Starting today, we will regularly post the latest research published by scientists and clinicians from the University of Chicago Comprehensive Cancer Center.
These experts are making great advances in the understanding and treatment of cancer and their work, published in peer-reviewed scientific and medical journals, does not always get a lot of external publicity.
We are using UChicago Cancer Conversations to highlight the latest research with the greatest impact.
We hope by publicizing this research readers will begin to get to know some of the areas of specialty of our members.
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The following represent some of the research accomplishments of the University of Chicago Medicine Comprehensive Cancer Center published over the past several months.
Modeling Therapy-related Myeloid Neoplasms with Egr1, Apc, and Tp53 Haploinsufficiency
A particularly challenging complication for cancer patients treated with cytotoxic therapies is the development of therapy-related myeloid neoplasms (t-MN). Loss of the long arm of chromosome 5 is a common genetic abnormality in these secondary cancers, although the identity of the specific tumor suppressor gene(s) that is deleted and contributes to carcinogenesis has remained elusive. Michelle Le Beau, PhD, Arthur and Marian Edelstein Professor of Medicine and director of the University of Chicago Medicine Comprehensive Cancer Center, and her laboratory, recently developed a mouse model in which one allele of each three candidate genes, Egr1, Apc, and TP53, was deleted simultaneously. This model recapitulated many features of early-stage t-MN in humans. The investigators also discovered that it was not simply deletion of these genes in the hematopoietic compartment that contributes to tumor formation, but required aberrant APC/Wnt signaling also in the bone marrow microenvironment. This microenvironment was also highly sensitive to mutagenesis by a DNA alkylating agent on a heterozygous Apc background. These findings are important because they indicate that Egr1, Apc, and Tp53 haploinsufficiency, i.e. loss of just one copy of each of these genes, in the hematopoietic cells, and aberrant APC function in the stromal cell compartment synergize to promote the t-MN phenotype. Importantly, this work also establishes a preclinical model of early t-MN necessary for determining the molecular basis of disease progression and interrogating potential therapies. (Stoddart et al., Blood Epub ahead of print, 2013)
This work was supported by grant number P01 CA40046 from the National Institutes of Health.
Milky Spots and Adipose in the Omentum Promote Metastasis of Ovarian Cancer Cells
The propensity of ovarian cancer cells to escape from the primary tumor and form metastases in the abdominal cavity is a major clinical challenge and significant cause of mortality for ovarian cancer patients. The omentum, a fold of peritoneum composed of immune and stromal cell-rich milky spots and adipose that covers and supports abdominal structures, is a common site of ovarian cancer metastasis. Carrie Rinker-Schaeffer, PhD, professor of surgery, and her team hypothesized that the omentum microenvironment plays an active role in facilitating ovarian cancer metastatic colonization. Using in vivo models, they demonstrated that human ovarian cancer cells preferred to grow in omental fat-containing milky spots rather than peritoneal fat, and there was an inverse relationship between ovarian cancer cell growth and adipocyte area in the omentum over time. In an effort to understand the mechanism responsible for omentum-dependent metastasis, they employed a novel ex vivo model system and discovered that omental tissue secretes a factor(s) that promotes ovarian cancer cell migration. This work highlights the complex interplay between ovarian cancer cells and the omental microenvironment and serves as a foundation for developing innovative strategies to interfere with ovarian cancer metastasis into the peritoneum. (Clark et al., Am J Pathol 183:576-91, 2013)
This work was supported by grants from the Department of Defense (W81XWH-09-1-0127), National Institutes of Health (R01 CA089569), the Elsa U. Pardee Foundation and the Marsha Rivkin Center for Ovarian Cancer Research, and funds from the Section of Urology, University of Chicago.
Novel Approaches Simplify Cancer-Related Complex Gene Classifiers
Despite the use of gene expression profiling, and other high-resolution genetic approaches, to identify distinct molecular subtypes of cancers, the wide-scale application of these molecular classifier tools into cancer clinics has been limited because they are generally time- and resource-consuming. Samuel Volchenboum, MD, PhD, assistant professor of pediatrics, in collaboration with University of Texas Southwestern Medical Center colleague Dr. Stephen Skapek and others, addressed whether an exhaustive search algorithm could replace a complex gene classifier. Focusing on rhabdomyosarcoma, the most common soft tissue tumor in children, the goal of the research team was to define the simplest molecular signature to discriminate between those cancers with and without the PAX-FOXO1 gene fusion. They demonstrated that an exhaustive iterative search algorithm could distill an existing 50-gene expression signature down to two or three features with equal discrimination. Validation of the two-gene signatures was accomplished using three additional independent datasets. By further extending the work to a lung cancer dataset, the investigators showed that this strategy could be generalized and applied to existing technical platforms and datasets to identify simplified signatures amenable to routine clinical use. Importantly, their methodology is being developed as open source software for the cancer research community to enhance the impact and clinical relevance of the work. (Wilson et al., Cancer Res 73:5625-32, 2013)
This work was supported by funding from the National Institutes of Health (RC2 CA148216), St. Baldrick’s Foundation, and the Intramural Research Program of the National Cancer Institute.
Phase II MEK Inhibitor Clinical Trial Confirms Safety and Anti-Leukemic Activity
The RAS/RAF/MEK/ERK signal transduction pathway is aberrantly activated in 70-80% of acute myeloid leukemias (AML), and inhibition of MEK in preclinical studies has shown promising anti-tumor effects. However, the clinical relevance of these findings was poorly understood. Olatoyosi Odenike, MBBS, associate professor of medicine, and colleagues including Wendy Stock, MD, professor of medicine; Richard Larson, MD, professor of medicine; Walter Stadler, MD, Fred C. Buffet Professor of Medicine and Surgery; and Theodore Karrison, PhD, research associate (associate professor) of health studies, conducted a Phase II multi-center study of single-agent selumetinib, a potent and selective orally bioavailable small molecule MEK1/2 inhibitor, in patients with advanced AML. They found that the drug had a favorable toxicity profile and was associated with modest anti-leukemic activity (i.e., 6/36 patients had a response). A single nucleotide polymorphism (SNP) in the KIT gene, a tyrosine kinase receptor known to activate RAS/RAF/MEK/ERK signaling, was identified in more patients with a response or stable disease as compared to non-responders. Collectively, these data suggest that larger clinical trials with this agent are warranted and, given its safety profile, indicate that selumetinib may be particularly useful in combination with drugs that target other signaling pathways activated in AML, such as the PI3K/AKT pathway. (Jain et al., Clin Cancer Res Epub ahead of print, 2013)
This work was supported by the National Cancer Institute Cancer Therapy and Evaluation Program (N01-CM-62201), AstraZeneca Pharmaceuticals, National Cancer Institute Translational Research Funds, and Specialized Center of Research Grant of the Leukemia and Lymphoma Society (#7015-09).
Chromatin Interactions Control Gene Regulation and Cell Fate
Straddling the fields of signal transduction, developmental biology, and cancer biology, Ilaria Rebay, PhD, professor of the Ben May Department for Cancer Research, focuses her research efforts on understanding the molecular mechanisms of gene regulation that control cell proliferation, fate specification, differentiation, and survival. Her group recently investigated how gene expression is controlled by long-range integration of transcriptional inputs through a detailed study of the even-skipped (eve) gene locus. They discovered two novel enhancer elements bound by the transcriptional repressor Yan that stabilize tissue-specific output from a third enhancer. Yan is an ETS-domain transcription factor and is functionally and structurally related to the human oncoproteins, ETS1 and TEL. Disruption of the individual enhancers impacted Yan occupancy at the other sites to subsequently perturb eve expression, cell fate specification, and tissue function. Their interpretation is that such long-range interactions prevent inappropriate cell fate specification, and integration of these repressive inputs at the level of chromatin may provide a general mechanism to drive high levels of gene expression. The implications of the work include an enhanced understanding of the fine tuning of cell fate and differentiation through transcriptional control and establishment of a new paradigm for gene regulation that might be broadly applied to other genes, cellular contexts, and model systems. (Webber et al., Genes Dev 27:2293-8, 2013)
This work was supported by National Institutes of Health grant numbers R01 CA127475 and R01 CA118153.
Needle-Based Confocal Laser Endomicroscopy Has a High Specificity for Detecting Pancreatic Cystic Neoplasms
Pancreatic cystic neoplasms, including intraductal papillary mucinous neoplasms or mucinous cystadenomas, are premalignant lesions that require surveillance or consideration for surgery; yet, they are often difficult to distinguish from benign pseudocysts and serous cysts. Development of a novel needle-based confocal laser endomicroscopy (nCLE) miniprobe may provide a powerful diagnostic tool for pancreatic cystic neoplasms. A team of UCCCC investigators including Vani Konda, MD, assistant professor of medicine, Irving Waxman, MD, professor of medicine, John Hart, MD, professor of pathology, and collaborators from other institutions assessed 66 patients from eight referral centers who underwent nCLE imaging. They found that the presence of epithelial villous structures using nCLE was associated with pancreatic cystic neoplasms at a high level of specificity and positive predictive value. However, a relatively low level of sensitivity suggests that this methodology may have limited application. Moreover, the associated overall complication rate of 9% indicates that safety of the approach also requires further study. (Konda et al., Endoscopy 45:1006-13, 2013)
mRNA Stability Is Controlled by N6-methyladenosine
Many cancer-related genes, including oncogenes, tumor suppressors, cell-cycle genes, and growth factors, are regulated post-transcriptionally, and, more specifically, at the level of mRNA turnover. Chuan He, PhD, professor of chemistry, and his research team uncovered a critical mechanism for dictating mRNA stability. In all higher eukaryotes, N6-methyladenosine (m6A) is the most common internal (non-cap) mRNA modification. Dr. He’s group found that m6A is selectively recognized by a ”reader” protein called YTH domain family 2 (YTHDF2) to regulate mRNA degradation. Using a transciptome-wide approach, more than 3,000 cellular RNAs were identified as targets of YTHDF2. Further, the precise biochemical role of YTHDF2 in RNA metabolism was defined. This work demonstrates that reversible m6A modifications may fine-tune mRNAs turnover via ”readers” to modulate protein expression levels in normal and tumor cells. (Wang et al., Nature 505:117-20, 2014).
This work was supported by National Institutes of Health grant numbers GM071440 and EUREKA GM088599.