In Brief

From OncoLog, March 2008, Vol. 53, No. 3

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Phase III Trial to Test Drug to Prevent Large B-Cell Lymphoma Recurrence

A clinical trial has opened for an experimental therapy to prevent recurrences in patients with a type of non-Hodgkin’s lymphoma. The phase III study of enzastaurin will investigate the drug’s ability to prevent relapse and increase overall and disease-free survival in patients with diffuse large B-cell lymphoma. Currently, no treatments are approved to help prevent relapse in such patients.

“Because no drugs exist to prevent relapse in high-risk patients with large B-cell lymphoma, we need to identify an effective maintenance therapy,” said Luis Eduardo Fayad, M.D., principal investigator of the trial at M. D. Anderson and an associate professor in the Department of Lymphoma and Myeloma.

The enzastaurin study (called Preventing Relapse in Lymphoma Using Daily Enzastaurin, or PRELUDE) is being conducted at M. D. Anderson and more than 150 other sites. Participants have a 66% chance of receiving daily enzastaurin therapy for up to 3 years and a 33% chance of receiving a placebo.

The standard chemotherapy regimen for large B-cell lymphoma is known as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), but about half the patients who achieve remission with this regimen experience disease recurrence within 3 years.

Side effects reported in a phase II study of enzastaurin included fatigue and nausea. No deaths or discontinuation of treatment because of toxicity were reported. Among inclusion criteria for the PRELUDE study are a clinical diagnosis of diffuse large B-cell lymphoma; recent completion of R-CHOP; disease remission; and high risk of disease recurrence as defined by the International Prognostic Index.

For more information, contact Dr. Fayad at lefayad@mdanderson.org or 713-792-2860, or search for “PRELUDE” at www.clinicaltrials.gov.

Kidney, Liver Cancer Drug May Also Have Anti-leukemia Benefit

Researchers at M. D. Anderson recently discovered that sorafenib, a drug used to treat kidney and liver cancers, also targets a kinase mutation active in about one-third of patients with acute myelogenous leukemia (AML), the most common and lethal form of adult leukemia.

“AML patients with this mutation have a particularly poor prognosis, so this highly targeted drug appears to be a significant step forward in leukemia therapy,” said Michael Andreeff, M.D., Ph.D., a professor in M. D. Anderson’s departments of Leukemia and Stem Cell Transplantation and Cellular Therapy.

In a phase I clinical trial, sorafenib reduced the median percentage of leukemia cells circulating in the blood from 81% to 7.5% and in the bone marrow from 75.5% to 34% among AML patients with FLT3-ITD, a mutation of the tyrosine kinase FLT3. In two patients, the percentage of circulating leukemia cells dropped to zero.

Patients in the clinical trial have not yet experienced any major side effects, so the maximum tolerated dose has not been reached, Dr. Andreeff said. Sorafenib has little effect on cells in patients with normal FLT3, and the drug does not interfere with normal blood cell formation.

Sorafenib targets tumor cell growth and angiogenesis by targeting two classes of kinases. While the drug’s ability to inhibit multiple kinases probably accounts for its anti-leukemia effects, Dr. Andreeff said, the exact molecular mechanisms involved require further study.

“Here we have a great response against an important mutation, but sorafenib alone will not cure patients,” Dr. Andreeff said. He and his colleagues plan to examine sorafenib combinations against other diseases with the FLT3-ITD mutation.

Currently, a phase I/II clinical trial that combines sorafenib with the standard-of-care chemotherapy combination for AML, idarubicin and cytosine arabinoside, is open at M. D. Anderson. Jorge Cortes, M.D., a professor in M. D. Anderson’s Department of Leukemia, said that patients with recurrent AML and those newly diagnosed with the disease are eligible for the study. As safety and dose escalation research progresses, it is hoped that sorafenib will be made available to other patients and assume a role in frontline therapy.

PET/CT May Provide Better Detection of Inflammatory Breast Cancer Spread

An imaging technology that can pinpoint active cancer cells in the body is effective at detecting the spread of a rare but very aggressive form of breast cancer, M. D. Anderson researchers reported recently. The technology is PET/CT, a combination of positron emission tomography and computed tomography.

Recent studies showed that PET/CT could identify whether a cancer therapy was working by revealing residual active cancer cells in the body. The researchers decided to test whether such imaging could also spot the spread of inflammatory breast cancer, which represents just 1%–5% of all breast cancers but is more likely than most to be diagnosed after metastasis.

In a study of 41 women with newly diagnosed inflammatory breast cancer, PET/CT correctly identified metastases 95% of the time, as confirmed by biopsy or correlative imaging. The PET/CT scans were 98% accurate in finding spread to local lymph nodes. The method is more accurate—and faster—than traditional modalities for detecting metastasis, which include CT, whole-body bone scan, ultrasonography, and magnetic resonance imaging.

In PET/CT, the patient is first injected with a radiolabeled glucose substance, which is taken up by metabolically active tumor cells. A PET scanner then detects the radiation emitted from these glucose concentrations, and the resulting image is paired with an anatomically detailed CT scan. In the combination picture, tumors show up as bright spots on what is essentially a crisp, clear x-ray image of the body’s structures.

Selin Carkaci, M.D., an assistant professor in diagnostic radiology and presenter of the research, said large-scale trials of PET/CT in inflammatory breast cancer may change how the disease is diagnosed and followed.

Two Proteins Shown to Destroy Tumor Suppressor Together

Researchers at M. D. Anderson have found that two cancer-promoting proteins work together to negate the protection of a critical tumor suppressor by forcing it from the cell’s nucleus and then instructing the body to destroy it.

The findings could lead to new therapeutic targets for cancer focused on FOXO3a, a member of the forkhead family of tumor-suppressing proteins. FOXO3a is inactivated in about 80% of breast tumors, and it’s likely to be inactivated in other solid tumors because three major oncogenic pathways separately target it, said Mien-Chie Hung, Ph.D., chair of M. D. Anderson’s Department of Molecular and Cellular Oncology and senior author of the research.

FOXO3a and other forkhead proteins have a structure known as the forkhead box that allows them to connect with DNA and in turn activate or repress genes involved in tumor suppression and DNA repair. Dr. Hung and colleagues found ERK, a known oncoprotein, attacks FOXO3a by attaching phosphate groups to it. This phosphorylated FOXO3a is removed from the nucleus and thus can no longer do its job as a tumor-suppressing protein.

The team’s laboratory studies revealed that a second known oncogenic protein, MDM2, completes the attack on FOXO3a by attaching a string of targeting proteins known as ubiquitins to the phosphorylated FOXO3a. This marks it for destruction by the ubiquitin-proteasome degradation pathway.

While both ERK and MDM2 were well known to have cancer-promoting functions, this research shows for the first time that the two work together against tumor suppression, Dr. Hung said.

In a sample of 125 breast cancer tumors, MDM2 expression and low FOXO3a expression were associated with higher-grade tumors. Additional experiments showed that breast cancer cells treated with healthy FOXO3a and injected into mice resulted in barely measurable tumor volumes after 56 days. However, tumors in mice injected with cells that had a disabled version of the tumor suppressor were large.

In addition to ERK, researchers have identified AKT and IKKb as cancer-causing proteins that target FOXO3a through phosphorylation. “At least one of these three pathways is active in about 80% of solid-tumor cancers,” Dr. Hung said. “ERK alone accounts for 30% of human cancers.”

So far, therapeutic agents have targeted the three proteins separately. “But activating these proteins’ forkhead target, FOXO3a, would work against all three of them. Enhancing FOXO3a could be an effective therapeutic strategy,” Dr. Hung said.

Results were published in the February 10 issue of Nature Cell Biology.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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