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Taxol, Immunotoxin Combo Boosts Antitumor Effect in Mice

In mice injected with mesothelin-bearing tumors, researchers observed a synergistic antitumor effect by combining the drug paclitaxel (Taxol) and an immunotoxin - a bacterial toxin genetically engineered to target cancer cells. The combination was more effective than either the immunotoxin, SS1P, or the drug alone, and caused long-lasting complete remission in these mice. 

"Either treatment alone had a small effect, but together they had an effect that was clearly more than additive," says lead researcher Dr. Ira Pastan of the Laboratory of Molecular Biology in NCI's Center for Cancer Research (CCR). His team previously reported an additive antitumor effect from combining the antibody bevacizumab (Avastin) with SS1P. The new study, in the August 1 Clinical Cancer Research, is the first description of a synergistic effect between a drug and an immunotoxin.

SS1P targets the protein mesothelin. This drug is active against both mouse tumors and tumor cells from patients with mesothelioma and ovarian cancer, all of which express mesothelin. Dr. Pastan's team showed that paclitaxel, at a dose that by itself has minimal antitumor effect, greatly increased the antitumor activity of SS1P against the injected tumors. They did not see a synergistic effect when the same tumors were treated in culture.

The researchers are still investigating the mechanism responsible for the different results. "The effect is what is important," says Dr. Pastan. "Even if we don't understand the mechanism, we should be able to design better treatment for patients with mesothelin-bearing tumors."

His team recently completed phase I trials with SS1P for mesothelioma and ovarian cancer, and a phase II trial is being planned. The researchers believe a paclitaxel/SS1P combination would be a good treatment plan for ovarian cancer because paclitaxel alone is effective for ovarian cancer and SS1P showed minor responses to ovarian cancer in the completed phase I trial. 

Loss of Cellular Motor Protein Contributes to Tumor Formation

Investigators in NCI's CCR have shown that loss of the cellular motor protein KIF4, which plays a role in mitosis, may contribute to tumor formation, according to a study in the August 8 Current Biology.

The investigators isolated mouse embryonic stem cells lacking KIF4 (KIF4 KO cells), and observed defects in mitosis leading to aneuploidy (abnormal chromosome number) in more than 70 percent of KIF4 KO cells. When KIF4 KO cells were injected into nude mice, they formed significantly more and larger tumors than control cells, likely due to an increase in cellular proliferation.

In further in vitro experiments, the investigators showed that cell-cycle checkpoints were overridden in KIF4 KO cells, and these cells were significantly more likely than control cells to contain aberrant centrosomes, organelles that organize the cellular microtubules during cell division. Loss of KIF4 caused activation of cellular DNA damage-response pathways, which is a sign of cells with potential to form tumor cells.

In a probe of human tumor cell lines, including ovarian, lung, breast, and central nervous system cancers, KIF4 was absent or underexpressed in 35 percent of samples, strongly suggesting a link between loss of function of this protein and human tumor formation. "These results are important for two reasons," says Dr. Tom Misteli, one of the paper's authors. "First, the demonstration of a link between a molecular motor and tumor formation represents a new paradigm in the fields of molecule motors and cancer biology. Second, although the hypothesis that mitotic defects and aneuploidy can be causative in tumor formation has been around for a long time, it has been very difficult to prove experimentally. Our experiments support this idea."

Prenatal DES Exposure Linked to Breast Cancer Risk

Daughters of women who took diethylstilbestrol (DES) during pregnancy have an increased risk of breast cancer after age 40, according to a study in the August Cancer Epidemiology Biomarkers & Prevention. 

DES is a synthetic estrogen prescribed to many pregnant women between 1938 and 1971 to prevent spontaneous abortion. It's estimated that one to two million women had prenatal exposure to DES.

The study followed four cohorts of DES-exposed and -unexposed women identified from the National Cooperative Diethylstilbestrol Adenosis Project, a University of Chicago clinical trial, a Massachusetts private infertility clinic, and a study of health effects in mothers who took DES. The women completed questionnaires in 1994, 1997, 2001, and 2003 that gathered information on lifestyle, reproductive and hormonal factors, occurrence of cancer, and frequency of mammographic screening.

Researchers found that DES-exposed women aged 40 and older had 1.9 times the risk of breast cancer of unexposed women of the same ages. Women with the highest cumulative dose of DES also had the highest relative risk of breast cancer.

"These findings support the hypothesis that prenatal hormone levels affect breast cancer risk," said senior author Dr. Robert Hoover of NCI's Division of Cancer Epidemiology and Genetics.

"The study also highlights two important clinical implications: DES-exposed women should rigorously follow breast cancer screening guidelines and should carefully consider whether to take female hormone supplements," added study author Dr. Julie Palmer of Boston University.

CHEK2 Gene Mutation Increases Risk of Breast Cancer

A prospective study of more than 9,000 Danish women found that those who had a specific mutation in the tumor-suppressor gene CHEK2 had a threefold increase in the lifetime risk for breast cancer compared with noncarriers of the mutation, according to a study published online July 31 in the Journal of Clinical Oncology.

Previously, smaller case-control studies suggested an association between the CHEK2*1100delC mutation and cancers of the breast, prostate, and colorectum. Researchers, led by Dr. Borge G. Nordestgaard at Herlev University Hospital in Denmark, decided to study the prevalence of the mutation and its impact on cancer risk in the general population. They randomly selected 9,231 participants from the Copenhagen City Heart Study who had been monitored for an average of 34 years for cancer development.

They found that 0.5 percent carried the CHEK2 mutation. Among the women carriers, 12.5 percent developed breast cancer compared with 5 percent of noncarriers. Adjusting for other risk factors, the scientists found that carriers were 3.2 times more likely to develop breast cancer. However, they found no statistically significant association among CHEK2 mutation carriers for prostate, colorectal, or general cancer risk.

Dr. Nordestgaard commented: "The identification of CHEK2 as a biomarker gives us a better picture of the genetic risk factors, and may help to identify a significant subset of women who would benefit from more vigilant screening for the disease." Additional research is needed to identify if the study's findings apply to other ethnic groups, including blacks and Hispanics.

Synthetic Scorpion Venom Targets Brain Tumor Cells

The giant yellow Israeli scorpion kills its prey with venom that blocks chloride channels, but its bite is not fatal to people. The first human trial testing a synthetic version of the active protein in this venom, known as TM-601, shows that it may be a safe way to improve results in recurrent glioblastoma multiforme (GBM), a deadly brain cancer.

The drug is "simple to deliver, well tolerated, remains highly localized to the treatment site, and preliminarily seems safe for repeated injections," writes Dr. Adam N. Mamelak, of Cedars-Sinai Medical Center in Los Angeles, and colleagues in the August 1 Journal of Clinical Oncology.

The 18 adult patients in this phase I trial underwent surgery for GBM that had relapsed after first-line treatment. After removing all visible tumor tissue, surgeons implanted a small device under the patients' scalps with a tube leading to the surgical site. Two to 4 weeks later, when the patients had recovered from surgery, TM-601 tagged with iodine-131 was injected directly into the tumor cavity, with six patients each getting 0.25, 0.50, and 1.0 mg of the drug.

Patients had very few and only minor adverse effects 3 weeks after receiving the drug. Imaging showed that TM-601 attached almost exclusively to tumor cells, with very little residue elsewhere in the body. Two-thirds of patients achieved stable disease, and two women receiving the 0.50 mg dose had complete responses, no recurrent disease, and were still alive 37 and 39 months, respectively, after surgery.