Ontario Cancer Institute

Leukemia: New Model Shows Human Disease Back to Its "Big Bang"
Cancer researchers led by OCI's Dr. John Dick have developed a method to convert normal human blood cells into "human" leukemia stem cells. The converted cells, when transplanted into special mice that permit the growth of human cells, can replicate the entire disease process from the very moment it begins.

Explains Dr. Dick: "Most human leukemia research involves studying a patient's diseased cells or a cell line grown from those cells. However, since cancer takes many months or years to develop, just studying the cells at the end of the process does not let you know what the series of changes were that caused the cells to become leukemic, and when they happened.

"With the method we developed, we have duplicated the natural process every step of the way. It opens the pathway generally to understanding the process of how cancer begins."

Science. 2007 Apr 27; 316(5824):600-4. [ Abstract ]

Cancer: Anti-Aging Molecule May Help in Cancer Fight
A UHN research team led by Dr. Tak Mak discovered that a molecule that helps extend the lifespan of flies and worms may also help protect against cancer.

FOXO3a, a member of a family of molecules that helps regulate anti-aging gene activity, was found to be capable of making cells self-destruct via a process that relies on the tumour suppressor molecule p53.

The researchers found that FOXO3a has a paradoxical role: If it is turned on in the cell's nucleus, it stops p53 from working; however, outside of the nucleus, it can do the opposite-actively inducing p53-dependent programmed cell death.

"Interestingly, FOXO3a could trigger programmed cell death even in situations where p53 has lost its ability to work directly with DNA," says Dr. Mak. "Pinpointing FOXO3a's involvement in programmed cell death gives researchers a new target for future anticancer therapies."

PNAS. 2006 Jun 13; 103(24):9051-6. Epub 2006 Jun 6. [ Abstract ]

Pancreatic Cancer: Combination Therapy Offers Promises
A new combination therapy has been demonstrated to prolong survival time in people with advanced pancreatic cancer, according to UHN researchers Dr. Malcolm Moore and Steven Gallinger. The new approach uses the compound erlotinib to target specific pathways overproduced in pancreatic cancer.

The two-year UHN-led National Cancer Institute of Canada Clinical Trials Group study followed 569 patients treated with either gemcitabine—the current treatment standard—alone or in combination with erlotinib. Patients who received the combination treatment experienced a significantly prolonged survival time and stabilization of disease.

"This combination therapy of gemcitabine plus erlotinib is the first advance in the treatment of pancreatic cancer in the past decade" says Dr. Moore. Erlotinib has been approved by the FDA and the European Medicines Evaluation Agency for the treatment of pancreatic cancer on the basis of this study and is under review by Health Canada.

J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23.
[ Abstract ]

Leukemia: Fusion Protein Structure Reveals Potential Target
Dr. Mitsu Ikura and postdoctoral fellow Dr. Michael Plevin have revealed the three-dimensional solution structure of the TAFH domain-a domain critical for E protein interactions-of the AML1-ETO fusion protein using NMR spectroscopy.

AML1-ETO is generated by a translocation between chromosomes 8 and 21, an event that occurs in up to 15% of acute myeloid leukemias (AML). AML1-ETO can silence E protein activation of transcription factors that are involved in regulating cell growth, differentiation and apoptosis. By mutating AML1-ETO, this activity is reduced.

"Resolving the structure of protein domains and doing mutational analysis is key to understanding protein function," says Dr. Ikura. "This domain of AML1-ETO showed a surprising similarity to another cancer gene regulator Sin3. Our findings help us to obtain deeper insights into leukemia and to design chemical inhibitors based on similarities and differences in their protein structures."

Proc. Natl. Acad. Sci. 2006. Jul 5; 103(27):10242-7. [ Abstract ]

Acute Myeloid Leukemia: Understanding Fatigue
A UHN study by researchers Drs. Shabbir Alibhai, George Tomlinson, Joseph Brandwein, Mark Minden and Matthew Kowgier and Mr. Marc Leach is the first to investigate fatigue associated with acute myeloid leukemia (AML) in detail. AML—a cancer of the blood—is more common in adults 60 years and older and has a significant effect on a patient's quality of life.

Patients were studied to characterize the prevalence and severity of fatigue. Study authors show that fatigue was universal for all patients throughout the study regardless of treatment therapy with 98% having reported fatigue.

"Fatigue has a significant effect on a patient's quality of life, so getting to the bottom is key," says Dr. Alibhai. "Our next steps are to dig deeper into causes of fatigue, and whether chemotherapy or improved disease control impact on fatigue and design interventions to alleviate fatigue."

Leukemia. 2007. Apr; 21(4):845-8. [ Abstract ]