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New leukemia drug shows promise in overriding all Gleevec resistance

Temple University researchers have developed a new drug that could potentially treat all forms of Gleevec-resistant chronic myelogenous leukemia (CML). Their work is published in this week's early edition of Proceedings of the National Academy of Sciences.

According to lead researcher, Prem Reddy, Ph.D., professor of biochemistry and Director of the Fels Institute for Cancer Research at Temple University School of Medicine, most patients with advanced CML, a rare but deadly form of cancer, typically develop resistance to Gleevec, the most successful treatment for CML to date, within a few years of starting the therapy.

CML is caused by the Philadelphia chromosome, an abnormality that produces a cancer protein called BCR-ABL. Gleevec works by binding to BCR-ABL and completely blocking its activity, thereby stopping cancer growth. When Gleevec came to market about four years ago, it was widely hailed as a miracle drug. For the first time, there was hope for this group of patients.

"Gleevec has been a remarkable success for the treatment of CML. However, a significant number of patients eventually develop resistance to it because their cancer cells are able to mutate and adapt," said Reddy.

Since discovering this phenomenon, scientists have sought new ways to prevent or overcome this resistance. Recently, two experimental drugs were found to be effective in circumventing some but not all forms of Gleevec resistance. Both, for instance, failed to block the activity of a mutant BCR-ABL, called T315I, which is one of the more predominant mutations seen in Gleevec-resistant patients.

Reddy and his research team sought instead to develop a drug that would circumvent all of the mutations and therefore all forms of resistance. They focused on other possible avenues to inhibit the actions of BCR-ABL. To do so, they targeted parts of the BCR-ABL protein that didn't appear to be mutating and adapting to Gleevec.

"We developed ON012380, a compound that specifically inhibits BCR-ABL by blocking a different site in the protein, which is essential for its activity. As a result, ON012380 was found to induce cell death of all of the known Gleevec-resistant mutants and cause regression of leukemias in human tumor cells and in animal models," said Reddy, who is currently seeking FDA approval to proceed with clinical trials. The drug is licensed to Onconova, Inc.

"Our drug works just like Gleevec but by blocking another part of the BCR-ABL protein. It can be combined with Gleevec to create synergy and when patients become resistant to Gleevec, our drug kills 100 percent of the cancer cells," said Reddy.

Obesity doubles leukaemia risk in older women

Being obese more than doubles the risk of acute myelogenous leukaemia (AML) in older women, according to a US study.
The report in the November issue of Cancer Epidemiology, Biomarkers and Prevention is based on analysis of data from more than 40,000 women, between 55 and 69 years of age, who participated in the Iowa Women's Health Study.

The subjects completed a health and lifestyle questionnaire when the study began in 1986 and then were followed until 2001.

During follow-up, 74 women developed AML and 88 developed chronic lymphocytic leukemia, the investigators note. Compared with normal weight status, obesity and overweight status increased the risk of AML by 140% and 90%, respectively.

Increased Leukemia Risk for Overweight Women

A recent study has found that older overweight and obese women have an increased risk of leukemia.

June 13, 2005 - The study, published in the November issue of Cancer Epidemiology, Biomarkers & Prevention found that older women who are overweight or obese could be more than twice as likely as normal-weight women to get acute myelogenous leukemia (AML). This is one of the most deadly kinds of leukemia, and accounts for about a third of the 33,000 leukemia cases diagnosed each year in the United States.

90% greater risk
This finding adds to growing evidence that carrying extra pounds may increase a person's chances of getting cancer.

The study found that the risk of AML was 90% greater in women 55 and older who had a body mass index (BMI) of 25 to 29considered overweight. The risk of AML was as much as 140 percent greater in older women with a BMI of 30 or moreconsidered obese.

Reference:

1. Julie A. Ross; et al., Body Mass Index and Risk of Leukemia in Older Women, Cancer Epidemiology Biomarkers Prevention, 2004 13: 1810-1813.

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