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Obesity Linked to Acute Leukemia

1 in 3 Acute Leukemia Cases in Older Women May Be Tied to Excess Weight

By Kelli Miller Stacy
WebMD Medical News Reviewed By Brunilda Nazario, MD

Nov. 8, 2004 -- Older overweight women have another compelling reason to shed excess pounds. A new study shows that older overweight women significantly increase their risk of acute leukemia.

Acute myelogenous leukemia (AML) is the most common form of leukemia in adults and the rates of this cancer are growing among older adults. It is not an inherited disease but the result of genetic damage to developing cells in the bone marrow.

Epidemiologist Julie Ross, PhD, and colleagues at the University of Minnesota observed more than 37,000 women for a period of approximately 14 years. At the start of the study the women were free of cancer. However 200 of them developed leukemia during the observational period.

Women diagnosed with leukemia are more likely to be overweight or obese compared with those without the disease. These women also reported less physical and leisure time activity compared with women not diagnosed with leukemia.

Of the women diagnosed with leukemia, 74 women were specifically diagnosed with acute myelogenous leukemia. An increased risk of acute myelogenous leukemia was seen with increasing BMI, an indirect measure of body fat. This association was not seen for other types of leukemia.

"We found that the risk for getting AML was 90% higher in overweight women aged 55 and older who had a body mass index of 25-29 (overweight)," says Ross, one of the study's researchers. In participants with a BMI of 30 or more (defined as obese), the risk of leukemia escalated to nearly 140% above those women who had reported normal weight.

Measures to reduce obesity may help prevent the incidence of adult AML, researchers say.

"The fact that survival rates for AML are extremely poor for older individuals makes identifying people who are at increased risk for this cancer of public health importance," Ross notes. "Given that fact that 65% of adults in the U.S. are overweight or obese, the projection that we can make from our study is that about 30% of AML in older adult women could be due to being overweight or obese."

Obesity has long been linked to a number of malignancies, including colon and breast cancer, but few prospective studies have explored the potential link with leukemia. Scientists are not sure why a higher BMI increases the risk of AML in older adult women, but theorize that an impaired immune system, common in obese individuals, may play a role. Changes in metabolism associated with obesity, and hormonal changes seen in overweight and obese individuals, might also contribute to this risk.

The findings are published in the November issue of Cancer Epidemiology, Biomarkers & Prevention.

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SOURCES: American Cancer Society. News release, University of Minnesota. Cancer Epidemiology, Biomarkers & Prevention, November 2004; vol 13: pp 11.

Compound Fights Gleevec-Resistant Leukemia
-- Robert Preidt

MONDAY, Feb. 14 (HealthDay News) -- The drug Gleevec has proven a lifesaver for people with a blood cancer called chronic myeloid leukemia (CML). However, a growing number of CML patients have cancers resistant to the medication.

Now, an experimental drug may offer those patients fresh hope, say researchers at the Dana-Farber Cancer Institute in Boston.

Their study, published in the February issue of Cancer Cell, found that a compound called AMN107 effectively blocked proliferation of Bcr-Ab1-dependent cells taken from CML patients. Bcr-Ab1 is a protein that's abnormally active in many CML patients. AMN107 proved to be a more potent inhibitor of Bcr-Ab1 than Gleevec (imatinib), inhibiting the growth of cells expressing numerous Bcr-Ab1 mutations resistant to Gleevec.

In addition, AMN107 prolonged the survival of mice with Gleevec-resistant CML, the researchers said.

The researchers have just started Phase I clinical trials of the experimental compound.

"If human clinical trials validate the effectiveness of AMN107 demonstrated in the preclinical studies reported here, it may be possible to either use AMN107 in selected patients with imatinib resistance, or to use both agents together, simultaneously or sequentially," research leader Dr. James D. Griffin said in a prepared statement.

Kosan Initiates Phase I Clinical Trial of Second-Generation Hsp90 Inhibitor KOS-1022 in Hematologic Cancers

Company Also Announces Grant of U.S. Patent Covering KOS-1022

HAYWARD, Calif., June 6 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated (Nasdaq: KOSN - News) announced today that it has initiated a company-sponsored multicenter Phase I clinical trial of KOS-1022 (DMAG) in patients with advanced hematologic malignancies. The Company also announced that the U.S. Patent & Trademark Office has granted patent No. 6,890,917 B2, entitled "Geldanamycin Derivative and Method of Treating Cancer Using Same," covering the KOS-1022 composition of matter and its use for treating a range of cancers. The Company is the exclusive licensee of the patent in these fields and others. KOS-1022 is a second-generation Hsp90 inhibitor that is highly potent and water soluble, with good bioavailability.

"The rationale for testing KOS-1022 in these hematologic cancers is particularly compelling. Preclinical data have demonstrated that KOS-1022 reduces the levels of several client proteins, such as Flt3, Akt, and Bcr-Abl, which may be important targets in leukemias," stated Daniel V. Santi, M.D., Ph.D., Kosan Chairman and Chief Executive Officer. "This Kosan-sponsored trial expands the clinical development program for KOS-1022, which is currently in Phase I testing through our collaboration with the National Cancer Institute. We are also pleased by the grant of this patent, which will accord us important intellectual property protections as we continue our work in this area."

The Phase I clinical trial will assess the safety, pharmacokinetics and pharmacodynamics of escalating doses of KOS-1022 in patients with acute myelogenous leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia. According to the Phase I trial design, KOS-1022 will be given by one-hour infusion on a twice-weekly schedule every three weeks. In addition, the pharmacodynamics of KOS-1022 in leukemic blast cells will be investigated in order to determine the biological activity of KOS-1022 against client proteins critical to the progression of leukemia. The clinical trial will be conducted at leading cancer centers in the United States.

In addition to the Phase I study announced today, KOS-1022 is being evaluated in Phase I clinical trials in advanced solid tumors sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA) between Kosan and the NCI Cancer Therapy Evaluation Program (CTEP). 17-AAG, a first-generation Hsp90 inhibitor, as well as KOS-953, Kosan's proprietary formulation of 17-AAG, are also currently being investigated in multiple Phase II single-agent and Phase Ib combination clinical trials in a variety of tumor types. In 2004, Kosan obtained orphan drug designation for 17-AAG from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of multiple myeloma and chronic myelogenous leukemia.

About Hsp90 Inhibitors

KOS-1022, 17-AAG, and KOS-953 inhibit Hsp90 (heat shock protein 90), a protein found in high levels in tumor cells. Hsp90 is a protein "chaperone" that maintains the stability of numerous "client proteins" implicated in tumor growth and metastasis, including protein kinases and transcription factors. By blocking the activity of Hsp90, Kosan's geldanamycin analogs disrupt the Hsp90-client protein complexes, leading to the degradation of the client proteins. By targeting multiple growth-signaling pathways involved in cancer, these compounds may have potential use in a variety of tumor types, both as single agents and in combination with other signal transduction inhibitors and cytotoxic drugs.

About Kosan

Kosan Biosciences has two first-in-class anticancer agents in Phase II and Phase Ib clinical trials: KOS-862 (Epothilone D) and 17-AAG, a geldanamycin analog and Hsp90 inhibitor. KOS-862, the Company's lead drug candidate, has a mechanism of action similar to taxanes and is partnered with Roche in a global development and commercialization agreement, along with a follow-on compound, KOS-1584, currently in Phase I testing. 17-AAG targets multiple pathways required for tumor growth and is being developed in collaboration with the National Cancer Institute, in addition to a second-generation geldanamycin analog, KOS-1022 (DMAG), now in Phase I trials. Kosan's proprietary formulation of 17-AAG, KOS-953, is in Phase I and Phase Ib trials. Kosan has generated a pipeline of potentially significant products for cancer, infectious disease and other therapeutic areas based on its proprietary technologies for discovering, developing and manufacturing polyketide analogs. Polyketides are an important class of natural products that have yielded numerous pharmaceuticals for the treatment of cancer, infectious diseases, high cholesterol, transplant rejection and other diseases. For additional information on Kosan Biosciences, please visit the Company's website at http://www.kosan.com .

This press release contains "forward-looking" statements, including statements with respect to: the Phase I clinical trial of KOS-1022 in patients with advanced hematologic malignancies; intellectual property protections provided by U.S. Patent No. 6,890,917 B2; and the further development and potential safety and efficacy of 17-AAG, KOS-953, and KOS-1022 in the treatment of cancer as monotherapy or in combination with other therapeutics. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. There are a number of important factors that could cause the results of Kosan to differ materially from those indicated by these forward-looking statements, including, among others, risks and uncertainties related to the clinical advancement of these product candidates and the costs of conducting clinical studies; the risk that clinical trials for these product candidates may not demonstrate safety and efficacy sufficient to obtain the requisite regulatory approvals or to result in a marketable product; the risk that a patent issued to Kosan or its licensors will not adequately protect Kosan's product candidates or other technologies ; and other risks detailed from time to time in the Company's SEC reports, including its Annual Report on Form 10-K for the year ended December 31, 2004, and other periodic filings with the SEC. Kosan does not undertake any obligation to update forward-looking statements.

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Source: Kosan Biosciences Incorporated

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