Hope for Hopeless Disease
Acute myeloid leukemia (AML) is another disease with a poor prognosis—only 30% of patients survive five years. “This disease can be so bad that treatment guidelines recommend clinical trials as the first option for nearly all patients with AML over the age of 60,” reported Katherine L.B. Borden, Ph.D., professor, department of pathology and cell biology, University of Montreal, and an investigator at the Institute for Research in Immunology and Cancer.
Dr. Borden and her team focus on understanding and treating the molecular basis of cancer, in particular AML. Their work has led to the development of a therapy based upon the inhibitory factor and a potent oncogene called eukaryotic translation initiation factor or eIF4E, also called 4E for short.
“Our goal is to understand the nuts and bolts of how 4E works. Its traditional role is to initiate translation by binding the 5´ m7G cap found on mRNAs. However, elevated levels of 4E are associated with increased mRNA export. Elevated 4E levels lead to oncogenic transformation in cell culture, tumorigenesis in mouse models, and a poor prognosis in AML and other cancers.”
To study 4E, Dr. Borden isolates leukemia cells from the blood of patients. “Our studies found that 4E also governs cell-cycle progression and cellular proliferation by orchestrating the expression of several key genes at the post-transcriptional level. We found that a commonly used drug called ribavirin impedes 4E’s ability to make cells cancerous without significantly affecting normal cells. We are targeting this in the clinic. We found that ribavirin was a natural mimic of 4E’s ligand and shuts down its transforming and apoptosis rescue functions. We had found this in patient specimens previously (for those with highly elevated 4E levels) and have concluded a Phase II trial with ribavirin.”
“We had previously seen that ribavirin inhibits growth in cell culture of patient specimens. The Phase II trials determined that ribavirin inhibits 4E function in vivo and that also correlates with response. There are still some challenges, however. Patients can develop resistance. So we are looking now at more targeted therapy such as combining ribavirin with chemotherapy. We’ll also perform high-throughput screening to find other chemicals that could have synergy with ribavirin.”
Metastasis of cancer cells is the final step in solid-tumor progression, and the most common cause of death in cancer patients. One culprit implicated in an aggressive form of breast cancer is special AT-rich sequence binding protein 1, or SATB1.
“SATB1 is a nuclear protein that normally plays a critical role in regulating gene expression during thymocyte differentiation and activation of T cells,” said Terumi Kohwi-Shigematsu, Ph.D., scientist in the life sciences division of the DOE’s Lawrence Berkeley National Laboratory. “However, in breast cancer cells, once SATB1 becomes expressed, it reprograms expression of a multitude of genes to promote tumor growth and metastasis.”
Dr. Kohwi-Shigematsu said that SATB1’s role in breast cancer represents a new paradigm. “We believe this is a new model of gene regulation leading to tumor progression. A key question we are investigating is how SATB1 alters expression of so many genes. In our studies, the expression of more than 1,000 genes is altered by SATB1 expression in breast cancer cells. SATB1 in the nucleus has a unique architectural distribution, onto which its target genes are anchored and assembled with chromatin-modifying enzymes and transcription factors, thus providing a regulatory network.
“Therefore, such a regulatory network must play a critical role in regulating the epigenetic status of chromatin and gene expression. Similar to the case found in activated T cells, it is also likely that in breast cancers, SATB1-targeted genes collect into intra- or even interchromosomal loci to form chromatin loops so that they can be coregulated. What we are seeing is an emerging link between chromatin remodeling enzymes, epigenetics, and cancer.”
Understanding the mechanisms used by SATB1 could provide a new diagnostic and prognostic marker as well as a therapeutic target for breast cancer. “Most companies are interested in targeting proteins on the cell surface. In the future, however, an effective strategy might be developed to target proteins in the nucleus such as SATB1. By discovering which signaling pathways are important for SATB1 activation we may be able to target them for therapeutics as well,” Dr. Kohwi-Shigematsu concluded.