address the causes and consequences of retrotransposition in malignancy by analyzing insertion timing, markers of tumor clonal evolution, evaluating mutational signatures of genes associated with retrotransposon mobilization, identifying clinical correlates of transposon activity, and conducting functional genetic assays."
"According to my current results, most colorectal and pancreatic carcinomas, as well as their metastases, are permissive for abundant somatic L1 retrotransposition. Most importantly, there appears to be excessive and clonal insertional mutagenesis already in preneoplastic colon lesions (polyps as well as dysplasias arising in inflammatory bowel disease), indicating early and potentially cancer-initiating events. I am currently investigating the cause and effect of retrotransposon mobilization in these tumors. I expect that this project will form the very basis for translational cancer research, especially for monitoring neoplastic disease progression and for the treatment of cancer patients with somatic insertions by gene therapy."
"I have been fortunate to be allowed to pursue my dreams by my mentor, Prof. Haig H. Kazazian Jr., and combine perhaps the two most exciting fields of human genetics, mobile elements and cancer. Therefore, I am so glad and thankful to be awarded the Basic Cancer Research Fellowship by the American Association for Cancer Research. This will enable me to characterize the impact of human retrotransposons on cancer, and will be a foundation for my future efforts to apply these findings for patient cure."
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