National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 17, 2009 • Volume 6 / Number 22

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Cancer Research Highlights

New Drug Blocks "Undruggable" Target in Cancer Cells

Researchers have created a new type of cancer drug that blocks a “master” protein considered to be untouchable by conventional agents. A team from Harvard University used the drug to suppress signals from a growth-promoting pathway, the Notch signaling pathway, that switches on inappropriately in some cancers. Cancer cells that depend on Notch signaling die when the pathway is blocked, Drs. Gregory L. Verdine, James Bradner, and their colleagues reported in the November 12 Nature.

The drug’s primary target is Notch1, a transcription factor that regulates genes involved in the growth and survival of cells. Transcription factors are mutated in various cancers, but these proteins have proved difficult to target directly because of their structures.

To solve this problem, the Harvard team, led in the lab by graduate student Raymond Moellering, designed a drug molecule (called SAHM1) that enters cells and interferes with a protein-protein interaction that is essential for the transmission of cell growth signals via the Notch pathway.

The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and produces an inappropriately active Notch1 protein. Activated Notch signaling has been seen in several other cancers, including lung, ovarian, and pancreatic cancer, and melanoma.

“We’ve drugged a so-called undruggable target,” said Dr. Verdine. “This study validates the notion that you can target a transcription factor by choosing a new class of molecules, namely stapled peptides.” The strategy may work for other transcription factors because the molecular logic of these proteins is similar to that of Notch1, he added.

In an accompanying editorial, Drs. Paramjit Arora and Aseem Ansari said that the group’s “remarkable results highlight the potential of molecules that mimic the secondary structures of proteins to target normally intractable protein-protein interactions.”

Treatment for Pancreatic Cancer May Target Tumor Microenvironment

Researchers have found some clues to suggest why combining nab-paclitaxel (Abraxane) with gemcitabine may be a more effective treatment for advanced pancreatic cancer than gemcitabine alone, the current standard of care.

This spring, updated results from an early stage clinical trial testing the combination therapy showed a promising response, particularly in patients whose tumors produced an abundance of the protein known as SPARC. Results from a mouse model study presented today at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston indicate that adding nab-paclitaxel to gemcitabine may improve response to treatment in part by altering the supportive tissue around the tumor, or stroma, allowing more gemcitabine to reach tumor cells.

The finding “shows that effective treatment does not necessarily require a fancy new molecular therapy, but just the smart combination of what is already available,” said the study’s lead investigator, Dr. Anirban Maitra from the Johns Hopkins University School of Medicine. Gemcitabine is the standard first-line treatment for pancreatic cancer, and nab-paclitaxel, a different form of paclitaxel (Taxol) that is bound to the protein albumin to improve its delivery, is approved for metastatic breast cancer.

To conduct the study, the research team tested the combination in pancreatic cancer mouse models generated at Johns Hopkins. Mice that received the combination were twice as likely to respond to the treatment as those that received gemcitabine alone, with an overall response rate (at least some tumor shrinkage) of 57 percent. They also found that mice given the combination therapy had significantly less of the “abundant fibrotic stroma” that typically surrounds pancreatic tumors and which was always seen in mice given only gemcitabine or no treatment at all. The concentration of gemcitabine in tumors from mice that received the combination therapy was 3.7-fold higher than in the animals given only gemcitabine.

Nab-paclitaxel was recently granted orphan drug status by the FDA (making it eligible for expedited FDA review and extended patent protection, among other things) for use in patients with pancreatic cancer and advanced melanoma. Enrollment is currently open for a phase III trial for pancreatic cancer that will compare gemcitabine plus nab-paclitaxel against gemcitabine alone.

Survey Finds Pain Is Common Years after Breast Cancer Surgery

A nationwide study of women who had breast cancer surgery in Denmark found that 47 percent of participants reported chronic pain 2 to 3 years after breast cancer treatment. Of these, 13 percent indicated severe pain, 39 percent moderate pain, and 48 percent light pain. In addition, 58 percent of participants experienced sensory disturbances or discomfort.

These results, which appeared November 11 in the Journal of the American Medical Association, could help doctors identify patients at high risk of chronic pain and may lead to progress in chronic pain prevention and treatment, the researchers said.

Women with the highest risk of both chronic pain and sensory disturbances were those ages 18 to 39 years who had undergone breast-conserving surgery, the researchers found. Adjuvant radiotherapy, but not chemotherapy, was also associated with chronic pain. Axillary lymph node dissection was associated with a greater likelihood of pain compared with sentinel lymph node biopsy.

The study included 3,253 Danish women who underwent surgery for unilateral primary breast cancer in 2005 and 2006. The large sample size and standardized treatment approaches required by national protocols make this study the first of its kind.

 “We think that our results, based on a very large study in very well-defined nationwide treatment, help to understand what the most important risk factors are for chronic pain after breast cancer surgery,” said senior author Dr. Henrik Kehlet of the University of Copenhagen.

The co-author of an accompanying editorial, Dr. Loretta Loftus of the University of South Florida H. Lee Moffitt Cancer Center, agreed, saying the findings “alert us to patients more prone to pain so that we might identify them earlier on, even prior to surgery, to develop a multidisciplinary approach to treatment that helps patients avoid long-term suffering.”

Hormone Therapy Use Linked to Benign Breast Condition

Women diagnosed with atypical ductal hyperplasia (ADH) have a three- to fivefold increased risk of developing breast cancer. Researchers led by Dr. Tehillah S. Menes from the Elmhurst Hospital Center in New York have discovered a link between postmenopausal hormone replacement therapy (HRT) and increased risk of ADH, similar to the link seen between HRT and breast cancer risk. These results were published November 9 in Cancer Epidemiology, Biomarkers & Prevention.

The researchers looked at data from more than 2 million screening mammograms performed on women ages 40 and older between 1996 and 2005 that were collected by the NCI-funded Breast Cancer Surveillance Consortium. During that period, 1,064 women were diagnosed with ADH alone and 833 women were diagnosed with breast cancer with ADH (found in the same biopsy samples).

The rates of both ADH alone and breast cancer with ADH were significantly higher in women who were using HRT at the time of their diagnoses. The rates of ADH alone peaked in 1999 and then decreased over the study period, with a notable drop starting in 2002. The rates of breast cancer with ADH peaked in 2002 and then decreased slightly over the course of the study.
The use of postmenopausal HRT has declined in U.S. women since 2002, after results from the Women’s Health Initiative indicated an association between HRT use and breast cancer. Rates of ADH and cancer with ADH in this screened population have also decreased since 2002, and “This finding may be partially explained by the decrease in rates of use of postmenopausal [hormone therapy],” concluded the authors.

The cancers with ADH were more likely to be either ductal carcinoma in situ (non-invasive) or low-grade invasive cancers (which have a better prognosis compared to more advanced cancers) than cancers found without ADH during the same time period. This supports the theory that low-grade and high-grade breast cancers develop via separate pathways, explained Dr. Menes in a press release.

Targeted Treatment Shows Promise for Older Patients with Advanced Leukemia

Older people are at higher risk of complications during treatment for some types of leukemia. For this reason, patients over the age of 55 are often treated with lower-intensity regimens, but consequently, the risk of disease relapse remains high. Now researchers at Fred Hutchinson Cancer Research Center have shown that combining radioactive iodine (I131) with an antibody can focus radiation at disease sites while sparing healthy tissues in older patients. This increased treatment efficacy while maintaining levels of side effects similar to what is seen in younger patients with better prognoses. Their report appeared in the November 5 issue of Blood.

The phase I study was designed to determine the maximum tolerated dose of the radioactive antibody when used with a reduced-intensity regimen of chemotherapy, total body irradiation, and hematopoietic stem cell transplant in older patients with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) for whom all previous treatments had failed. Fifty-eight patients ages 50 to 74 participated.

The patients were first injected with trace amounts of the radioactive antibody, which targets the CD45 protein found on leukemia cells. Researchers then used a special camera to determine the location and concentration of the antibody throughout the patient’s body over the next 3 days. These studies showed that the antibody delivered multiple times more radiation to the bone marrow, lymph nodes, and spleen than to the liver, lungs, or kidneys.

Eight to 14 days later, patients received a therapeutic dose of the radioactive antibody, followed by 3 days of chemotherapy with the drug fludarabine, total body irradiation, and a transplant with blood-forming stem cells. The maximum tolerated dose of antibody radiation, received by 21 patients, was found to be 24 Gy to the liver.

All patients went into remission immediately after treatment, and all of them showed engraftment of the donated stem cells by 28 days after their transplant. The 1-year survival estimate for all patients in the trial was 41 percent (46 percent for those treated at the maximum tolerated dose). The rate of relapse was 40 percent, one that the authors indicated is still high, but similar to that seen in younger cohorts.

While acknowledging that their study was not designed to test efficacy, the authors were optimistic that the approach could be used to improve cure rates for older patients with AML or MDS who need to be treated with reduced intensity regimens. They noted that other radioactive compounds, as well as antibodies against other targets in the disease, should also be explored.

Potential Strategy for Treating Diffuse Large B-cell Lymphoma Found

Two research teams working independently have identified a potential strategy for treating a form of diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adults. Each group found that blocking a protein called MALT1 resulted in the death of cells from patients with the activated B-cell-like (ABC) type. These patients have poor prognoses, and the findings could point to new treatment strategies, the researchers said.

MALT1 is an enzyme that breaks down proteins in cells (a protease). Previous studies have shown that the enzyme helps to activate a signaling pathway that drives the growth of ABC DLBCL cells, called the nuclear factor-kappa B (NF-κB) pathway. The new findings suggest that inhibiting MALT1 switches the pathway off, and as a consequence the ABC DLBCL cells die.

“This discovery is the beginning of new research aimed at inhibiting the NF-κB pathway in tumors,” said Dr. Louis Staudt from NCI’s Center for Cancer Research, who co-led one of the studies with Dr. Margot Thome of the University of Lausanne, Switzerland. Their results appeared online November 6 in the Proceedings of the National Academy of Sciences.

Dr. Jürgen Ruland of the Technical University of Munich led the other study, published last month in the Journal of Experimental Medicine. Both groups conducted similar experiments with the same types of cells and inhibitors. While these inhibitors are unlikely to be used in the clinic, the fact that both groups achieved the same result strongly suggests that MALT1 could have a role in future strategies for treating this lymphoma, Dr. Staudt said.

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