Journal Watch

Vanderbilt-Ingram Cancer Center is committed to conducting innovative, high-impact basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of recent work published in peer-reviewed journals by center investigators:

Tumor “tag” shines light on cancer response
A technique that specifically “tags” tumors responding to chemotherapy may offer a new strategy for determining a cancer treatment’s effectiveness within days of starting treatment. A team at Vanderbilt-Ingram reports in Nature Medicine the identification of a small protein that specifically recognizes tumors responding to chemotherapy. They show that the protein, when tagged with a light-emitting molecule, can be used to visualize cancer response in mice just two days after starting therapy. Currently, response to chemotherapy is determined by measuring changes in tumor size with imaging techniques like CT and MRI (magnetic resonance imaging). “It takes two to three months of cancer therapy before we can determine whether the therapy has been effective for a patient,” says senior investigator Dennis Hallahan, M.D. “If we can get that answer within one to two days, we can switch that patient to an alternative regimen very quickly.”

Cancer-related protein yields to ‘peer pressure’
When it comes to cancer, the protein EphA2 appears heavily influenced by peer pressure. This protein is commonly expressed in aggressive breast cancers. In some circumstances, it seems to promote cancer growth and metastasis, but at other times, it appears to inhibit tumor growth. Which role it plays depends in particular on the presence of another famous human breast cancer gene, Her2, write Jin Chen, M.D., Ph.D., and colleagues in The Journal of Clinical Investigation. In cell and animal models, the researchers found that EphA2 interacts with Neu, the rodent version of the human Her2 gene, and this complex activates cell signaling pathways that promote cell growth and motility. The results suggest that EphA2 cooperates with Neu (Her2) to promote tumor progression and could be a potentially useful target for Her2-dependent tumors, particularly in combination with a drug like Herceptin, which targets Her2. Chen is studying whether cells resistant to Herceptin might benefit from treatment with EphA2-targeted treatments, which are currently in development.

Finding could help time cancer treatment
Researchers led by Li Yang, Ph.D., and Hal Moses, M.D., have found a clue to the seemingly contradictory nature of the protein TGF-beta that could someday help doctors determine the best timing for cancer treatment. They report in Cancer Cell a critical role for the body’s own immune cells in causing TGF-beta’s change from a tumor suppressor in early stages of cancer to a promoter of tumor growth and spread in advanced cancer. This dual identity of TGF-beta presents a serious patient care challenge. Treatments designed to inhibit TGF-beta signaling are currently being developed and tested – but what if treatment is given when the protein is acting as a tumor suppressor and inadvertently promotes cancer progression instead? In animal models of breast cancer, the investigators found immune cells called myeloid immune suppressor cells (MISCs) in greater numbers in tumors in which TGF-beta function had been eliminated. The cells were found mostly at the “invasive front” of tumors, suggesting that they are called to where the tumors are spreading into normal tissue. These cells produce TGF-beta and a kind of enzyme called MMPs that are known to be important in cancer metastasis. The investigators suggest that recruitment of these cells is important in the switch from tumor suppressor to promoter. MISCs are known to circulate in the bloodstream, so it may be possible to develop a blood test for these cells that could indicate whether timing is right for TGF-beta inhibitor treatments.

Molecule may put brakes on head and neck cancers
A molecule that is lost in about one-third of a type of head and neck cancers has properties that suggest it acts to put the brakes on cancer, a team led by Wendell Yarbrough, M.D., reports. “If loss of LZAP is a mechanism that enables head and neck cancer formation or tumor growth, understanding how it works will, in the long run, help us to better treat these tumors,” says Yarbrough. The investigators were looking for proteins that regulate the tumor suppressor ARF. The team screened for proteins that bind to ARF and found LZAP. The new protein had the interesting ability to inhibit cell growth. A new tumor suppressor gene doesn’t come along every day, making the findings very exciting, he says. The investigators linked LZAP activity to NF-kappa-B, a family of transcription factors that regulates genes involved in inflammatory and immune responses and that has been implicated in tumor development. The current paper reports that LZAP inhibits NF-kappa-B, and that when LZAP is lost, NF-kappa-B activity increases. The work appeared in Cancer Cell.

This work supported in part by the National Institutes of Health, the Ingram Charitable Fund, the T.J. Martell Foundation, the Robert J. and Helen C. Kleberg Foundation, the Barry Baker Laboratory for Head and Neck Cancer Research and others.

Newly identified section of receptor may be target
Many targeted anti-cancer agents try to disable or prevent activation of the receptor for the epidermal growth factor, which drives cell growth characteristic to cancers. A study by Graham Carpenter, Ph.D., and colleagues identifies a portion of the EGR receptor – previously an unrecognized contributor to the activation process – as essential for the receptor to be active. In addition to increased understanding of this important therapeutic target, the paper suggests a new site for attacking this regulator of cancer growth. The work appeared in the Proceedings of the National Academy of Sciences.

Work reported in Journal Watch was supported in part by the National Institutes of Health, the Ingram Charitable Fund, the T.J. Martell Foundation, the Robert J. and Helen C. Kleberg Foundation, the Barry Baker Laboratory for Head and Neck Oncology, and others.

More info about our research at www.vicc.org/research