June 17, 2010
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:
Protein suppressor of colon tumors
In the March 1 Journal of Clinical Investigation, James Goldenring, M.D., Ph.D., and colleagues report that expression of Rab25 – a protein known to regulate protein trafficking within the cell – may play a role in early colon tumor development. The investigators found substantially decreased Rab25 expression in human colorectal tumors compared with normal colon and that lower Rab25 expression levels predicted poorer survival. To clarify Rab25’s role in colorectal tumor formation, the investigators generated mice lacking Rab25 and found that Rab25-deficient mice developed more intestinal polyps and colon tumors than parental mice. The findings suggest that Rab25 may act as a tumor suppressor in the colon lining and that reduction of Rab25 expression may be an early event in colon cancer formation.
Gene signature for colon cancer prognosis
R. Daniel Beauchamp, M.D., and colleagues have identified a gene signature that may help identify patients at risk of colon cancer recurrence – and identify patients most likely to benefit from chemotherapy. From a 300-gene expression signature initially identified in mouse colon cancer cells, the investigators developed a 34-gene signature most closely associated with metastasis and death (in a set of Vanderbilt patient samples). In a larger patient population, they found that patients with the “poor prognosis” signature – the expression pattern seen in highly invasive mouse cells – were five times more likely to have a cancer recurrence than those with a “good” prognosis signature. Also, stage III patients with the “poor prognosis” signature appeared to benefit from chemotherapy whereas those with the “good prognosis” signature showed little benefit. The findings, published in the March issue of Gastroenterology, could help personalize treatments for colon cancer.
Protein protector against DNA stress
Genome maintenance systems prevent and repair DNA damage to maintain the genome’s stability and protect against mutations that cause cancer and other diseases. In their search for novel genome maintenance factors, David Cortez, Ph.D., and colleagues have identified SMARCAL1 as a genome maintenance protein. Mutations in SMARCAL1 are known to cause the rare genetic disorder Schimke immunoosseous dysplasia (SIOD), but the function of SMARCAL1 and its mechanistic role in the disease have remained unclear. In the Oct. 15 Genes & Development, the researchers report that SMARCAL1 protein acts to limit DNA damage at stalled replication “forks” (sections of unwound DNA undergoing replication). The findings suggest that mutations in SMARCAL that result in defective cellular responses to replication stress may at least partially explain the variety of symptoms associated with SIOD.
Drugs join forces to overcome lung cancer resistance
William Pao, M.D., Ph.D., and colleagues have found that combining two targeted cancer therapies may overcome resistance of lung cancers to Iressa and Tarceva – drugs that initially work well against lung cancers with mutations in the epidermal growth factor (EGF) receptor but lose their effectiveness over time. About half of drug-resistant lung tumors harbor a new mutation (called T790M) in the EGF receptor. The researchers found that mouse tumors with the T790M mutation did not respond to Iressa, Tarceva, an experimental EGF receptor inhibitor (BIBW-2992), or Erbitux – an antibody that blocks the interaction of EGF receptor binding proteins with the EGF receptor. However, the combination of Erbitux and BIBW-2992 effectively “melted away” T790M-containing tumors. The results, in the Oct.1 Journal of Clinical Investigation, suggest a way to overcome T790M-mediated resistance and support moving forward with clinical trials in patients with lung cancer.
New target for severing cancer’s access to supplies
Charles Lin, Ph.D., and colleagues have identified a protein – delta-catenin – involved in blood vessel development (angiogenesis) during disease conditions, but not during normal physiological processes. They found that endothelial cells from mice missing delta-catenin had reduced motility and vascular structure formation, compared to cells from normal mice. And in models of tumor growth and wound healing, mice missing delta-catenin showed reduced tumor growth and blood vessel density and impaired angiogenesis and wound closure. In contrast, these mice had normal physiological hormone-induced angiogenesis in the uterus. The findings, reported in the January Journal of Experimental Medicine suggest that delta-catenin may be a promising therapeutic target for blocking blood vessel growth in disease conditions like cancer.
Food, exercise, blood type and cancer
Two studies on breast cancer survivors in Shanghai, China, have revealed dietary and lifestyle factors that influence cancer risk and quality of life. In a study published in the Dec. 9 Journal of the American Medical Association, Xiao Ou Shu, M.D., Ph.D., and colleagues found that women who reported the highest soy food intake had the lowest breast cancer mortality and recurrence rates compared with women in the lowest soy food intake group. And in the January Journal of Clinical Oncology, they reported that breast cancer patients who exercise and drink tea on a regular basis may be less likely to suffer from depression than other patients.