Nanoparticles Deliver Chemotherapy and Block Cancer's Spread

By using targeted nanoparticles carrying significantly reduced doses of chemotherapy, researchers have demonstrated the ability to preferentially block the spread of cancer, while largely sparing the surrounding tissues. A series of experiments in animals with forms of pancreatic and kidney cancer showed that the nanotechnology therapy consistently reduced the incidence of metastasis by 90 percent as compared with untreated mice.

The results, reported online July 8 in the Proceedings of the National Academy of Sciences ¹, suggest possible new approaches for inhibiting tumor angiogenesis, the formation of blood vessels that supply tumors with the nutrients needed to grow and spread. Dr. David Cheresh, a participant in the NCI Center of Cancer Nanotechnology Excellence ² (CCNE) at the University of California, San Diego (UCSD), led the study. Dr. Cheresh leads efforts to develop "smart" nanoparticle platforms at the Center ³.

"Particularly significant and promising is the fact that tumor metastases were reduced in the treated animals," said Dr. Piotr Grodzinski, program director for the NCI Alliance for Nanotechnology in Cancer ⁴.

The research builds upon a discovery made earlier by Dr. Cheresh's group showing that a protein called integrin ανβ3 is often found on growing tumor blood vessels but not on preexisting ones. The lipid-based nanoparticles were designed to attach to the protein receptor and deliver doxorubicin ⁵, a chemotherapeutic agent typically delivered systemically but with undesirable toxic side-effects.

By encapsulating and targeting the drug through the use of these nanoparticles, the investigators observed a 15-fold improvement in drug efficacy relative to conventional delivery. While the effect on primary tumors was modest, treatment with the nanoparticles was effective in preventing dissemination of the cancer. The researchers noted that this is a highly significant finding since more than 90 percent of patients with solid tumors die due to metastasis.

Dr. Cheresh noted that the CCNE researchers are continuing their work with collaborators at the Moores UCSD Cancer Center to repeat the doxorubicin experiments with newer agents that target additional pathways involved in angiogenesis.

Fewer Americans Exposed to Secondhand Smoke

The prevalence of self-reported secondhand smoke ⁶ (SHS) exposure at home and changes in any exposure, as measured by serum cotinine (a biologic indicator of recent SHS exposure), declined significantly in nonsmoking children, adolescents, and adults in recent years, according to a report in the July 11 Morbidity and Mortality Weekly Report ⁷ (MMWR).

The MMWR analysis used data from the National Health and Nutrition Examination Surveys to determine at-home SHS exposure and serum cotinine levels in nonsmokers aged 4 years and older, from 1988-1994 and from 1999-2004. The percentage of U.S. nonsmokers who reported SHS exposure at home declined from 20.9 percent to 10.2 percent between the two time periods. Similarly, the percent of nonsmokers with any exposure to SHS declined significantly, from 83.9 percent to 46.4 percent.

However, between 1999 and 2004, children and adolescents remained at higher risk of SHS exposure than adults, with nearly one in four children aged 4 to 11 and one in five adolescents aged 12 to 19 exposed to SHS in the home, compared with only one in twenty adults aged 20 years or older. Non-Hispanic blacks and low-income Americans were also at significantly higher risk of SHS exposure.

The authors attribute the broad declines in SHS exposure to laws and policies that restrict or eliminate smoking in workplaces and public places, the increased percentage of households that have rules against smoking in the home, and the declining prevalence of smoking among Americans. The authors note that "the results of this study underscore the need for ongoing prevention efforts to reduce SHS exposure with strategies that focus on protection for those at greatest risk."

Gene Signatures Point to Therapy for Neuroblastoma

Patients with neuroblastoma may benefit from the combination of a histone deacetylase (HDAC) inhibitor and a retinoid, two types of drugs used in differentiation therapy (an approach which causes cancerous cells to resume the process of maturation and differentiation into mature cells), researchers report. Neuroblastoma is a cancer of the nervous system in children, and differentiation therapy is a potential strategy for treating the disease.

Dr. Kimberly Stegmaier of Dana-Farber Cancer Institute and her colleagues used a high-throughput screening strategy ⁸ to identify drugs that could be used in combination with HDAC inhibitors to cause neuroblastoma cells to differentiate. They screened more than a thousand compounds to find those that could induce a genetic signature associated with differentiation in neuroblastoma cells.

The best candidate was all-trans retinoic acid, a type of retinoid. Further studies showed that the combination of an HDAC inhibitor and a retinoid resulted in greater neuroblastoma differentiation than either alone, while there was also evidence of synergistic effects on cell death. The combination therapy led to the longest survival among mice with a form of neuroblastoma.

The findings, reported online July 8 in Proceedings of the National Academy of Sciences ⁹, coincide with a recent phase I study ¹⁰ showing that this type of drug combination was well tolerated in children with a variety of cancers, including neuroblastoma. The drugs have also been tested extensively as single agents in adults.

"One of the most exciting aspects of this work was that as the study neared completion, we learned that the drug combination was well tolerated in children," said Dr. Stegmaier, a pediatric oncologist. "Our study adds to the growing body of data that this combination of drugs may make sense for patients with neuroblastoma."

Study Suggests Therapeutic Avenue for Transplant-Related Cancers

Results from a new study suggest that certain anti-angiogenic agents could be used to prevent or treat the cancers that occur in 15-20 percent of patients who receive an organ transplant. The study, which relied on laboratory and animal models, showed that a common and effective immunosuppressive agent used in organ transplant procedures increases the expression of vascular endothelial growth factor (VEGF), which is critical to a tumor's ability to develop blood vessels and recruit a blood supply. The study was published July 15 in Cancer Research ¹¹.

"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence," said the study's lead author, Dr. Soumitro Pal of the Transplantation Research Center at Children's Hospital Boston and Brigham and Women's Hospital. "We would need to figure out how to balance benefit and risk to keep cancer at bay."

Although there are several potential causes of cancer in patients following a transplant, the authors noted, this study focused on whether the drug cyclosporine could promote the growth of pre-existing "microtumors" in a mouse model of post-transplantation kidney cancer. First, however, they used kidney cancer cell lines to demonstrate that cyclosporine caused activation of the VEGF gene, that the extent of this activation was dose dependent, and that it increased expression of the VEGF protein. They found that cyclosporine also activates the intracellular signaling pathway PKC, which in turn increases the transcription of the VEGF gene.

Tumor growth was greater in mice given cyclosporine than untreated mice, they discovered. But simultaneously treating the mice with VEGF inhibitors slowed tumor growth. The authors noted that other studies have found pathways other than PKC via which cyclosporine could increase VEGF expression.