National Cancer Institute (NCI) Director Dr. Andrew C. von Eschenbach was named by President George W. Bush last Friday to assume the role of acting commissioner of the U.S. Food and Drug Administration (FDA). Dr. von Eschenbach also will continue in his role as NCI director.

"I am excited and eager to accept the challenge," Dr. von Eschenbach said. "The FDA has a critical mission in protecting and improving the health of the American people.

"With the leadership and support of Health and Human Services Secretary Mike Leavitt, I will work to ensure an orderly transition to new, permanent leadership at FDA, while continuing my commitment to NCI."

The appointment of Dr. von Eschenbach to acting FDA commissioner followed the resignation from that position by Dr. Lester Crawford. In addition to his time as the FDA commissioner, Dr. Crawford also served as deputy commissioner and acting commissioner at the agency.

Prior to accepting the appointment to lead NCI in January 2002, Dr. von Eschenbach, a renowned urologic oncologist, served as executive vice president and chief academic officer of the University of Texas M.D. Anderson Cancer Center in Houston. In his 26-year career at M.D. Anderson, he was instrumental in fostering integrated research programs in the biology, epidemiology, prevention, and treatment of prostate cancer.

At NCI, he has been a strong proponent of a more collaborative, team-science approach to research and the movement toward individualized medicine based on the growing understanding of the molecular underpinnings of many diseases.

With more than 3 years under his belt as NCI director, Dr. von Eschenbach is optimistic about the new appointment.

"When I came to NCI in 2002, I made this our challenge goal: to eliminate the suffering and death due to cancer by 2015," he said. "I will work to ensure that this critically important work continues at NCI, even as the crucial initiatives at FDA continue unabated during this time of transition."

Other factors will ensure that the change will in no way hamper NCI's and FDA's ability to continue their work.

"It is the strong professionalism in the leadership and staff at both organizations that will enable me to carry out the dual roles," Dr. von Eschenbach explained.

"I have the utmost confidence in FDA staff members' skill and commitment," he continued. "The caliber of the staffs at both NCI and FDA will allow the organizations to continue their important public service during this time of transition at FDA, and I am deeply grateful for all of their contributions."

By Carmen Phillips

The Center for Cancer Research: Finding Opportunities, Facing Challenges

In 2001, the NCI intramural Divisions of Basic Sciences and Clinical Sciences were merged to form the Center for Cancer Research (CCR). This reengineering was fueled by the rapid pace of biotechnology advancement and the growing need for multidisciplinary approaches to the complex scientific problems NCI researchers are increasingly tackling. CCR's mission is to reduce the burden of cancer through exploration, discovery, and translation. This integrated structure is intended to promote rapid bench-to-bedside translation of promising cancer therapies. In turn, results from the clinic are informing the work of laboratory investigators to further refine therapies. In CCR, we value high-quality investigator-initiated research but we are also challenging the customary ways of thinking and organizing, fostering cross-disciplinary and multi-institutional research to solve complex problems in cancer research.

Within the last year, research initiated and developed at the Center culminated in a number of notable advances, including a vaccine against cervical cancer, a promising new immunotherapy against melanoma and renal carcinoma, an FDA-approved drug to treat oral mucositis, a protective agent to prevent hair loss in cancer patients undergoing radiotherapy, and a cutting-edge molecular profiling technology. These advances are impacting the NCI challenge goal of eliminating the suffering and death due to cancer by 2015 and improving the quality of life for cancer survivors. At present, a number of additional therapies are working their way through clinical trials to reach the patients.

Going forward, we are leveraging our strengths to respond to emerging needs and opportunities, as well as quickly establishing programs in high-priority areas. We are pursuing an interdisciplinary and multidisciplinary team-science approach to address the complexity of cancer research, exemplified by the formation of several Centers of Excellence. One example is the Center of Excellence in Immunology (CEI), created to foster discovery, development, and delivery of novel immunologic approaches to prevent and treat cancer and cancer-associated viral diseases. CEI's objectives include defining emerging opportunities, overseeing programs in specific areas in immunology and virology, and fine-tuning immunotherapeutic approaches in cancer treatment. CEI sponsored a very successful national conference in immunotherapy September 22-23 on the National Institutes of Health campus.

NIH Research Festival Set for October The NIH Research Festival will take place October 18-21 on the NIH campus in Bethesda, Md. For information about the schedule of presentations, job fairs, activities, and other events, go to http://researchfestival.nih.gov.

Another guiding principle is the redeployment of existing resources into new and promising areas where CCR can make a distinct contribution. An excellent example of this is the realignment of the Laboratory of Experimental and Computational Biology to support NCI's nanotechnology effort, creating an Intramural Cancer Nanotechnology Program (ICNP). CCR investigators seized the opportunity in NCI's new National Advanced Technologies Initiative for Cancer, redirecting their scientific expertise to develop a research portfolio to complement the NCI Alliance for Nanotechnology in Cancer - especially the Nanotechnology Standards Laboratory, and molecular targets/molecular oncology efforts.

While our challenges are many, the CCR staff will continue to seek innovative solutions to the complex problems of cancer by leveraging our internal strengths, identifying new opportunities, and forging fruitful collaborations.

Researchers studying the body's response to prostate cancer have developed a blood test for diagnosing the disease, and preliminary experiments suggest that it may be more reliable than the standard diagnostic blood test, the prostate-specific antigen (PSA) test.

The PSA test measures the blood levels of a single enzyme that is elevated in some men with the disease. But the levels can be elevated for reasons other than cancer, resulting in many biopsies that ultimately do not diagnose cancer.

The new test detects 22 proteins made by the immune system to fight the cancer. In a comparison, testing for the proteins was more accurate than PSA testing to correctly identify blood from prostate cancer patients while not misidentifying blood from a group of controls, according to findings in the September 22 New England Journal of Medicine.

"We view this study as a demonstration that screening blood for proteins produced in response to prostate cancer is a potential strategy for detecting the disease," says Dr. Arul Chinnaiyan of the University of Michigan Medical School in Ann Arbor, who led the study.

His team analyzed blood samples from 331 prostate cancer patients in the early stages of disease, and from 159 men with no history of cancer. Using a combination of technologies, they identified a "protein signature" for the disease.

The signature consists of 22 antitumor proteins known as "autoantibodies." All tumors produce abnormal proteins that are recognized by the immune system as foreign; the body responds by producing autoantibodies against them.

"Our strategy was to take advantage of the body's own immune system, which fights things that are foreign, like bacteria and viruses and cancer," says Dr. Chinnaiyan. The test is experimental and the results need to be validated, he adds.

Similar approaches have been used in other cancers to study individual autoantibodies. Last year, Dr. Chinnaiyan and his colleagues reported that some prostate cancer patients make autoantibodies against an enzyme called α-methylacyl-CoA racemase.

The new study defines a more representative collection, or panel, of autoantibodies, though the panel is a continual work in progress, notes Dr. Chinnaiyan. Efforts to define the autoantibodies for a given cancer characterize the emerging field of cancer immunomics.

A clinically validated panel, the researchers suggest, might be used in conjunction with PSA testing to help determine which patients truly need a biopsy to rule out a cancer diagnosis. The test could be given to patients who receive a positive PSA test but have not yet had a biopsy.

"We are cautiously optimistic, but there's a tendency to sensationalize results from early studies like this one," says Dr. James Montie, chairman of the Department of Urology at Michigan and a member of the research team.

He and others would certainly welcome a diagnostic test that is less vulnerable than the PSA test to confounding factors such as benign enlargement of the prostate.

Dr. Sudhir Srivastava, chief of NCI's Cancer Biomarkers Research Program and director of the Early Detection Research Network, which supported the study, is also optimistic. "I'm hopeful the results will be validated because the research was done so elegantly in terms of technology," he says.

"This is all part of continuing efforts to learn what goes wrong during prostate cancer and to identify biomarkers," says Dr. Srivastava. "The novelty comes from using the body's defense system to detect cancer rather than looking at, say, genetic mutations."

By Edward R. Winstead

Higher Radiation Dose Reduces Recurrence of Local Prostate Cancer

A prospective randomized study in 393 early-stage prostate cancer patients has found that increasing the energy delivered during primary radiotherapy from the conventional dose of 70 Gy to 79.2 Gy results in a 49 percent reduction in the risk of increased PSA levels. The finding is "pivotal," said an accompanying editorial in the September 14 Journal of the American Medical Association, because it "provides support for dose escalation in men with lower-risk disease."

Researchers followed the men for 5.5 years, looking primarily at PSA levels. Biochemical recurrence of the cancer was diagnosed in 38.6 percent of those who had been treated with 70 Gy, compared with 19.6 percent who had received 79.2 Gy. While this result mirrors other studies, a subset of 227 men whose clinical findings at diagnosis put them at lowest risk also fared significantly better with the higher dose: Only 19.5 percent relapsed, compared with 39.9 percent who received the conventional dose.

Lead author Dr. Anthony L. Zietman of Harvard Medical School and colleagues emphasized that the advantage of high-dose radiation for low-risk patients must be balanced against the possibility of increased side effects such as rectal bleeding. Such increases in this study were seen only at the Grade 2 level.

The editorial noted the general trend toward higher radiation in the last two decades, which has been made safer by more precise three-dimensional conformal therapy techniques that shape the radiation to minimize damage to surrounding and intervening tissue.

The editorial also noted that while this study used an advanced proton-beam radiation delivery system, the effect on tissue is comparable to standard photon radiation.

Gene Inactivation May Indicate Colon Cancer "Field Defect"

The inactivation of a specific gene by a process called DNA methylation may be a marker by which to detect or assess the risk of developing sporadic colorectal cancer, according to a new study. The study, led by researchers from the University of Texas M.D. Anderson Cancer Center, focused on whether DNA methylation of the MGMT gene, which repairs damaged DNA, is a marker for a "field defect" (a region of unstable, potentially precancerous cells) in colon tissues that predisposes people to colon cancer.

Previous research has linked methylation of MGMT to mutations of the KRAS gene, which is thought to play an important role in colon cancer development. In a study published in the September 21 Journal of the National Cancer Institute (JNCI), Dr. Jean-Pierre Issa and colleagues used several different methods to assess MGMT promoter methylation in samples from colon cancer tumors and in the adjacent or nearby mucosa in 95 patients. They also analyzed colon tissue samples of 33 people without colon cancer.

More than 45 percent of tumor samples had MGMT promoter methylation. Depending on the method used, anywhere from 50 to 94 percent of adjacent cells demonstrated DNA methylation, as did 10 of the 13 available nonadjacent samples. Methylation of MGMT was also detected in the normal colon mucosa from several healthy participants. The study results, the researchers argue, point to the possibility of conducting clinical trials using MGMT promoter methylation as a "marker of risk" of colon cancer.

An editorial notes that DNA methylation-related field defects raise important questions about testing chemopreventive agents - such as folate for colon cancer prevention - in that such agents could have varied effects depending on the presence of a field defect.

Beta-Carotene Found to be Carcinogenic for Women Smokers but Protective for Nonsmokers

Beta-carotene supplements have been found to increase lung cancer risk in males who smoke. New results from a large prospective observational cohort study in the September 21 JNCI extend this finding to women - and to other tobacco-related cancers.

Women in the study who were current or ever-smokers who took beta-carotene at the high levels found in supplements more than doubled their risk of tobacco-related cancers, compared with women getting the lower amounts found naturally in certain foods (3.1 mg/day or less). In contrast, among those who had never smoked, the relationship was reversed: Those taking high levels of beta-carotene as a supplement cut their risk by 56 percent compared with those taking the smaller amount.

The study known as E3N is the French component of the European Prospective Investigation into Cancer and Nutrition. Lead author Dr. Marie-Christine Boutron-Ruault, of INSERM in Villejuif, France, and colleagues collected questionnaires about beta-carotene consumption from 59,910 women who enrolled in the prospective study, which began in 1990. During a median follow-up of 7.4 years, 700 women developed tobacco-related cancers. From most to least frequent incidence, these included colorectal, thyroid, ovarian, cervical, lung, urinary tract, pancreatic, head-and-neck, stomach, anal, and liver cancer.

In an accompanying editorial, Dr. Susan T. Mayne of the Yale University School of Medicine and Dr. Scott M. Lippman of the University of Texas M.D. Anderson Cancer Center observed that "Evidence suggesting tobacco exposure modifies the chemo-preventive efficacy of nutrients/nutrient derivatives continues to mount."

Erlotinib Studied as First-Line Treatment in Lung Cancer Patients

The targeted drug erlotinib (Tarceva) showed promising activity and tolerable toxicity as a first-line treatment for elderly patients with advanced, non-small-cell lung cancer (NSCLC), according to a phase II study reported last week at the European Respiratory Society Annual Congress in Copenhagen, Denmark.

The single-center study included 80 NSCLC patients aged 70 and older (median 75 years) who had never undergone chemotherapy, and most (69 percent) had not had other treatments, such as surgery or radiation. The researchers at Dana-Farber Cancer Institute reported a median survival time of 46 weeks among the patients.

Although none of the patients had complete responses to erlotinib, 60 percent had either partial responses (median duration 65 weeks) or stable disease (median duration 24 weeks).

In addition, the drug was well tolerated by most patients, with rashes and diarrhea being the most common side effects. Ten patients were discontinued from the study due to toxicity and there was one treatment-related death due to pneumonitis.

Current chemotherapy for older patients with advanced NSCLC is associated with some survival benefits but also significant toxicity, the researchers noted. Dana-Farber's Dr. Bruce Johnson, who headed the research, commented, "While further research is needed, our findings suggest that it may be beneficial to use erlotinib - a relatively non-toxic targeted agent - to initially treat patients with advanced lung cancer, rather than use conventional chemotherapy regimens."

The investigators recommended that a larger phase III trial be considered for this population to compare first-line erlotinib against single agent vinorelbine (Navelbine). Erlotinib is already approved as a second-line therapy for NSCLC after chemotherapy has failed.

NCAB Update Among the topics discussed at last week's National Cancer Advisory Board (NCAB) meeting, NCI's plan for standardizing the collection and analysis of biological samples was at the top of the list. "When we started this project 3 years ago, none of us recognized the complexities surrounding the policy and technical issues," said Dr. Anna Barker, NCI deputy directory for Strategic Scientific Initiatives. She explained that biorepositories are crucial to cancer research because, "More data is encoded in a person's biological samples than in the rest of their medical record combined." Along with the U.S. Department of Defense, NCI houses one of the largest collections of biological samples in the world, Dr. Barker said. "We have learned that it is time to begin harmonizing our approaches and technologies for all phases of biospecimen collection and management." Dr. John Niederhuber announced his formal resignation as NCAB chair; Dr. Paul Van Hoff will serve as interim chair. Dr. Niederhuber has been named NCI deputy director for Translational and Clinical Sciences (see Notes). Dr. Andrew von Eschenbach presented Dr. Niederhuber with the NCI Director's Award for his contributions during his tenure as NCAB chair. "John was committed and effective in integrating the NCAB into the leadership of NCI," said Dr. von Eschenbach. To view an archived webcast of the September 20-21 meeting, go to http://videocast.nih.gov/ PastEvents.asp?c=39

Letter of Intent Receipt Date: Oct. 20, 2005. Application Receipt Date: Nov. 22, 2005.

This funding opportunity will use the U01 award mechanism. For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=3114.

Inquiries: Dr. Jane L. Peterson - jane_peterson@nih.gov and Dr. Mark W. Moore - mmoore3@mail.nih.gov

The Obese and Diabetic Intrauterine Environment: Long-Term Metabolic or Cardiovascular Consequences in the Offspring
RFA-DK-05-014

Letter of Intent Receipt Date: Feb. 16, 2006. Application Receipt Date: March 16, 2006.

This funding opportunity will use the R21 and R01 award mechanisms. For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=3129.

Inquiries: Dr. Karen Teff - kt216q@nih.gov; Dr. Cristina Rabadan-Diehl - cr225k@nih.gov; Dr. Cindy Davis - davisci@mail.nih.gov

Exploratory Studies in Cancer Detection, Diagnosis,
and Prognosis
PA-05-165

Application Receipt Dates: New applications: Oct. 1, 2005; Feb. 1, June 1, and Oct. 1, 2006; Feb. 1, June 1, and Oct. 1, 2007; Feb. 1, June 1, and Oct. 1, 2008. Competing continuation, revised, supplemental applications: Nov. 1, 2005; March 1, July 1, and Nov. 1, 2006; March 1, July 1, and Nov. 1, 2007; March 1, July 1, and Nov. 1, 2008.

This is a renewal of PA-03-003. This funding opportunity will use the R21 award mechanism. For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=3128.

Inquiries: Dr. James V. Tricoli - tricolij@mail.nih.gov; Dr. Karl Krueger - kruegerk@mail.nih.gov; Dr. Heng Xie - xieh@ctep.nci.nih.gov

Name of the Trial
Phase II Study of Isolated Hepatic Perfusion with Melphalan followed by Leucovorin Calcium, Oxaliplatin, and Fluorouracil in Patients with Previously Untreated Unresectable Liver Metastases Secondary to Colorectal Cancer (NCI-05-C-0025). See the protocol summary at http://cancer.gov/clinicaltrials/NCI-05-C-0025.

Principal Investigator
Dr. H. Richard Alexander, CCR, NCI

Why Is This Trial Important?
Colorectal cancer is expected to cause more than 56,000 deaths in the United States in 2005. Mortality is high because colorectal cancer is usually diagnosed at an advanced stage when the cancer has metastasized (spread) to other parts of the body, most frequently to the liver. Almost 70 percent of deaths attributed to colorectal cancer occur in patients with liver metastases.

The only curative treatment available for liver metastases resulting from colorectal cancer is surgical removal (resection). However, most patients are not eligible for tumor resection because of the size, number, or location of their metastases.

In this study, researchers are combining local treatment of liver metastases through isolated hepatic perfusion (IHP) and standard systemic chemotherapy to determine whether this combined approach may prolong patients' lives. In IHP, the flow of blood to and from the liver is temporarily isolated from the rest of the body so that high doses of anticancer drugs, such as melphalan, can be delivered to the liver while sparing other tissues. Response rates to IHP in other clinical trials have been promising, with significant regression of visible metastases occurring in many patients.

However, patients with liver metastases are at high risk of having developed undetectable (occult) metastases elsewhere in the body. The researchers hope that following IHP with systemic chemotherapy may not only enhance the effects of IHP on detectable liver metastases but also eradicate occult metastatic tumors.

Who Can Join This Trial?
Researchers will recruit 30 colorectal cancer patients over 18 years of age who have been diagnosed with liver metastases. See the complete list of eligibility criteria at http://www.cancer.gov/clinicaltrials/NCI-05-C-0025.

Where Is This Trial Taking Place?
The study is taking place at the NIH Clinical Center in Bethesda, Md.

Contact Information
For more information, call the NCI Clinical Studies Support Center at 1-888-NCI-1937. The toll-free call is confidential.

Niederhuber Joins NCI as Deputy Director for Translational Research
Dr. John Niederhuber, who recently stepped down as chair of the NCAB, has been named NCI deputy director for Translational and Clinical Sciences, effective October 2. Dr. Niederhuber is a surgical oncologist and past director of the University of Wisconsin Comprehensive Cancer Center. He pioneered a totally implanted drug delivery system to provide continuous hepatic arterial infusion for patients with liver metastases from colorectal cancer. He also was the first to implant venous access devices, which proved to be an exceptional benefit for cancer patients receiving chemotherapy. He was supported for many years by the NCI extramural program as a laboratory investigator with interests in tumor immunology and cellular signaling pathways involved in abnormal cell growth.

NCI and NSF Partner to Support Nanotech Training
NCI and the National Science Foundation (NSF) announced this week a partnership that will prepare extramural, multidisciplinary researchers to apply nanotechnology to cancer diagnosis and therapy. The partnership, which provides $12.8 million to four institutions over 5 years, is part of NCI's Alliance for Nanotechnology in Cancer. Each award will support about 30 students and link the principal investigators' labs with local cancer centers and research institutions.

Recipients include: Dr. Diana Huffaker, University of New Mexico; Dr. Fernando Muzzio, Rutgers University; Dr. Srinivas Sridhar, Northeastern University; and Dr. Marjorie Olmstead, University of Washington. The awards are made through NSF's Integrative Graduate Education and Research Traineeship Program, which targets underrepresented groups in engineering, science, and mathematic doctoral programs. For more information go to http://nano.cancer.gov.

NCI Fellow to Ride in Tour of Hope
Dr. Keith Bellizzi, a DCP Cancer Prevention Fellow working in NCI's Office of Cancer Survivorship, is 1 of 24 cyclists riding in this year's Bristol-Myers Squibb Tour of Hope™. Dr. Bellizzi is a 10-year, two-time cancer survivor and a cancer researcher focusing on survivorship and aging, coping, and health behaviors.

On September 29, the Tour of Hope riders will begin their cross-country ride in San Diego. They will travel through California, Arizona, New Mexico, Texas, Louisiana, Mississippi, Alabama, Georgia, South Carolina, North Carolina, Virginia, and Maryland and conclude the ride on October 8 in Washington, D.C. Riders include cancer researchers, nurses, physicians, caregivers, and cancer survivors who will ride in relays. For more information, go to http://www.tourofhope.org.

Strathern Named Deputy Director of CCR-Frederick
Dr. Robert Wiltrout has appointed Dr. Jeffrey Strathern Deputy Director of CCR-Frederick. Dr. Strathern will work closely with senior CCR staff to ensure that the needs of CCR labs in Frederick are represented at the Division level, while also representing CCR in interactions with NCI-Frederick senior management. Dr. Strathern will work with the broad CCR research community, promoting the use of the Frederick campus' biotechnology and computational resources.

Dr. Strathern received his doctorate from the University of Oregon in 1977, and then joined Cold Spring Harbor Laboratory. In 1984, he accepted a post at the ABL-Basic Research Program at NCI's Frederick Cancer Research Development Center (now NCI-Frederick). In 1999, Dr. Strathern joined NCI's intramural program.

Study of Avastin in Ovarian Cancer Discontinued
On Friday, Genentech, Inc., announced that enrollment has been discontinued in a multicenter, single-arm phase II study of bevacizumab (Avastin) in platinum-refractory ovarian cancer patients because of a higher rate of gastrointestinal perforations than in previous studies with Avastin.

Enrollment was stopped after reports of 5 gastrointestinal perforations in the first 44 patients enrolled in the proposed 53-patient study. Though it is already known that Avastin use can result in gastrointestinal perforation, "We chose to discontinue enrollment…due to the observation of a higher rate seen in this study than in other trials of Avastin in ovarian cancer or other tumor types," said Dr. Hal Barron of Genentech.