Inhibition of Metastases in Preclinical Models of Osteosarcoma

Two NCI studies presented at the American Association for Cancer Research (AACR) annual meeting show the potential to decrease metastases in osteosarcoma by inhibiting an interaction or pathway involved in its spread.

Dr. Su Young Kim and colleagues in CCR's Pediatric Oncology Branch studied the effects of disrupting the interaction between the chemokine stromal-derived factor 1 (SDF-1) and its receptor, CXCR4, on lung metastases in a mouse model. SDF-1 and CXCR4 have been shown to be involved in the regulation of metastases of many human tumors, and CXCR4 expression in human osteosarcoma often correlates with poor prognosis.

The researchers collaborated with Chemokine Therapeutics of Vancouver, BC, and used their drug, CTCE-9908, a molecule that prevents CXCR4 from interacting with SDF-1. They saw a 67-percent decrease in the number of surface lung metastases in mice treated with CTCE-9908 compared with the controls.

"A previous phase I study of CTCE-9908 in healthy adults did not reveal any significant toxicities," comments Dr. Kim. "Combined with our current results, this suggests that clinical studies of CTCE-9908 in human osteosarcomas may be warranted."

In the second study, Dr. Xiaolin Wan and colleagues, also from the Pediatric Oncology Branch, examined the effects of the drug rapamycin on metastases mediated by the protein ezrin. The lab previously showed that ezrin expression is necessary for metastatic behavior in a mouse model of osteosarcoma.

The scientists discovered that the ezrin-related metastatic behavior was linked to an Akt-dependent mTOR pathway, the mammalian target of rapamycin. Blockading this pathway with rapamycin or its analog, cell cycle inhibitor-779 (CCI-779), led to significant inhibition of experimental lung metastasis in vivo, and prolonged survival of the treated mice. Whereas all 8 mice in the control group developed lung metastases, only 1 in 7 mice given rapamycin and 0 of 9 given the highest dose of CCI-779 developed lung metastases.

"These results suggest that blocking the mTOR pathway may be an appropriate target for strategies to reduce tumor cell metastasis," comments Dr. Wan. "However, we need to conduct more preclinical studies before we can begin to design clinical trials."

Novel MRI Approach Measures Early Tumor Response

A novel MRI approach reported at the AACR meeting may allow clinicians to assess an individual's response to a particular treatment with better accuracy and less toxicity than can currently be done.

Dr. Brian Ross of the University of Michigan used a technique called diffusional MRI to measure changes in the Brownian motion of water molecules within brain tumors before and after treatment with chemotherapy and/or radiation. The technique capitalizes on the fact that as cells die, their membranes break down, allowing greater movement of the water molecules that were once bound by them.

Cell death changes the diffusion of water within a tumor, allowing pretreatment measurements to be compared with those taken shortly after treatment. The researchers map their data onto a functional diffusion map (fDM), enabling them to visualize treatment-induced tumor changes, as well as regions not affected by treatment.

Dr. Ross reported on the results from 29 patients with malignant glioma. Not only could the researchers distinguish between stable and progressive disease at 3 weeks, the patients could also be successfully stratified, based upon the fDM measurement, into two populations based on their overall survival (18 months vs. 8 months).

"This study was the first series of clinical data on a single tumor type allowing for fDM to be clinically validated as a biomarker," said Dr. Ross. "Our results are completely independent of the field strength or manufacturer of the equipment used, allowing for easy testing in multicenter clinical trials."

Green Tea Compound Shows Prevention Prowess

Results from a small clinical trial presented last week at the AACR meeting provide strong evidence that a green tea compound may be able to prevent prostate cancer.

Italian researchers reported on a small, randomized, double-blind, placebo-controlled study testing whether EGCG, considered the most potent form of substances found in green tea leaves called catechins, could prevent prostate cancer in men at high risk for the disease. The study included 60 previously untreated men between 45 and 75 years old with high-grade prostatic intraepithelial neoplasia lesions. Approximately 25 to 35 percent of men with such lesions on prostate biopsy will have prostate cancer diagnosed within 1 year. Of the 30 men in the treatment arm, only 1 developed prostate cancer, compared with 9 of 30 in the placebo arm.

"This is quite impressive because the difference is highly significant," said study leader Dr. Saverio Bettuzzi. "Thirty patients in each arm is fine as a proof-of-principle study," he continued, while cautioning that many questions remain unanswered, including whether the treatment actually prevented cancer or simply delayed it.

Dr. Bettuzzi and colleagues, who will follow these trial participants for up to 5 years, hope to launch a larger trial that includes men from both Italy and the United States.

Potential Breast Cancer Drug Targets Tumors with BRCA Mutations

Scientists have discovered a drug that slows the growth of some breast tumors containing mutations in the genes BRCA1 and BRCA2, according to a study in mice reported in the April 14 Nature. BRCA mutations, which are usually inherited, account for only 5 to 10 percent of breast cancers, but women carrying them have up to an 80 percent chance of developing breast cancer by age 80.

The researchers found that giving the experimental drug to mice caused some tumors with BRCA mutations to become unstable and die. The drug inhibited an enzyme called PARP (poly [ADP-ribose] polymerase) that repairs DNA in tumor cells and is essential for the survival of tumors with BRCA mutations.

"These data in mice are exciting because they suggest that BRCA1- and BRCA2-associated cancers may be treated - and perhaps prevented - with an agent that targets a specific molecular pathway," says Dr. Sheila Prindiville of NCI's CCR. "The question now is whether the findings in mice translate to humans."

Chemopreventive Tamoxifen Use Rejected by Most Women At Risk

Among healthy women at high risk for breast cancer, only a small minority were willing to take tamoxifen as a chemopreventive agent to lower their risk for developing the disease, according to a study published April 11 online in Cancer.

The findings are based on interviews with 255 at-risk women, each of whom received a 15-minute educational session about tamoxifen's benefits and risks. "After the intervention, only 45 women (17.6 percent) said they were inclined to take tamoxifen," report researchers from the University of California, Davis.

Among those who rejected using tamoxifen preventively, many voiced concerns about adverse effects from the drug, especially risks for pulmonary embolism, painful intercourse, and cataracts. Most women said they were less concerned about tamoxifen's association with increased risks of endometrial cancer.

Rather than taking a drug to lower their risk, many women mentioned using other "self-preventive strategies," including breast exams, mammograms, and changes in diet and exercise, the researchers report.