Recent Publications by VICC Researchers

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 work published recently in peer-reviewed journals by Cancer Center investigators:

Studies Offer Insights into Melanoma Treatment

Vanderbilt-Ingram investigators were involved in three high-profile studies on targeted therapy for melanoma. In the Feb. 23 New England Journal of Medicine, co-principal investigator Jeffrey Sosman, M.D., and colleagues showed that more than half of patients with a mutation in the BRAF gene responded to treatment with vemurafenib (Zelboraf), with a median overall survival of nearly 16 months – nearly double the typical survival of just six to 10 months. In the Nov. 23, 2011 issue of Nature, Sosman, Mark Kelley, M.D., and Kimberly Dahlman, Ph.D., and colleagues showed that melanoma cells resistant to the drug produce an abnormal form of the BRAF protein that can circumvent the inhibiting effect of the drug. Sosman, along with Igor Puzanov, M.D., and collaborators recently showed that mutations in the RAS gene may trigger a common side effect of vemurafenib treatment – the development of secondary skin cancers. The study, published Jan. 19 in the New England Journal of Medicine, suggests that combining vemurafenib with a MEK inhibitor may be useful in patients who harbor the RAS mutation.

Stem Cells May Hold Clues to Colon Cancer

Colorectal cancer is thought to arise from a series of mutations in intestinal stem cells – long-lived, self-renewing cells that gives rise to all cell types in the intestinal tract. Robert Coffey Jr., M.D., and colleagues recently identified a new population of intestinal stem cells that may hold clues to the origin of colorectal cancer. This new stem cell population, reported March 30 in the journal Cell, appears to be relatively quiescent (inactive) – in contrast to the recent discovery of intestinal stem cells that multiply rapidly – and is marked by a protein, Lrig1, that may act as a “brake” on cell growth and proliferation. The researchers have also developed a new, clinically relevant mouse model of colorectal cancer that investigators can now use to better understand where and how the disease arises and to identify new therapeutic targets.

Kif18A’s Tail Goes the Distance

Mitosis, the process by which chromosomes are separated during cell division, requires tight regulation of the string-like structures (microtubules) that originate at the cell poles, attach to chromosomes, and pull them apart. Kif18A, a motor protein involved in properly aligning chromosomes for mitosis, accumulates at the dynamic plus-ends of microtubules and suppresses their dynamics. In the Sept. 2, 2011 issue of Molecular Cell, Ryoma Ohi, Ph.D., and colleagues show that accumulation of Kif18A at microtubule plus-ends depends on its C-terminal “tail” domain, whereas the N-terminal motor domain is involved in suppression of microtubule growth. Since some chemotherapy drugs, like Taxol, act by disrupting microtubule dynamics, the findings may have implications for cancer therapeutics.

No Increased Birth Defect Risk for Childhood Cancer Survivors

Childhood cancer patients frequently receive aggressive, life-saving radiation and chemotherapy treatments that can affect their ability to have children. Lisa Signorello, Sc.D., and colleagues conducted a large, retrospective study of the children of childhood cancer survivors who were treated with radiation therapy and/or some forms of chemotherapy. They reported, in the Jan. 20 Journal of Clinical Oncology that the survivors’ offspring do not have an increased risk for birth defects compared to children of cancer survivors who did not receive these treatments. The findings provide reassurance that increased risks of birth defects are unlikely for the children of childhood cancers survivors and can help guide family planning choices for those survivors.

Ensuring the Health of Oncology Training Programs

With an anticipated shortage of up to 4,000 oncologists by 2020, retaining hematologists and oncologists in academic medicine – where they play critical roles in driving research and innovation and in training and mentoring future oncologists – is increasingly important. In the Oct. 10, 2011 issue of the Journal of Clinical Oncology, Leora Horn, M.D., and colleagues reported that less than half of surveyed fellows responded that a career in academic medicine was important to them, and approximately 40 percent of fellows graduating from academic institutions entered nonacademic careers. The results suggest that increased focus on factors like mentorship, research opportunities and ensuring a nurturing intellectual environment during fellowship training may improve efforts to retain fellows as academic faculty.

Studies Pinpoint New Anti-Cancer Drug Target

Mutations that activate the Wnt signaling pathway occur in more than 90 percent of sporadic (non-inherited) colorectal cancers and may be involved in breast, liver and other major cancers. Blocking the Wnt pathway has been a desirable therapeutic target, but its complexity has made it difficult to find “druggable” targets. Ethan Lee, M.D., Ph.D., and colleagues have discovered a new molecular participant, called XIAP, in the Wnt signaling pathway. The protein, which inhibits cell death and has been the focus of recent anti-cancer drug development, removes a molecular “safety switch” in the cell nucleus, which then activates the Wnt pathway. The findings, reported March 9 in Molecular Cell, suggest that targeting XIAP’s role in Wnt signaling – in addition to its role in cell death – may allow for the development of improved cancer therapeutics.