Rare pancreatic cancer slowed by Pfizer drug

* Sutent study stopped after delayed progression seen

* Patients taking placebos allowed to switch to Sutent

* Pfizer shrs rise almost 10 percent, helped by drug study

By Ransdell Pierson

NEW YORK (Reuters) - A rare form of pancreatic cancer that has afflicted Apple Inc CEO Steve Jobs responded so well to Pfizer Inc's drug, Sutent, that a study was stopped early so all patients could take the pill.

An independent safety board monitoring the late-stage study recommended halting it after concluding that Sutent delayed progression of the cancer compared with people taking a placebo along with standard treatment, Pfizer said on Thursday.

Patients who took Sutent in the trial will be allowed to continue doing so, and those who were given placebos will now have the option of taking the drug.

Patients in the study had advanced pancreatic islet cell tumors, also known as neuroendocrine cancer. It occurs in specialized cells of the pancreas that secrete a variety of hormones, including insulin and enzymes involved in digestion.

Other types of pancreatic cancer occur in ducts of the pancreas -- small tubes that transport digestive enzymes produced in the pancreas to the small intestine.

"This form of pancreatic cancer involves only about 5 percent of all pancreatic cancer cases, and grows and spreads more slowly" than other types of pancreatic cancer, said Mace Rothenberg, a senior Pfizer research executive.

When surgery to remove the cancer is not possible, or when cancer returns after surgery, Rothenberg said life expectancy is only several years, and patients can experience difficult symptoms, such as life-threatening high levels of insulin and stomach ulcers.

Sutent is currently approved for treating advanced kidney cancer as well as gastrointestinal tract tumors.

JOBS HAD SURGERY

Jobs, who co-founded Apple Computer and turned it into a consumer juggernaut after returning as chief executive a decade ago, underwent surgery in 2004 to remove an islet cell tumor from his pancreas.

In January, Jobs said he would take a five-month medical leave because his health problems were more complex than originally thought.

The tech innovator acknowledged that he had been losing weight throughout 2008 and said his doctors determined a hormone imbalance had been depriving him of vital proteins. That triggered speculation that his cancer had returned and was upsetting hormones involved in digestion.

BLOCKBUSTER IN THE MAKING

Sutent, which had fourth-quarter sales of $220 million, is also undergoing late-stage studies against cancers of the breast, lungs, colon, prostate and liver.

Herman Saftlas, an analyst with Standard & Poor's, predicted on Thursday that Sutent would generate annual sales of $1.5 billion by 2013, up from his earlier view of $1.4 billion.

"Pfizer has had a lackluster history of drug development, but got some good news today," said Saftlas, adding that the trial results bolstered company shares in an already strong rally for the broad stock market.

Pfizer's stock was up 9.7 percent to $14.03 in afternoon trading, outpacing a 4.6 percent rise in the American Stock Exchange Pharmaceutical Index of large U.S. and European drugmakers.

(Additional reporting by Lewis Krauskopf; editing by Gunna Dickson)

MECHANISM OF SYNERGY OF LEUKEMIA DRUGS

Findings Shed Light on Synergy of Leukemia Drugs

NEW YORK (Reuters Health) Feb 27 - Prior research has shown that the novel proteasome inhibitor NPI-0052 and histone deacetylase inhibitors (HDACi) are much more effective against leukemia when given together than either agent alone. Now, new research clarifies the mechanisms involved in the synergy. In short, it appears that NPI-0052 and HDACi share certain functions.

In an earlier study, Dr. Joya Chandra, from MD Anderson Cancer Center in Houston, and colleagues showed that the drugs synergistically induce apoptosis in leukemic cells through mechanisms dependent on caspase-8 activation and oxidative stress.

To further explore the mechanisms, the research team began by focusing on the proximal targets of NPI-0052 and HDACi, namely, blockage of proteasome activity and histone acetylation.

The new findings are reported in Blood, prepublished online on January 30.

NPI-0052 was found to have functions similar to HDACi. Alone or in combination with HDACi, NPI-0052 induced hyperacetylation in leukemic cells. This hyperacetylation was attenuated in cells lacking caspase-8 or those treated with an antioxidant. "These results indicate that NPI-0052 is eliciting caspase-8- and oxidative stress-dependent epigenetic alterations," the authors explain.

Likewise, HDACi were found to have functions of NPI-0052. One HDACi tested had repressed expression of proteasomal subunits.

"Our results suggest that crosstalk by NPI-0052 and HDACi are contributing, along with caspase-8 activation and oxidative stress, to their cytotoxic effects in leukemia cells, reinforcing the potential clinical utility of combining these two agents," the researchers conclude.

PET/CT FOR INFLAMMATORY BREAST CANCER

PET/CT Useful for Initial Staging of Inflammatory Breast Cancer

NEW YORK (Reuters Health) Mar 03 - PET/CT is useful for the initial staging of inflammatory breast cancer (IBC), according to a report in the February Journal of Nuclear Medicine.

"IBC is a distinct and separate entity from common garden-variety cancer or early breast cancer," Dr. Wei-Tse Yang from the University of Texas M.D. Anderson Cancer Center, Houston, told Reuters Health. "PET/CT has found a role in this subset of patients, by outlining the extent of global and loco-regional disease, which in turn influences treatment strategy."

Dr. Yang and colleagues evaluated the accuracy of 18F-FDG PET/CT in the initial staging of IBC in 41 women with newly diagnosed, unilateral, primary IBC.

PET/CT showed hypermetabolic uptake in the affected breast in all but one patient, the authors report, and all patients had skin thickening.

PET/CT detected nodal metastases in 37 patients, which was confirmed by biopsy, the researchers note.

Distant metastases were found by PET/CT in 20 patients, including 7 patients with negative findings by other methods. Bone metastases were identified in 9 patients, liver metastases in 6 patients, pulmonary parenchymal metastases in 2 patients, and contralateral lymph node metastases in 7 patients.

"Although PET/CT is currently unable to allow clinicians to bypass all other imaging studies," the investigators say, "further prospective studies are warranted to determine the validity of these preliminary findings."

"We will be studying in greater detail the impact of SUV (standardized uptake values) as an aid in the diagnosis of metastases in the body in this subset of patients," Dr. Yang said.

"If validated, the cost of a PET/CT study in these patients may be equivalent to the total cost of imaging multiple organs and allow a single hospital visit and decreased imaging time, when compared with the time required for a battery of staging studies," the researchers add.

REVASCULARIZATION IN NONACUTE CAD

Meta-Analysis Shows Benefits of Revascularization in Nonacute CAD

NEW YORK (Reuters Health) Mar 02 - In patients with nonacute coronary artery disease (CAD), surgical or percutaneous coronary artery revascularization in conjunction with medical therapy yields a survival advantage compared with medical management alone, according to a systematic review and meta-analysis of relevant published studies.

While timely revascularization significantly improves outcomes in patients with acute coronary syndromes, data are scarce regarding the impact of revascularization on patients with nonacute CAD, Dr. Allen Jeremias from New York's Stony Brook University Medical Center and colleagues note in the February issue of the American Journal of Medicine.

They identified 28 randomized clinical trials of coronary revascularization (surgical or percutaneous intervention) versus medical therapy alone in patients with nonacute CAD. The studies, which were published from 1977 to 2007, involved a total of 13,121 patients, of whom 6476 were randomized to revascularization and 6645 to medical therapy alone. Follow-up ranged from 1 to 10 years, with a median of 3 years.

A random effects model was used to calculate odds ratios for the two prespecified outcomes - death and nonfatal myocardial infarction reported at a minimum follow-up of 1 year, Dr. Jeremias and colleagues explain.

"In this large meta-analysis, what we find is that there is, in fact, a significant benefit in terms of mortality reduction in patients who do get revascularization," Dr. Jeremias noted in an interview with Reuters Health.

The odds ratio for revascularization versus medical therapy for mortality was 0.74. In an analysis stratified by revascularization mode, both bypass grafting (OR 0.62) and percutaneous intervention (OR 0.82) were found to be superior to medical therapy in avoiding mortality.

Revascularization was not associated with a significant reduction in nonfatal MI compared with medical therapy (OR 0.91).

IONIZED CALCIUM AND PROSTATE CANCER

Ionized Serum Calcium a Potential Biomarker of Fatal Prostate Cancer

NEW YORK (Reuters Health) Feb 27 - New evidence indicates that elevated serum levels of ionized calcium may predict the risk of death from prostate cancer. If verified in future prospective studies, levels of ionized calcium in serum could assist physicians and patients in making decisions regarding treatment.

In a previous analysis of data from the National Health and Nutrition Examination Survey (NHANES I) study, Dr. Halcyon G. Skinner, at the University of Wisconsin-Madison, and Dr. Gary G. Schwartz at Wake Forest University in Winston-Salem, North Carolina, observed a link between elevated serum calcium and risk of fatal prostate cancer.

For their current report in the February issue of Cancer Epidemiology, Biomarkers & Prevention, the researchers examined associations between total and ionized serum calcium and prostate cancer fatalities among 6710 men examined between 1988 and 1994 for the NHANES III, which was linked to the National Death Index.

During a mean of 5.3 years of follow-up, there were 25 prostate cancer deaths. Average age at death was 78.1 years.

Compared with men in the lowest tertile, men in the highest tertile of total serum calcium had a relative risk for prostate cancer mortality of 2.02, after adjusting for sociodemographics, body mass index, and general health status.

The relative risk associated with ionized serum calcium corrected for serum pH was 3.12. After excluding three cases that died within the first 3 years of follow-up, the relative hazard in the highest tertile was 4.65.

In a Wake Forest press release, Dr. Schwartz comments that many men with prostate cancer are treated unnecessarily. "These new findings, if confirmed, suggest that men in the lower end of the normal distribution of ionized serum calcium are three times less likely than men in the upper distribution to develop fatal disease."

"These men may choose to delay treatment or perhaps defer it altogether," Dr. Schwartz added.

TAMOXIFEN SENSITIVITY CAN BE RESTORED

Tamoxifen Sensitivity Can Be Restored in Breast Cancer Cells

NEW YORK (Reuters Health) Feb 27 - Restoration of Wnt-5a signaling in breast cancer cells negative for estrogen receptor alpha (ER-alpha) upregulates expression of the receptor, making the cells susceptible to tamoxifen, investigators report in the February 23 early online edition of the Proceedings of the National Academy of Sciences.

"This novel approach of reconstituting ER-alpha expression... to render tumors responsive to current endocrine treatments could be of significant importance to future clinical management of breast cancer," the researchers conclude.

Dr. Caroline E. Ford and associates at Lund University in Malmo, Sweden, explain that Wnt-5a is a cell surface receptor ligand that increases adhesion and reduces migration of epithelial cells. Previous research has indicated that loss of Wnt-5a and ER-alpha expression tend to occur in tandem.

The researchers theorized that Wnt-5a regulates ER-alpha levels, and that restoring Wnt-5a signaling would reestablish ER-alpha positivity.

To test their theory, they treated several ER-alpha-negative breast cancer cell lines with recombinant Wnt-5a, which did restore mRNA and protein expression of the receptor.

After Wnt-5a stimulation, treatment of the cultured cells with the selective estrogen receptor modulator tamoxifen increased apoptosis and cell growth inhibition.

They replicated their findings in the cultured cells using a small-molecule Wnt-5a-derived hexapeptide (Foxy-5).

They also conducted an in vivo study, in which mice were inoculated with rapidly metastatic, ER-alpha negative breast cancer cells into their mammary fat pads. Treatment with Foxy-5 every 4th day for 25 days significantly upregulated ER-alpha expression compared with control treatment.

Because of its smaller size and binding characteristics that would enhance its distribution in the body, Dr. Ford's team predicts that a molecule such as Foxy-5 will have greater therapeutic potential than recombinant Wnt-5a.

They conclude: "Concordant treatment with a Wnt-5a-mimicking hexapeptide and currently available ER-alpha modulators may represent a novel and beneficial treatment strategy for breast cancer patients with ER-alpha-negative tumors."

HIGH FAT DIET AND METASTASIS

High-Fat Diet Dramatically Increases Cancer Metastasis

March 5, 2009 — Although the link between obesity and cancer is well established, exactly why there is a link remains unclear. Now, an animal study shows that a high-fat diet dramatically increases cancer metastasis, and offers a mechanistic explanation for what has been, up to now, anecdotal evidence.

The study was published online January 30 in BMC Cancer.

"These findings demonstrate than an increase in lipids leads directly to a rise in cancer metastasis", said senior author Ji-Xin Cheng, PhD, assistant professor at the Weldon School of Biomedical Engineering, Purdue University, in West Lafayette, Indiana.

The study was conducted in mice implanted with a tumor that metastasized, but there was a 300% increase in metastases in mice fed a high-fat diet, compared with those fed a lean diet. In addition, the researchers showed that the high-fat diet had a direct effect on cancer-cell membranes, which increased their aggressiveness.

The implication from this study is that patients who already have cancer could be increasing the risk of it spreading if they eat a high-fat diet, comments lead author Thuc Le, PhD, also from Weldon School of Biomedical Engineering.

However, when asked whether physicians should advise their patients about this, Dr. Le told Medscape Oncology that there are "many caveats."

"Firstly, our study was performed in laboratory animals," he noted. "It's unclear whether our observations hold true in humans."

"But, when our study is viewed in the context of many other clinical studies of human patients and the strong correlation between lipid-rich breast cancer and aggressive clinical behavior, including early death, then a link (albeit indirect) between high-fat diet and cancer aggressiveness should emerge," he added.

Dramatic Increase in Metastasis

The study was carried out in 32 mice implanted with a lung cancer cell line, injected subcutaneously into a hind leg. One group of animals was fed a lean diet (4.2% fat and 3.82 kcal/g) and the other was fed a high-fat diet (34.9% fat and 5.24 kcal/g).

The mice on the high-fat diet became "very sick" after 4 weeks, Dr. Le explained; this was "clearly due to a very high number of tumor colonies and very large tumor colonies in the lungs." These animals also "lost tremendous body weight and mobility. To minimize their suffering, they were euthanized on week 4."

In contrast, the mice fed a lean diet survived with normal weight and mobility until week 6, he added.

At 4 weeks after tumor implantation, there was a 3-fold increase in lung metastasis in mice on the high-fat diet, compared with mice on the lean diet.

There was a strong correlation between the high-fat diet and increased cancer metastasis, Dr. Le noted.

However, there may also be a more general conclusion. The mice on the high-fat diet had elevated visceral adipose tissue weight (belly-fat weight) and elevated levels of free fatty acids, and "these conditions are normally observed in obesity," Dr. Le pointed out. This suggests that obesity or a high-fat diet might accelerate cancer spread, he commented.

Increase in Circulating Tumor Cells

In addition, mice on the high-fat diet also showed an early increase in circulating tumor cells, with levels 3-fold higher than those seen in the lean-diet mice 2 weeks after tumor implantation. However, this difference gradually declined and became indistinguishable by week 4, the researchers note.

"We don't know the exact reason because we don't have direct evidence showing the whereabouts of the circulating cancer cells at all times," Dr. Le explained. However, one speculative explanation is that, in the mice fed the high-fat diet, the cancer cells escaped from the primary tumor and into the bloodstream (intravasion) at a faster rate than in mice fed the lean diet.

A more detailed study of the cancer cells themselves revealed a direct effect of the diet on the cancer-cell membrane. The researchers studied this using an imaging method known as coherent anti-Stokes Raman scattering, and they found "physical perturbations" in the cancer-cell membrane, which contributed to increased cancer aggressiveness.

In mice fed a high-fat diet, the increased lipid levels resulted in increased membrane phase separation and membrane rounding in cancer cells, which enhanced their ability to separate and spread through the body. The more rounded shape leads to reduced cell–cell adhesion and increased tissue invasion, the authors explain.

"If the cancer cells don't have excess lipids, they stick together and form very tight junctions in tumors, but increasing lipids causes them to take on a rounded shape and separate from each other," Dr. Le explained.

The team further demonstrated that linoleic acid, which is predominant in polyunsaturated fats, causes increasing membrane phase separation, whereas oleic acid, found in monounsaturated fats, does not.

PROTECTIVE EFFECT OF CAFFEINE

Protective Effect of Caffeine Against UV Damage Clarified

NEW YORK (Reuters Health) Feb 26 - New research suggests that caffeine protects human keratinocytes from UV damage and does this, at least in part, by inhibiting the ATR-Chk1 pathway.

In murine studies, both oral and topical caffeine have been found to induce apoptosis of UV-damaged keratinocytes and reduce the subsequent development of skin cancer, senior author Dr. Paul Nghiem, from the University of Washington, Seattle, and colleagues note. Whether this also occurs in human cells and the mechanisms involved were unclear.

According to the report published online February 26th by the Journal of Investigative Dermatology, caffeine did, in fact, more than double apoptosis of UVB-exposed human keratinocytes.

Further analysis suggested that caffeine targeted ataxia-telangiectasia and Rad3-related kinase (ATR) and checkpoint kinase 1 (Chk1) in inducing apoptosis of damaged keratinocytes. The researchers base that conclusion on the finding that silencing of these genes increased apoptosis of UV-damaged cells and that caffeine did not further enhance apoptosis when ATR had been depleted.

"These data suggest that a relevant target of caffeine is the ATR-Chk1 pathway and that inhibiting ATR or Chk1 might have promise in preventing or reversing UV damage," the authors conclude.