On Dec. 9 2004, the President signed the Omnibus Appropriations bill into law. As noted in the December 14 NCI Cancer Bulletin, the initial National Cancer Institute (NCI) appropriation increase was $141 million; however, after adjustments are made for rescissions, assessments, and mandatory increases, NCI starts with fewer dollars than in fiscal year 2004. Shortly following receipt of the FY 2005 budget, NCI's director and its senior management team reviewed all of the program needs from across NCI and established operating policies and paylines for Research Project Grants (RPGs). For this year - FY 2005 - the success rate for RPGs is expected to be 21 percent, or 1,346 competing RPGs; the R01 payline for percentiled grants is established at the 16th percentile; increases for competing renewal RPGs will range from 5 to 10 percent above current levels; and full cost-of-living adjustments will be provided for RPG noncompeting (type 5), nonmodular grants.

Last week, members of three key NCI advisory boards held a joint retreat to discuss issues facing the institute in light of diminishing resources. The meeting of the Board of Scientific Advisors (BSA), Board of Scientific Counselors (BSC), and National Cancer Advisory Board (NCAB), including the Chairs of the President's Cancer Panel and the Director's Consumer Liaison Group, served as a backdrop for what NCI Director Dr. Andrew C. von Eschenbach described as a discussion "not just about where we are, but where we want to be."

Acknowledging that essentially flat budgets are likely for the near future, Dr. von Eschenbach stressed that, nonetheless, "We are going to continue to grow, to become more innovative, more focused…and we're going to have to make tough decisions."

NCI's allocated budget for FY 2005 is up 1.8 percent from FY 2004. However, that full increase is not available to NCI to allocate for program initiatives. After covering reductions and assessments from outside NCI and approximately $110 million in continuing funding obligations within the RPG pool, NCI will actually start the year with approximately $62 million less than in FY 2004. The $110 million in existing commitments, Dr. von Eschenbach explained, is largely a result of the 80 percent increase in funding that NCI received during the period that the NIH budget doubled between 1998 and 2003. "With these increases, so grew our portfolio, and so grew our commitments," he said.

Dr. von Eschenbach noted that the majority of FY 2005 spending ($2.223 billion, or 46 percent), as it has been in the past, is directed toward RPGs. Funding for both RPGs and cancer centers will see a slight increase in FY 2005; funding for training, the cooperative research groups, specialized programs of research excellence, and the intramural program will remain essentially flat. In a flat budget scenario, he emphasized, growth in any area will require reductions elsewhere in NCI's portfolio.

Looking to FY 2006 and beyond, Dr. von Eschenbach reminded board members that they wear three hats: providing oversight of NCI activities, serving as stewards of taxpayer dollars, and advocating for a continued national commitment to cancer research. Breakout groups then discussed several questions and provided their perspectives on some of the most difficult issues facing NCI and the cancer research community, including how to best manage the RPG portfolio and protect young investigators.

As a result of the retreat, several topics that will be explored further by NCAB, BSA, and BSC at future meetings are the importance of finding ways to ensure continued innovation in research, promoting partnerships with industry and other outside groups, shoring up the peer review of grant applications to better recognize innovative projects, continuing to support training and new investigators, and finding new mechanisms to measure progress and evaluate programs.

By Brittany Moya del Pino

Al launched the NCI Combined Intramural Principal Investigator retreat as he introduced Dr. Susan Gottesman, the winner of the first annual Alan Rabson Award for NCI Intramural Research. Dr. Gottesman, of the Laboratory of Molecular Biology in NCI's Center for Cancer Research (CCR), has been with NCI for 28 years and is internationally recognized as a leader in identifying small RNA and its function.

Like Dr. Rabson, she too typifies dedication to public service and exemplary basic and clinical research. That same commitment to service and scientific excellence was on display among the investigators in attendance at the retreat, many of whom presented data from their research - a rich array of investigation being performed by researchers from CCR and the Division of Cancer Epidemiology and Genetics, often in collaboration with outside researchers.

The poster presentations at the retreat covered everything from basic research in cell signaling to development of predictive models to novel clinical interventions to cohort consortium studies and genetics determinants of cancer susceptibility. It's this sort of investigative diversity that makes the NCI intramural research program unique and so valuable to the overall cancer research enterprise.

The intramural retreat came just one day after the second annual retreat of three of NCI's primary advisory boards (see lead story), during which the participants grappled with how, given the current fiscal limitations facing biomedical research, NCI can continue its upward, forward-thinking trajectory. To be certain, budget limitations mean we need to make difficult but creative choices; hurdles must be overcome. At both meetings last week - and in every visit I have made to cancer centers or in meetings with advocacy groups - I am struck by the robust undercurrent of sincere optimism that our progress against cancer will not just continue, but accelerate.

In large part, I think that optimism is rooted in the cancer community's belief in its mission and the remarkable people who compose it. Whether it's NCI advisory boards or visits to NCI-funded cancer centers, there is unprecedented support for collaboration and team science, for new technologies, for revamping the clinical trials infrastructure, and for working with industry to sort through thorny issues such as intellectual property rights. So when somebody asks me why I'm so optimistic about our future, I can tell them it's because of this indefatigable momentum that I see every day - a momentum that will spur us to make the sort of reasoned, intelligent choices that will allow us to achieve the 2015 goal.

Dr. Andrew C. von Eschenbach
Director, National Cancer Institute

In the public perception, medical research involving animals is sometimes controversial and misunderstood. But a new program under the auspices of NCI's Center for Cancer Research (CCR) - the Comparative Oncology Program (COP) - may help change that view. "This program will provide pet owners with access to some very novel experimental options if their pet is stricken by cancer," says Dr. Robert Wiltrout, deputy director for science at CCR, "while also providing new information that may ultimately contribute to the treatment of cancer in humans."

COP is headed by Dr. Chand Khanna, a veterinarian and scientist who conducts research on cancer metastasis and basic cancer biology within CCR's Pediatric Oncology Branch. "Both before and during the clinical development of a new drug, there are many questions to be answered," says Dr. Khanna. "What we're suggesting is that we integrate these complicated, large-animal models with naturally occurring cancers to help answer those questions."

Key to the COP program, he says, is the fact that pet animals, such as dogs, share many features with human cancer patients. Dogs develop cancer spontaneously, share environmental risk factors with their human owners, and their genome is more closely related to humans than that of the mouse, a more typical research model. The types of cancer in dogs that could translate into results for humans include osteosarcoma, breast and prostate cancer, melanoma, non-Hodgkin's lymphoma, head and neck carcinoma, and soft-tissue sarcoma.

These facts have already come to the attention of the clinical trials community. Several veterinary teaching hospitals have agreements with comprehensive cancer centers to conduct comparative oncology trials parallel to human clinical research. But COP will offer the opportunity to conduct research on a much larger level through a consortium of university veterinary teaching hospitals.

"The goal is for the consortium members to start with small trials that answer questions about the biology and activity of a drug, with the help of NCI, but then to take the results towards larger trials, often working directly with pharmaceutical companies," says Dr. Khanna. "So far, we've had a very positive response from colleges of veterinary medicine, the FDA, and the pharmaceutical industry."

The COP consortium is still being developed, but Dr. Khanna plans to invite veterinary teaching hospitals around the country - and even overseas - to participate. "This organizational structure would greatly enhance our abilities to streamline the development of novel therapeutics," says Dr. David Vail, a veterinarian and professor of oncology at Colorado State University's Animal Cancer Center. "Pet owners, in general, are more than willing to enroll their companion animals in a clinical trial to pursue an honest and aggressive new approach to cancer, provided we can maintain good quality of life, and they are equally devoted to the creation of new information and treatments that could someday help people."

So what does COP mean for pet owners? Initially, explains Dr. Khanna, someone whose dog is diagnosed with cancer may be referred by their veterinarian to a local veterinary teaching hospital. If that hospital is a member of the COP consortium and is participating in a clinical trial for that dog's cancer diagnosis, the owner will have the option of enrolling their pet. Although these trials will be organized by COP staff at NCI, the animal patients will not be seen at the NIH campus, but at the veterinary teaching hospitals participating in the COP consortium. The COP Web site will eventually feature a list of all of the trials sponsored at the various consortium hospitals.

Conventional cancer treatments can cost thousands of dollars - Dr. Khanna estimates between $4,000 and $7,000 for a dog, though it can be much higher - but the COP trials are expected to be very low-cost, or free. "It is likely that pet owners will be asked to pay only for the initial evaluation, in the range of a couple of hundred dollars," he says.

Dr. Khanna also notes that COP trials will not be limited to the size or breed of dog, but rather by the type of cancer that a dog has. "Cats could be considered for these trials down the road, but at this point, we know a lot more about dogs. Their metabolism is much closer to that of humans, and there are more reagents available for them."

By Brittany Moya del Pino

On January 7 the US Food and Drug Administration (FDA) approved Abraxane for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Abraxane is the first in a new class of "protein-bound particle" drugs and consists only of albumin-bound paclitaxel nanoparticles. This new formulation of paclitaxel does not have to be dissolved in a toxic solvent or require steroids or special equipment for administration. The solvent needed to dissolve the original paclitaxel often causes severe allergic side effects requiring treatment with steroids, which can cause additional side effects.

Androgen Deprivation Therapy Increases Fracture Risk

Elderly prostate cancer patients taking androgen deprivation therapy have a greater risk of bone fractures compared with prostate cancer patients who don't use the increasingly popular treatment, according to a study published in the January 13 New England Journal of Medicine.

The potential for fracture risk from androgen deprivation therapy - whether through use of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy - has long been suspected. However, "our study is the first to provide an estimate of the risk of fracture attributable to androgen deprivation therapy by including prostate cancer patients not treated with androgen deprivation, and adjusting for known confounding variables," noted Dr. Vahakn B. Shahinian and colleagues from the University of Texas Medical Branch at Galveston.

The study is based on data from NCI's Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. It used a sample of 51,218 prostate cancer patients aged 65 and older who were first diagnosed between 1993 and 1997. After a follow-up period of 60 months, the researchers found that 19.4 percent of the androgen deprivation group had a fracture, versus 12.6 percent in the control group.

Authors cautioned that the "relatively modest hazard ratios found in our study could have a major adverse impact." The researchers estimated "there would be approximately 2,800 excess fractures per year attributable to GnRH agonist therapy." They noted a dramatic rise in use of GnRH agonists for treatment of early stages of the disease although "there has been no evidence from clinical trials of survival benefit."

Deficient DNA Repair Capacity Increases Breast Cancer Risk

By comparing female breast cancer patients with their healthy biological sisters, researchers at Columbia University found that the body's deficient ability to repair DNA damage may be "a valuable in vitro biomarker to identify high-risk subjects, especially in familial breast cancer families."

The study, in the January 19 issue of the Journal of the National Cancer Institute, compared blood tissue samples from sisters who participated in the Metropolitan New York Registry of Breast Cancer Families. This is one of six major sites funded by NCI as part of the Breast Cancer Family Registry.

Researchers exposed the sisters' lymphoblastoid cells in vitro to the chemical carcinogen benzo[a]pyrene diolepoxide (BPDE), which is known to cause DNA damage. They initially found that the number of BPDE-DNA adducts - bonds between the chemical and DNA - created were comparable between and across all subject groups. However, after allowing 4 hours for DNA repair to occur, they found that significantly more of the adducts had been removed in the healthy sisters' cells than in the cells of the breast cancer patients.

The cancer patients' cells were 8.6 percent less effective than their sisters' cells in responding to the mutagenic assault. Also, women who had the lowest levels of DNA repair capability had double the risk for breast cancer compared with women who had the highest capability. The largest differences were found between patients and controls younger than age 40. The relative risk of breast cancer was nearly 3 times greater between the groups with the most and the least DNA repair capabilities.

Findings from the new study echo results from previous studies on DNA repair capacity for lung cancer patients and their family members.

Diabetes and Cancer Risk Link Not Tied to Obesity

A prospective cohort study of almost 1.3 million Korean men and women confirmed previous research showing a link between increased levels of fasting serum glucose and an increased risk of various types of cancer. The NCI-funded study, published in the January 11 Journal of the American Medical Association, noted the additional finding that the risk wasn't related to the subjects' body weights because the Korean study population was "far leaner than the Western populations in other studies."

Overall, only about one-fourth of the men and women in the Korean Cancer Prevention Study (KCPS) had body mass index rankings greater than 25. As a consequence, the researchers explained, the study's findings "do not reflect confounding by obesity, suggesting that the mechanism of cancer risk reflects the consequences of hyperinsulinemia."

KCPS assessed the association between high levels of fasting serum glucose, or diabetes, with cancer risk. During the 10 years of follow-up since 1993, researchers found "linear trends in mortality with increasing serum glucose levels for all cancers combined and for cancers of several sites."

The strongest link was found with pancreatic cancer - an estimated two-fold increase in risk compared with nondiabetic men. KCPS also found significant associations with increased risk in men for cancers of the esophagus, liver, and colorectal system and increased risks for liver and cervix cancers in women.

The researchers reported that being overweight does increase the likelihood of developing glucose intolerance and that "may be one pathway by which obesity increases cancer risk."

Study Demonstrates Gene Expression Microarrays are Comparable and Reproducible

An NCI-funded study shows for the first time that independently prepared gene expression microarrays can produce highly comparable results. Four separate laboratories prepared microarrays on portions of the same set of samples; their comparisons, appearing in the January 15 Clinical Cancer Research, showed that overall correlation of similar samples was extremely high, and expression correlation between separate labs was only slightly lower than correlation within the same labs.

The potential clinical use of microarrays may require large-scale studies and necessitate that data be produced in different laboratories and subsequently combined for analysis. However, even if all procedures and equipment were standardized, small differences between labs could produce different profiles.

Twelve different tumor tissues, five cancer cell lines, and five purified RNA samples were blinded and randomized to one of four testing laboratories that followed a common protocol for all steps of sample preparation and microarray analysis. All within-lab profiles were highly reproducible and, while between-lab correlation values decreased slightly, expression profiles of all similar samples could be accurately grouped together. The researchers also found that laboratory practices comprised the smallest source of variation in the expression profiles; biological differences in the tissue samples were the largest source of variation.

"This evaluation is a key step in moving gene expression data from small-scale bench science into large-scale clinical practice," said Dr. James Jacobson, chief of NCI's Diagnostic Biomarkers and Technology Branch.

Featured Meetings and Events A comprehensive calendar of cancer-related scientific meetings and events sponsored by NCI and other scientific organizations, is available at: http://calendar.cancer.gov/

"The timing for this could not be better," said HHS Secretary Tommy Thompson, noting that January is the month for New Year's resolutions. "The guidelines offer Americans achievable goals for controlling weight, building stronger muscles and bones, and preventing chronic diseases." "They provide a blueprint for action, based on the latest and best science available," added USDA Secretary Ann Veneman.

The Dietary Guidelines for Americans are released every 5 years, as required by Federal law. They direct the practices of all government nutrition programs, including school breakfast and lunch programs; the Food Stamps program; the WIC nutrition program for women, infants, and children; and labeling practices. There are 41 recommendations in the new Guidelines, 23 for the general public and 18 for children, women who may become pregnant, and older adults.

The guideline development process began in 2003, when a panel of 13 scientists and physicians reviewed the literature on diet and health patterns; nearly a year later, they issued a report, which was then reviewed by government scientists and officials, and made available for public comment. The final guidelines were crafted from that initial report and feedback from these meetings.

Dr. Susan Krebs-Smith of NCI's Division of Cancer Control and Population Sciences (DCCPS), who was a member of the committee that helped draft the final report, said that the new guidelines are an important advance over earlier editions. "Rather than condensing the information into a handful of simple statements, they have expanded the number of key recommendations and clarified points that were only hinted at previously," she said. "Instead of saying, 'Eat less' of something, these guidelines give specifics," adds Dr. Rachel Ballard-Barbash, of DCCPS, who provided input as part of the peer review of the Guidelines.

The new Guidelines contain elements with particular relevance for cancer control efforts, says Dr. Ballard-Barbash. "Because of the increasing rate of obesity in the United States, the guidelines have a strong focus on weight control and physical activity, providing specific guidance in these areas," she says, noting that research within the last few years has identified the benefit of being physically active and avoiding weight gain for cancer prevention.

As a supplement to the 80-page Guidelines document, a 12-page consumer brochure, Finding Your Way to a Healthier You, is also available. Both documents can be downloaded from the Web at http://www.healthierus.gov/dietaryguidelines/; print copies can be ordered by phone after February 4 through the Government Printing Office toll free at 1-866-512-1800.

NIH Director's Pioneer Award Program
(NOT-OD-05-021)
In September 2005, NIH expects to make 5 to 10 new Pioneer Awards to provide individual scientists with up to $500,000 in direct costs per year for 5 years. Nominations may be submitted between March 1 and April 1 at http://nihroadmap.nih.gov/pioneer. See http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-05-021.html for the complete Pioneer Award announcement. Additional information about the High-Risk Research component of the NIH Roadmap is available at http://nihroadmap.nih.gov/highrisk/index.asp.

Multidisciplinary Clinical Research Career Development Programs
(RFA-RM-05-016)
This RFA will support the early career development of clinical researchers who would be expected to achieve excellence in their ability to design and oversee research in multidisciplinary team settings, and who have a high potential to become leaders of various fields of clinical research. The NIH Roadmap plans to provide approximately $4 million for this initiative in FY 2005. The complete RFA is available at http://grants1.nih.gov/grants/guide/rfa-files/RFA-RM-05-016.html. For more information on clinical research workforce training and re-engineering the clinical research enterprise, go to http://nihroadmap.nih.gov/clinicalresearch/overview-training.asp.

Principal Investigators
Dr. Antonio Tito Fojo and Dr. Michael Menefee (protocol chair), NCI Center for Cancer Research

Why Is This Trial Important?
Adrenocortical carcinoma is cancer that develops in the outside layer (cortex) of the adrenal gland. Surgery is the preferred method for treating adrenocortical carcinoma. However, patients with advanced cancer may have tumors that cannot be completely removed by surgery. Chemotherapy may be used alone or in combination with surgery to treat advanced adrenocortical carcinoma.

A drug called tariquidar may make cancer cells more sensitive to chemotherapy. Tariquidar inhibits a protein called p-glycoprotein, which is found in high amounts on adrenocortical carcinoma cells. This trial combines tariquidar with chemotherapy to treat adrenocortical carcinoma. Selected patients may undergo surgery after achieving their best response to chemotherapy.

"This trial is the second of two trials to evaluate the effect of inhibiting p-glycoprotein in the treatment of adrenocortical cancer," said Dr. Menefee. "The first trial added the drug mitotane to combination chemotherapy, and with this trial we are adding tariquidar, a more potent p-glycoprotein inhibitor, to the mitotane and chemotherapy regimen.

"We believe that effective inhibition of p-glycoprotein may increase the response rate of systemic chemotherapy in adrenocortical carcinoma," Dr. Menefee explained.

Who Can Join This Trial?
Researchers seek to enroll up to 47 patients aged 18 and over who have recurrent, metastatic, or primary unresectable adrenocortical carcinoma. See the list of eligibility criteria at http://cancer.gov/clinicaltrials/NCI-04-C-0011

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

Contact Information
For more information, call the NCI Clinical Studies Support Center (CSSC) at 1-888-NCI-1937. The CSSC provides information about cancer trials taking place on the NIH campus in Bethesda, Md. The call is toll free and confidential.

	CCR Grand Rounds
	January 25: Dr. Carter Van Waes, Clinical Director, National Institute on Deafness and Other Communication Disorders, Principal Investigator, Radiation Oncology Sciences Program, CCR, NCI; "Nuclear Factor-kappaB in Regulation of Gene Expression and as a Target for Molecular Therapy in Head and Neck Cancer" February 8: Dr. J. Carl Barrett, Director, CCR, NCI; "Biosystems and Cancer: Implications for Cancer Development and Therapy"

The new and returning members make up a group that has had personal and professional experience with cancer in a broad spectrum of disease sites, including kidney, ovarian, breast, and prostate cancers and leukemia and lymphoma. The members are active in survivor and community groups and represent underserved populations.

Launched in 1997, the DCLG - a federally chartered committee - was the first all-consumer advisory board at NIH. The DCLG's 15 members, headed by Doug Ulman, advise NCI's director about a wide variety of issues, programs, and research priorities from the perspective of people whose lives are affected by cancer. For more information and a listing of DCLG members, go to http://la.cancer.gov/dclg.html.

NCI Scientists to Speak at Gordon Conference
The Gordon Research Conferences will present "New Frontiers in Cancer Detection and Diagnosis" January 16-21, in Buellton, Calif.

Drs. J. Carl Barrett, Peter Greenwald, Richard Simon, and Sudhir Srivastava, all of NCI, will speak about molecular basis for early detection, biomarker validation methodology, and high throughput technology enabling cancer detection.

The Gordon Research Conferences provide an international forum for the presentation and discussion of frontier research in the biological, chemical, and physical sciences and their related technologies. For more information, go to http://www.grc.org/programs/2005/newfront.htm.

NCI Launches Nanotechnology Seminar Series
NCI will host a new lecture series featuring innovative perspectives on current research and development efforts in nanotechnology applied to cancer diagnosis, treatment, and prevention, presented by leaders from both the cancer and nanotechnology research communities. The inaugural lecture, to be held on Thursday, Jan. 27, will feature Dr. Esther Chang, professor of oncology and otolaryngology at the Lombardi Comprehensive Cancer Center. Her lecture, "Tumor Targeting Nanodelivery Systems: Expanding the Potential for Cancer Therapy and Diagnosis," will be held from 2:00 to 3:00 p.m. in Balcony B, Natcher (Building 45), on the NIH campus.

This presentation will be webcast at http://videocast.nih.gov. Sign language interpreters will be provided. For more information on the lecture, visit http://nano.cancer.gov/events_nanotech_seminar_series.asp.