NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 8, 2005 • Volume 2 / Number 6 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Initial Glioma Treatment Shows Wide Variation

Care patterns for patients newly diagnosed with the most common form of advanced brain tumors can vary dramatically, according to a study published in the February 2 Journal of the American Medical Association (JAMA). In some areas, the study authors reported, care patterns closely followed results from published literature, such as the heavy use of contrast-enhanced MRI at diagnosis (92 percent of patients) and postoperative radiation therapy (87 percent).

Other care patterns, however, contrasted sharply with published literature and the few practice guidelines available for treating patients with grade III or IV gliomas. Nearly 9 in 10 patients received antiepileptic drugs (AEDs), despite the fact that only 32 percent of patients presented with seizures - meaning that many patients received the antiepileptic drugs prophylactically. According to published guidelines on antiepileptic prophylaxis for patients with newly diagnosed tumors, lead author Dr. Susan M. Chang of the University of California, San Francisco noted that AEDs "have little value for seizure-free patients…and actually are associated with significant adverse effects."

The study, funded in part by NCI, was conducted by the Glioma Outcomes Project, a prospective, longitudinal database that tracks clinical practice patterns and outcomes among malignant glioma patients. The analysis published in JAMA included 565 patients.

Among other findings were the limited use of antidepressants, even among patients who reported depression symptoms, and the near universal use of corticosteroids to limit neurologic symptoms. Although corticosteroid use is supported by the published literature, the authors wrote, the drugs can have significant adverse effects, including immunosuppression and hypertension. These effects, they added, "may be ameliorated by lower doses," and consensus guidelines on corticosteroids may be needed "to optimize corticosteroid dosing."

False-Positives Cause Some Men to Skip Subsequent Prostate Cancer Screening

Researchers have found that, among men undergoing a baseline round of prostate cancer screening, African Americans, men who have a high school education or less, and men with a false-positive baseline screen are less likely to return for subsequent screening. These findings are published in the January issue of Cancer Epidemiology Biomarkers & Prevention, and are based on 2,290 Caucasian and African American patients enrolled at the Detroit site of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

The researchers found that men who received false-positive test results at baseline were 1.9 times as likely not to return for subsequent screening appointments, compared with those who tested negative. African American men were 1.6 times as likely not to return for screening as Caucasians, and men with a high school education or less were 1.6 times as likely not to return as those with a post-high school education. A total of 184 patients did not return for their appointments, their reasons being refusal (61 percent), scheduling problems (29 percent), illness (4 percent), and travel out of the area (6 percent).

The authors concluded that when clinicians discuss prostate cancer screening with their patients, they should cover the likelihood of false-positives, the meaning of these results, the anxiety that may occur after receiving abnormal results, and the relationship between screening and mortality due to prostate cancer. "During the shared decision-making process, patients' attitudes and perceptions should be ascertained," they wrote. "This process could assist clinicians in ensuring that patients make informed choices about subsequent prostate cancer screening."

Researchers Synthesize Dendrimer Clusters for Targeted Therapy

Scientists at the University of Michigan have devised a method to easily create multipurpose molecules for use in targeted anticancer therapy. By attaching single-stranded DNA linkers to dendrimers - polymers that branch out like a tree - the researchers could bridge together individual dendrimer subunits with specific functions and create a multifunctional dendrimer cluster. This bridging technique, described in the January Chemistry and Biology, could potentially lead the way to developing customized therapies for individual patients.

Dendrimers are promising candidates for use as the base of anticancer drugs, to which functional molecules can be attached. Ideally, an anticancer therapeutic agent would have multiple functional groups; for example, a targeting molecule to bind a cell, a radioactive compound to kill the cell, and a fluorescent probe so the process can be imaged. However, there are problems synthesizing these compounds, and different drugs would have to be designed for each different tumor with this approach.

Dr. James Baker, Jr., and colleagues improved compound synthesis through a "building block" approach in this NCI-funded study. They created two single-function dendrimers; one with a molecule to bind folate receptors, and the other with a fluorescein molecule for imaging. They then added complimentary 34-base stretches of single-stranded DNA to each, and the two dendrimers conjugated through base pairing. Using fluorescence imaging, they observed that the dendrimer cluster specifically bound to a cancer cell line overexpressing the folate receptor. Compared with traditional chemistry, DNA-linked dendrimers could provide a more effective way to mix and match different therapeutic combinations to better treat individual patients.

Sunlight May Also Reduce Some Cancers

Two case-control population studies appearing in the February 2 Journal of the National Cancer Institute provide evidence that sunlight, a known cause of skin cancer, may actually reduce the risk of certain other cancers.

In a large study of Scandinavians, Dr. Karin Ekström Smedby and colleagues at the Karolinska Institutet in Stockholm looked for links between ultraviolet exposure from sunlight and several types of lymphomas, in part because the incidence of melanoma has been found to rise in parallel with the incidence of non-Hodgkin's lymphoma (NHL). Instead, the researchers found that increased sun exposure was associated with reduced risk for NHL, and also, though less clearly, with decreased risk for Hodgkin's lymphoma.

In a second, smaller study of 528 people living in Connecticut, Dr. Marianne Berwick's team from the University of New Mexico conducted a 5-year follow-up to her earlier trial looking at skin self-examination and melanoma mortality. Her results clearly show that increased sun exposure and heightened skin awareness reduce the risk of dying from melanoma.

Sunlight's salutary influence on some cancers has been discussed for several decades, according to an accompanying editorial. The editorial noted that breast, colon, and prostate cancer mortality all show "a striking latitudinal gradient," increasing from the southern to the northern United States. Dr. Berwick suggested that the greater exposure to sunlight could enhance DNA repair mechanisms, and/or leading to less fatal forms of melanoma. Vitamin D is synthesized when the skin is exposed to ultraviolet B light, which may also have a protective effect.

New Drug Shows Promise in Combating Imatinib-Resistant CML

Temple University researchers have developed a new drug, ON012380, that can override imatinib (Gleevec) resistance in chronic myelogenous leukemia (CML). Similar to imatinib and other CML drugs, ON012380 works by inactivating the key oncoprotein BCR-ABL, but targets a different site on the protein. The study, which appeared in Proceedings of the National Academy of Sciences online on January 27, showed that ON012380 was about 10 times more potent than imatinib and could induce apoptosis in all of the known imatinib-resistant leukemia cells.

Imatinib treats CML by inhibiting BCR-ABL, a cancer-inducing protein created by a rearrangement of two chromosomes that bring the Bcr and Abl genes together. It blocks BCR-ABL's ability to bind ATP. While imatinib has been extremely effective, many patients eventually develop resistance to it because BCR-ABL can mutate and adapt. Currently, 17 clinically identified mutations in this ATP-binding region have been identified.

Dr. E. Premkumar Reddy and his team circumvented imatinib resistance by targeting a different, but equally critical, part of BCR-ABL: the substrate binding domain. They found that ON012380 was effective at inhibiting the growth of all 17 imatinib-resistant human cell lines, working at a 10-fold lower concentration than imatinib. In mice expressing T315I, the most common BCR-ABL mutant, ON012380 was able to induce a regression in the leukemia while being extremely well tolerated.

The 100-percent efficacy and low toxicity of ON012380 potentially make it an important new drug against imatinib-resistant CML, and Dr. Reddy is currently seeking Food and Drug Administration approval to proceed with clinical trials.