Coffee drinking improves hepatitis C treatment response, study suggests

ScienceDaily (June 8, 2011) — Advanced hepatitis C patients with chronic liver disease may benefit from drinking coffee during treatment, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute. Patients who received peginterferon plus ribavirin treatment and who drank three or more cups of coffee per day were two times more likely to respond to treatment than non-drinkers.

See Also:Health & MedicineLiver DiseaseChronic IllnessDiseases and ConditionsPlants & AnimalsVirologyFoodVeterinary MedicineReferenceHealth benefits of teaHepatitis BHepatitisHepatitis A

"Coffee intake has been associated with a lower level of liver enzymes, reduced progression of chronic liver disease and reduced incidence of liver cancer," said Neal Freedman, PhD, MPH, of the National Cancer Institute and lead author of this study. "Although we observed an independent association between coffee intake and virologic response to treatment, this association needs replication in other studies."

Among non-drinkers, 46 percent had an early virologic response; 26 percent had no detectable serum hepatitis C virus (HCV) ribonucleic acid at week 20; 22 percent had no detectable serum at week 48; and 11 percent had a sustained virologic response. In contrast, the corresponding proportions for those who drank three or more cups of coffee per day were 73 percent, 52 percent, 49 percent and 26 percent, respectively.

Approximately 70 to 80 percent of individuals exposed to HCV become chronically infected. Worldwide, these individuals are estimated to number between 130 and 170 million. Higher coffee consumption has been associated with slower progression of pre-existing liver disease and lower risk of liver cancer. However, the relationship with response to anti-HCV treatment had not been previously evaluated. Treatment with peginterferon and ribavirin resolves chronic hepatitis C in about half of patients. It is unknown whether coffee will improve response with the addition of new drugs that were recently approved for use in the U.S.

Because patients in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial also had previously failed interferon therapy, it is not clear whether the results can be generalized to other patient populations. Future studies among patients with less advanced disease, those who are treatment-naïve to prior therapy, or who are being treated with newer antiviral agents are needed.

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New drug treatment extends lives of men with prostate cancer

ScienceDaily (May 28, 2011) — A drug recently approved by the Food & Drug Administration for the treatment of prostate cancer is proving to give some patients the gift of time. A new study shows abiraterone acetate extends the lives of men with the most advanced form of the disease by about four months.

See Also:Health & MedicineProstate CancerMen's HealthPersonalized MedicineColon CancerDiseases and ConditionsProstate HealthReferenceClinical trialDouble blindUrologyMetastasis

The study in the May 26, 2011 issue of the New England Journal of Medicine was co-authored by Thomas W. Flaig, MD, medical oncologist at the University of Colorado Hospital's Tony Grampsas Urologic Oncology Clinic and assistant professor at the University of Colorado School of Medicine.

"Abiraterone acetate is a new, life-extending pill for the treatment of advanced prostate cancer. Unlike the traditional chemotherapy drugs used in these situations, abiraterone is generally very well tolerated," said Flaig.

The multi-center Phase III clinical trial of 1195 participants looked at the effectiveness of treating patients who had received prior chemotherapy with a combination of abiraterone acetate (ZytigaTM ) and prednisone. When this trial was initiated, there were no treatments that clearly prolonged survival in this late phase of prostate cancer. The patients were randomized to receive abiraterone acetate plus prednisone or a placebo plus prednisone each day. Treatment continued until the cancer progressed, there were unfavorable reactions, a new treatment was initiated or the patient withdrew from the trial.

The study shows participants taking abiraterone acetate lived about four months longer than participants taking the placebo. In addition, more patients receiving abiraterone acetate experienced a significant drop in the PSA blood level than those on the placebo.

"The survival benefit observed in this study is especially notable, since this was seen in the most advanced cases of prostate cancer," said Flaig. "Other studies are being done to examine the benefit of using abiraterone acetate earlier in the disease process, where it may be even more effective."

The FDA approved abiraterone acetate at the end of April. The tablet has few side effects but careful medical attention is required to monitor for specific potential side effects including liver blood test changes, low potassium levels, leg swelling and high blood pressure.

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Targeted testing offers treatment hope for ovarian cancer patients

ScienceDaily (May 31, 2011) — Women with ovarian cancer could be helped by a new test that identifies the specific type of tumour they have, a conference will hear this week.

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Researchers at the University of Edinburgh hope this improved diagnosis will help doctors to personalise treatment programmes so that patients receive the most effective drugs.

The Edinburgh team worked with scientists from Ireland to identify six subgroups of the disease, each of which had a different genetic signature.

To do this, they analysed tissue samples from more than 350 ovarian cancer patients and compared this information with the patients' medical records.

The results show how genetic profiling of ovarian cancers might predict a person's response to drug treatments.

Researchers say the development may be particularly helpful for women with an aggressive form of ovarian cancer, which is typically caught late by current diagnostic tests.

This type of aggressive -- or 'high grade' -- cancer can respond well to a recently-developed drug that targets the blood supply of the cancer cells.

The team hopes that by identifying the women with this type of cancer at the earliest opportunity, they could use the drug more effectively and help to improve survival rates.

The findings will be presented at the American Society of Clinical Oncology (ASCO) conference, being held in Chicago this week.

Dr Charlie Gourley of the University of Edinburgh, who led the study, said: "This research shows that by conducting a detailed analysis of the genes of ovarian cancers we may be able to identify those patients who will respond well to new drug treatments. This could bring valuable improvements in survival rates for the disease and would help us to personalise a patient's care to ensure the greatest possible success."

Ovarian cancer is the fifth most common cancer in women, with around 6,800 women being diagnosed every year in the UK.

Of these, nearly two-thirds will not live beyond five years of their diagnosis.

Chemotherapy and surgery can be effective treatments, but women could have a greater chance of surviving the disease if it is identified earlier on.

The findings will be presented at ASCO on the 4th of June.

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Gene change identifies brain cancer patients that respond better to treatment

ScienceDaily (May 31, 2011) — New research proves that a change in a particular gene can identify which patients with a specific kind of brain cancer will respond better to treatment. Testing for the gene can distinguish patients with a more- or less-aggressive form of glioblastoma, the most common and an often-fatal type of primary brain cancer, and help guide therapy, the researchers say.

See Also:Health & MedicineBrain TumorPersonalized MedicineGene TherapyMind & BrainStrokeHuntington's DiseaseDepressionReferenceGliomaTumor suppressor geneMetastasisClinical trial

The prospective study looked at a gene called MGMT in tumors removed from 833 glioblastoma patients. It showed that when the gene promoter is altered by a chemical change called methylation, patients respond better to treatment.

"We show that MGMT methylation represents a new genetic test that can predict clinical outcomes in glioblastoma patients who have been treated with radiation combined with the chemotherapeutic drug temozolomide," says coauthor Dr. Arnab Chakravarti, chair and professor of Radiation Oncology and co-director of the brain tumor program at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute (OSUCCC -- James).

"Clearly, all glioblastomas are not the same. Rather, they are a collection of different molecular and genetic entities that behave uniquely and require personalized treatment," says Chakravarti, who is the translational-research study chair for the study.

Principal investigator Dr. Mark Gilbert, professor of neuro-oncology at M.D. Anderson Cancer Center, will present the research June 5, 2011, at the 2011 American Society of Clinical Oncology annual meeting in Chicago. It comes from a prospective international phase III clinical trial sponsored by the Radiation Therapy Oncology Group (RTOG).

"Our study confirms the prognostic significance of MGMT gene methylation and demonstrates the feasibility of prospective tumor-tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial," Gilbert says.

A tentative indication that MGMT methylation status might have prognostic importance emerged from an earlier retrospective study sponsored by the European Organisation for Research and Treatment of Cancer (EORTC).

The current study (RTOG 0525) validates that finding. Patients with tumors carrying the methylated gene had an overall survival of 21 months versus 14 months for those with the unmethylated gene. The difference in progression-free survival -- the period after treatment during which cancer does not worsen -- was 8.7 months and 5.7 months for methylated versus unmethylated tumors respectively. The narrow difference, Chakravarti says, indicates that patients with the methylated gene had slower growing tumors.

About 18,500 new cases of glioblastoma multiforme are expected annually in the U.S., and 12,760 Americans are expected to die of the disease. Symptoms often include headache, seizures and motor or sensory changes. A brain scan detects the tumor. After a surgeon removes the tumor, it can be tested for MGMT methylation.

"Patients with the methylated gene could receive the standard treatment, radiation therapy plus the chemotherapeutic drug temozolomide," Chakravarti says. "Those with an unmethylated gene might receive an experimental treatment through a clinical trial."

Research is now needed, he says, to learn whether MGMT contributes directly to tumor aggressiveness, or whether it is just an indicator of other changes that cause tumor aggressiveness. "If the gene itself helps cause aggressive disease, MGMT or related DNA repair pathways might be an important targets for a novel therapies," Chakravarti says.

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Cancer drug holds promise as first treatment for common, inherited dementia

ScienceDaily (June 1, 2011) — A drug already approved for people with cancer shows early potential as a therapy for a common form of dementia, UT Southwestern Medical Center researchers report.

See Also:Health & MedicineAlzheimer's ResearchDiseases and ConditionsHealthy AgingMind & BrainAlzheimer'sDementiaDisorders and SyndromesReferenceDementia with Lewy bodiesDementiaHuntington's diseaseTransmissible spongiform encephalopathy

"Suberoylanilide hydroxamic acid (SAHA) holds promise as a first-generation drug for the prevention and treatment of familial frontotemporal dementia (FTD), a progressive, inherited neurodegenerative disease for which there is no treatment," said Dr. Joachim Herz, director of the Center for Alzheimer's and Neurodegenerative Diseases and the study's senior author.

"SAHA is already approved for clinical use in an unrelated condition, which should make it easier to move quickly to human trials," added Dr. Herz, professor of molecular genetics and neuroscience at UT Southwestern.

FTD -- usually diagnosed around age 60 -- trails only Alzheimer's disease among non-elderly dementias. The as-yet untreatable condition is marked by a progressive deterioration in decision-making ability, behavioral control and/or language skills.

In a study available online and in the current issue of the Journal of Biological Chemistry, UT Southwestern researchers from the Alzheimer's Center, the Harold C. Simmons Comprehensive Cancer Center and the Protein Chemistry Technology Center showed that SAHA increased the cell-signalling protein progranulin (GRN) levels in a dose-dependent way in cultured mouse cells and also demonstrated that it restored near-normal GRN production in cells from human subjects with FTD.

Up to 25 percent of patients with FTD have an inherited form of the disease that is thought to be caused by one of several genetic mutations that reduce production of GRN, Dr. Herz said. Because familial FTD patients inherit one working copy of the GRN gene and one mutated one, the researchers wanted to identify a drug that would make the working copy of the gene work harder.

In an attempt to move as quickly as possible from basic science to clinical trials, the team established a method to quickly screen 1,200 drugs that already had Food and Drug Administration approval. SAHA emerged as the most active of the chemicals they screened, said lead author and graduate student Basar Cenik, who works in the laboratories of both Dr. Herz and co-senior author Dr. Gang Yu, associate professor of neuroscience.

SAHA is in a class of drugs called histone deacetylase inhibitors, and is approved for use in a cancer called cutaneous T-cell lymphoma.

"We found a drug that can overcome the chemical deficiency associated with the condition, and we showed that it worked in cells taken from humans with FTD," Dr. Yu said.

It is not yet known if the drug will efficiently cross the blood-brain barrier, a biologically protective system that keeps many chemicals from reaching the brain, Dr. Yu said. The next research step, he said, will be to screen larger chemical libraries in an effort to find other promising GRN-stimulating drugs for human trials.

Drs. Herz and Yu are both investigators for the Consortium for Frontotemporal Dementia Research and are working toward human trials with that national network, which is based at the University of California at San Francisco.

Other UT Southwestern authors are Drs. Chantelle Sephton, Wenze Niu and Daniel R. Dries, all postdoctoral researchers of neuroscience; Colleen Dewey, graduate student in neuroscience; Dr. Xunde Xian, postdoctoral researcher of molecular genetics; Dr. Shuguang Wei, senior research scientist of biochemistry; Dr. Bruce A. Posner, associate professor of biochemistry; and Kimberly Yu, summer high school intern researcher. Researchers from the University of California, Los Angeles, the Gladstone Institute for Cardiovascular Disease, the University of Massachusetts Medical School, and the University of California, San Francisco also participated in the research.

The study received support from the National Institutes of Health, the Consortium for Frontotemporal Dementia Research, the California Institute for Regenerative Medicine, the National Cell Repository for Alzheimer's Disease, the Ted Nash Long Life Foundation, the Welch Foundation, the Humboldt Foundation and the American Health Assistance Foundation.

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Kidney cancer discovery could expand treatment options

ScienceDaily (June 1, 2011) — Oregon Health & Science University Knight Cancer Institute researchers uncovered a gene that may be the key to helping kidney cancer patients who don't respond to current therapies. This discovery could also provide a toolkit to identify patients who are most likely to benefit from drugs that block this gene from causing cancer cells to grow.

See Also:Health & MedicineCancerKidney DiseaseBrain TumorLung CancerColon CancerBreast CancerReferenceMetastasisNanomedicineClinical trialRenal cell carcinoma

The OHSU study, published in the June 1 edition of Science Translational Medicine, identified a gene called Src that helps certain kidney cancers grow. Discovering that Src plays a role in kidney cancer could help in delivering more effective, individualized treatments to patients, said George Thomas, M.D., the study's senior author and a surgical pathologist at the OHSU Knight Cancer Institute.

The next step, Thomas said, is initiating clinical trials to test how these tumors respond to drugs already available and approved by the FDA.

There are many implications for the Src findings. Last year alone, kidney cancer accounted for about 58,000 new cases of cancer and 13,000 deaths in the United States. More than a quarter of these patients have metastatic disease when their cancer is discovered, and patients who are treated with surgery frequently relapse.

Currently, treatment of kidney cancer is primarily focused on blocking the formation of new blood vessels. While this strategy has been successful in the short term, it does not cure the patient and, more importantly, there are subgroups of patients who don't experience any benefit from these drugs.

"Our preclinical tests found that cancer cells that have increased Src activity were more sensitive to dasatinib (Sprycel), an FDA-approved drug that inhibits Src, both in tissue culture and when grown as tumors in mice," Thomas said.

But there's also a kicker. Thomas and his colleagues developed a panel of clinical markers that could potentially select patients most likely to benefit from Src inhibitors.

Thomas credits the multidisciplinary approach for the study's success. The importance of Src was discovered because of a sophisticated mass spectrometry based assay, called a phospho-proteomics that analyzes activated proteins.

"We had hypothesized that phospho-proteomic screens could rapidly uncover proteins that could be targets for drugs, so that is why we pursued this line of research," Thomas said.

When the screening process suggested that the Src signaling network was activated, indicating that it was playing a role in the growth of cancer cells, it was a surprise. "Src was certainly was not on my radar," Thomas said.

The next step was to look at the role of Src expression in tumor tissues from patients who had previously had their kidney cancers removed.

"We found that patients with tumors expressing high levels of Src had worse survival rates than those patients whose tumors had weak expression of Src. This suggested to us that Src played a role in kidney cancer and that it was a therapeutic target worth exploring."

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Stem cell treatment to prevent leukemia returning is a step closer, say scientists

ScienceDaily (June 3, 2011) — Researchers at King's College London have identified a way of eliminating leukemic stem cells, which could lead to new treatments that may enable complete remission for leukemia patients. An early study in mice has shown that leukemic stem cells can be abolished by suppressing two proteins found in the body.

See Also:Health & MedicineStem CellsLeukemiaProstate CancerSkin CancerLymphomaCancerReferenceEmbryonic stem cellStem cell treatmentsLeukemiaSomatic cell

Leukemic stem cells sustain the disease and are likely to be responsible for relapse, so elimination of these cells is believed to be key for achieving complete remission. These encouraging findings highlight the two proteins as potential therapeutic targets to prevent the most aggressive forms of leukemia returning. The study, funded by Cancer Research UK and leukemia Lymphoma Research, is to be published in the journal Cell Stem Cell.

King's scientists looked at leukemic stem cells found in a type of leukemia that involves mutations of the MLL gene. This accounts for around 70 per cent of infant leukemias and 10 per cent of adult acute leukemias. The prognosis for MLL in children is not good -- only 50 per cent survive past two years after receiving standard treatment.

The protein Bmi1 was already known to play a key role in the survival and proliferation of various cancer stem cells. But this study has for the first time shown that, although the protein is needed for survival of various Acute Myeloid leukemia (AML) cells, in MLL leukemia the cancer stem cells actually survive independently of Bmi1. This shows that for these MLL patients, targeting Bmi1 alone would not have a major impact on eradicating leukemic stem cells, as was previously thought.

However, the team also found high levels of another protein called Hoxa9 in the MLL mice and human patients. Similar to Bmi1, a major role of this protein is to ensure leukemia cells divide and grow by allowing their escape from the inherent surveillance system, which will otherwise cause cell death. They found that in mice with MLL leukemic stem cells (that can proliferate without Bmi1), suppression of both Bmi1 and Hoxa9 completely abolishes the ability of MLL mutation to induce leukemia.

These findings provide evidence for the different pathways involved in the development of different types of leukemic stem cells, and highlight the importance of targeting Bmi1 and Hoxa9 together to abolish MLL leukemic stem cells in particular.

Professor Eric So, Head of the leukemia and Stem Cell Biology group at King's, said: 'These findings take us a step forward in our understanding of how this devastating disease can return in patients after they have received the standard treatment.

'Now we know that leukemic stem cells in certain types of leukemia, such as MLL, can survive and proliferate independently of the Bmi1 protein, we need to consider more carefully the future of stem cell therapy to treat the disease. It's not as easy as people originally thought it might be.

'But these findings provide us with vital information that will help us look at alternative ways of combating different forms of the disease, which will ultimately allow patients to achieve long-term complete remission.

'What we need to do now is to find out exactly how Bmi1 and Hoxa9 proteins sustains the growth of cancer cells in order to develop an effective treatment to stop the disease returning.'

Professor Peter Johnson, Cancer Research UK's chief clinician, said: 'This study builds on previous Cancer Research UK-funded work trying to pinpoint the molecules responsible for driving the development of MLL-related leukemia stem cells.

'Cancer stem cells appear to be more resistant to radiotherapy and chemotherapy than the other leukemia cells, so understanding how they originate -- and how we can kill them -- will be a major step in being able to help even more people survive leukemia in future.'

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Possible new target for sarcoma treatment and prevention

ScienceDaily (May 23, 2011) — Researchers from Mount Sinai School of Medicine have discovered a protein signaling pathway that becomes hyperactivated in human sarcoma cells, suggesting that medications to inhibit this pathway may be effective in the treatment of human sarcomas. The research is published in the current issue of the journal Cancer Cell.

See Also:Health & MedicineStem CellsLymphomaBrain TumorCancerLeukemiaSkin CancerReferenceTumor suppressor geneTumorMetastasisHeat shock protein

A team of researchers led by Stuart Aaronson, MD, Jack and Jane B. Aron Professor and Chairman of the Department of Oncological Sciences at Mount Sinai School of Medicine, compared normal human mesenchymal stem cells to human sarcoma cells and found that the sarcoma cells displayed hyperactive signaling along the Wnt pathway -- a complex network of proteins that interact with each other in a highly ordered manner to regulate numerous biological functions of various species.

The hyperactive Wnt signaling increased the growth of several subtypes of human sarcoma cells by increasing the expression of CDC25A, a gene previously shown to be deregulated in various types of cancer. Increased protein levels of CDC25A enhances the rate of cell proliferation, and cancer cells often exhibit very high CDC25A protein levels compared to normal cells.

"The prevalence of Wnt signaling hyperactivity in human sarcoma cells gives researchers a potential new target as they develop medications to target human sarcoma," said Dr. Aaronson.

"Since several cancer types show increased CDC25A levels, it is regarded as a good target to generate therapeutic agents to dampen its functions and thus will be an important candidate in future drug development," said Sapna Vijayakumar, PhD, Instructor of Oncological Sciences, Mount Sinai School of Medicine, who was the first author of the study.

Normal Wnt functioning is critical for maintaining tissue homeostasis. Hyperactive (deregulated) Wnt signaling is reported to be one of the early causes of colon cancer, and it is also implicated in several other cancer types.

In many instances, hyperactive Wnt signaling increases the expression of certain genes that cause the cell to proliferate faster than normal. This uncontrolled proliferation, often accompanied by additional changes in gene or genes independent of Wnt signaling, can transform a normal cell into a cancerous one.

Sarcomas comprise about one percent of all adult cancers, but about 15 percent of all childhood cancers. There are many sarcoma "subtypes" that can arise from a variety of connective tissue structures, including nerves, muscles, joints, bone, fat, and blood vessels. The most frequent location for sarcomas are the limbs, where the majority of the body's connective tissue is located. About 20 percent of sarcomas are curable by surgery, while 30 percent can be cured by surgery with chemotherapy and/or radiation. About 12,000 new cases are diagnosed in the US each year and about 5,000 people die each year from sarcoma.

Sarcomas are subtyped based on where they occur in the body (in the bone, they are called osteosarcoma, in the smooth muscle they are leiomyosarcoma, in the cartilage they are chondrosarcoma, and so on). Studies suggest that even though sarcomas can occur in any part of the body, they commonly arise from the transformation of mesenchymal stem cells.

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Lipofilling may be safe during conservation treatment for breast cancer, study suggests

ScienceDaily (May 24, 2011) — A new study has gone some way to answering the question about whether or not a technique called lipofilling is safe for women who are having their breasts reconstructed after surgery for breast cancer.

See Also:Health & MedicineBreast CancerWomen's HealthCancerLung CancerBrain TumorLeukemiaReferenceBreast reconstructionMetastasisMammographyMenopause

Lipofilling involves taking some fat from another area of a woman's body, such as her abdomen, and using it to fill in small defects or asymmetry that may occur during breast reconstruction. However, until now, there has been a lack of evidence as to whether or not the technique could trigger a recurrence of the original breast cancer, and so plastic surgeons have not been able to advise patients fully on the pros and cons of lipofilling, despite the fact that it has been used for over 30 years.

Now, a study published in the cancer journal Annals of Oncology suggests that lipofilling seems to be a safe procedure for breast cancer patients, although the authors say that longer follow-up and more research is required in order to confirm their findings.

The researchers analysed data on 321 women who had been operated on for primary breast cancer at the European Institute of Oncology (IEO) in Milan, Italy, between 1997 and 2008, and who had then had lipofilling as part of their breast reconstruction. These women were matched with double the number (642) of women who had also had surgery for primary breast cancer, but who did not undergo lipofilling.

The researchers followed up the women for an average of 56 months from the time of the primary surgery and 26 months from the lipofilling. They found that eight women in the lipofillling group and 19 women in the control group had a local recurrence of their cancer -- a difference that was not statistically significant. When they analysed the data to look specifically at recurrences in women with non-invasive cancer (in situ cancer) they found there were three cases of recurrence in the lipofilling group and none in the control group; this was statistically significant, but may have been affected by the very small numbers involved, the short follow-up and the fact that there were no recurrences in the control group despite previous research suggesting there should be an average recurrence rate of over two percent during this period of time. "This indicates there might have been some bias in the selection of the women with non-invasive breast cancer in the control group," explained one of the authors, Professor Jean Yves Petit.

Prof Petit, from the Division of Plastic Surgery at the IEO in Milan, said: "To date, only a few studies have focused on cancer recurrences after lipofilling, and this is the first case-control study to investigate the question and the first publication to show the safety of the procedure. Our overall results do not find any difference in recurrences between the women in the lipofilling and control groups. However, it is still too early in the follow-up to be able to draw any definitive conclusions. We urge other teams working in the same field to gather their own results concerning local recurrences after lipofilling in breast conservation treatment."

This study is important because other, experimental work in the laboratory has shown that fatty tissue is capable of producing growth factors that can trigger cancer cells to multiply. This raised the question of whether this might happen in humans.

"Work by other researchers has shown that secretions from transplanted fat tissues can stimulate angiogenesis

New discoveries about tumor-suppressing protein could help reduce treatment side effects

ScienceDaily (May 12, 2011) — Researchers at the Stanford University School of Medicine have untangled two distinct ways in which a common, naturally occurring "tumor-suppressor" protein works. The separation of these two functions -- which can have quite different consequences -- could enhance efforts to develop treatment approaches that mitigate the sometimes-devastating side effects of radiotherapy and chemotherapy.

See Also:Health & MedicineBrain TumorGenesLung CancerCancerBreast CancerColon CancerReferenceTumor suppressor geneBRCA1TumorBRCA2

The protein, p53, is mutated or missing in more than half of all human cancers, and most cancers involve at least some compromise in its function.

Cancer is caused by two categories of mutations: those that activate oncogenes, whose protein products drive cells into overzealous replication, and those that disable tumor-suppressor genes, which code for proteins that sense this abnormal behavior and put the brakes on it.

"We knew that p53 responds to two different types of signals: DNA damage and oncogene activity," said Laura Attardi, PhD, associate professor of radiation oncology and of genetics. "We wanted to know if p53 responds to both in the same way." Attardi is senior author of a study to be published May 13 in Cell that throws light on crucial molecular details about how p53 works.

It is widely understood that p53 can temporarily or permanently shut down cell division in response to either acute damage to a cell's DNA or biochemical signals within a cell that suggest it's prone to becoming a cancer cell. In extreme cases, p53 convincingly counsels the cell to commit suicide, thereby preventing the possibility of a tumor arising.

Attardi and her colleagues created bioengineered mice in which various parts of p53 were incapacitated. This allowed them to determine which genes are activated by different parts of the protein, and to show that p53's aggressive DNA-damage response and its gentler tumor-suppression response are separable functions.

"We've determined, for the first time, that the gene expression program p53 requires in its tumor-suppression role is distinct from that which it requires in the context of acute DNA damage," Attardi said. "Separating these responses may allow the identification of ways to inhibit the detrimental effects of radiotherapy and chemotherapy -- both of which damage DNA -- without putting a patient at risk for developing new tumors."

While most tumors lack a working p53 protein, radiotherapy and chemotherapy activate the p53 present in healthy tissues, producing serious side effects by destroying cells in the gastrointestinal tract, blood, hair follicles and brain. That's because these treatments cause profound DNA damage, a trigger for p53 action.

It's known that p53 is a transcription factor: a protein that can regulate the production of numerous other proteins inside a cell. According to scientists, p53 recognizes and perches upon a particular DNA sequence found near large numbers of genes. Once p53 has seated itself near such a gene, two different regions of the protein, called TAD1 and TAD2, can serve as landing beacons that attract mammoth molecular copying machines to the gene -- a key early step in protein generation.

But the response is very different depending on which of the two beacons, TAD1 or TAD2, is calling in the copying machinery.

Attardi's group used bioengineered mice in which TAD1, TAD2 or both had been disabled by mutations. This allowed the investigators to show that these two beacons flag different sets of genes.

The genes that TAD1 turns on are the ones involved in p53's show-stopping response to DNA-damage. More than 100 such genes had already been identified.

But when the investigators disabled TAD1 while leaving TAD2 intact, they were able to unmask a set of 50 or so genes turned on by TAD2. These genes, the team showed, mediate p53's ability to stimulate cells' somewhat more nuanced tumor-suppression response, which shuts down a cell only upon sensing oncogene activity, a more direct sign of potential cancer than mere DNA damage.

"When we treated the TAD1-disabled mice with high-dose radiation, they didn't suffer the DNA-damage-induced side effects that we saw in wild-type mice," said the study's lead author, Colleen Brady, a PhD student in Attardi's lab. "But TAD1-disabled mice were resistant to tumor development."

"This is an important advance," said molecular biologist and oncologist Arnold Levine, PhD, a professor at the Institute of Advanced Studies in Princeton, N.J. "The team has uncovered half of what the biggest player in human cancers does." Levine, who didn't participate in the study but is familiar with it, is one of three scientists credited for p53's discovery in 1979.

The finding that p53 can suppress tumors, even when the part of it that shuts down cells in response to DNA damage has been disabled, holds significant implications for therapy. If the two distinct activities of p53 in healthy cells can be decoupled -- say, by a drug impairing TAD1's function but sparing TAD2's -- it might be possible to avoid the massive healthy-cell die-off responsible for nausea, hair loss, immune deficiency and nerve damage that usually occur during radiotherapy or chemotherapy, without promoting new tumor development. Disabling p53's TAD1 region would allow cells that have sustained DNA damage in the course of these therapies to live to another day, but TAD2's still-intact tumor-suppressor function in those otherwise normal cells would guard against those cells becoming cancer cells.

The study was funded by the American Cancer Society, the Leukemia & Lymphoma Society and the National Institutes of Health. Other Stanford co-authors were postdoctoral researchers Dadi Jiang, PhD; Stephano Spano Mello, PhD; Daniela Kenzelmann Broz, PhD; Lesley Jarvis, MD, PhD; and Shashwati Basak, PhD; medical students Margaret Kozak and Thomas Johnson, PhD; and research assistant Eunice Park, all of Attardi's lab. Jarvis is now an assistant professor of medicine at Dartmouth-Hitchcock Medical Center, and Basak is scientific manager at BBRC Syngene International Ltd.

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Surgeon caseload, practice setting affect treatment of small kidney tumors

ScienceDaily (May 14, 2011) — Patients with small kidney tumors are more likely to be offered treatment options based on surgeons' case volume and type of practice than on tumor characteristics, a Mayo Clinic study has found. Fellowship-trained surgeons who practice in academic medical centers with high volumes of patients with kidney tumors were 70 to 80 percent more likely to follow American Urological Association (AUA) guidelines by recommending partial nephrectomy. Surgeons in private practice who see few patients with kidney tumors more often offered radical nephrectomy: removal of the entire kidney.

See Also:Health & MedicineKidney DiseaseToday's HealthcareBrain TumorWounds and HealingCancerOvarian CancerReferenceRenal cell carcinomaKidneyDialysisExcretory system

Mayo Clinic researchers presented their findings during the AUA Annual Meeting in Washington.

"There is wide variability in how renal masses are managed. We must recognize these discrepancies may be due to different perceptions of technical feasibility in performing a partial nephrectomy," says Christopher Weight, M.D., of Mayo Clinic's Department of Urology. "What we're encouraging is a discussion between physicians and patients about all options available. Some patients may benefit from a referral to surgeons with more experience with renal tumors."

The study shows that as kidney tumors get larger and more complex, all surgeons tend to offer a radical nephrectomy. However, the tumor complexity that may result in one surgeon recommending total removal of the kidney may be well below a more experienced surgeon's threshold. Approximately 45,000 Americans require radical or partial nephrectomy each year.

Other study investigators include Simon Kim, M.D., Christine Lohse, Stephen Boorjian, M.D., R. Houston Thompson, M.D., and Bradley Leibovich, M.D., all of Mayo Clinic; and Rodney Breau, M.D., and Paul Cripsen, M.D., formerly of Mayo Clinic.

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Study reveals need for personalized approach in treatment of acute myeloid leukemia

ScienceDaily (May 16, 2011) — A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

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AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease -- affecting about 20 to 30 percent of AML patients -- and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.

This research was funded by several sources including the Leukemia and Lymphoma Society, National Cancer Institute, and Wake Forest University Comprehensive Cancer Center. Johannes Zuber, M.D., and Scott W. Lowe, Ph.D., of the Cold Spring Harbor Laboratory, in New York, appear as co-authors on the paper. Lowe is also affiliated with Howard Hughes Medical Institute, in New York.

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Rapid growth may be appropriate trigger for treatment in patients with renal masses

ScienceDaily (May 15, 2011) — With an increase in abdominal imaging over the past decade, there has been an increase in the detection of incidental kidney cancer, which has led to concerns that we may be over-treating indolent disease. As part of this effort, clinicians have started to investigate the effectiveness of active surveillance (AS), or close observation as opposed to immediate surgery, for select patients with small renal masses (SRMs).

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Fox Chase Cancer Center researchers have announced the results of its systematic review and pooled analysis, which for the first time combined several institutions' experience with active surveillance of small renal masses. Their goal was to identify trends in radiographic tumor growth rates and progression to either treatment or metastasis, and found that in select patients, active surveillance may be a viable option when surgery is risky due to poor health or advanced age.

Marc Smaldone, M.D., urologic oncology fellow at Fox Chase and lead author on the study, will present the results at the AUA 2011 Annual Meeting on Tuesday, May 17, 2011.

"Kidney cancer is most often a surgically treated disease, so studies such as this one, which help to confirm that active surveillance with curative intent can be an effective strategy for certain patients, are crucial," says Smaldone. "Surgery has substantial consequences for many patients with competing risks such as heart or lung disease. The ability to offer a management strategy that avoids the risks of potentially unnecessary surgery is an attractive concept in contemporary cancer treatment."

To further investigate the risks of cancer progression in patients undergoing active surveillance, Fox Chase researchers combined all the available individual data published by institutions examining the observation of small renal masses. The team identified and pooled a total of 18 institutional series, of which Fox Chase's experience represented the largest published series. The researchers then examined the pooled experience for trends in radiographic growth rates, tumor size at presentation, and progression to treatment or metastasis.

They found that, of the observed 936 SRMs in 880 patients, only a very small proportion -- 2.1% (18 patients) -- progressed to metastasis. Pooled analysis of progressors and non-progressors revealed significant trends including increased age, increased tumor size at presentation, and increased growth rates in the progression group. These metrics can be used to help determine if a patient should stop surveillance and undergo surgical intervention for his or her SRM. However, Fox Chase researchers learned that growth kinetics alone cannot predict a tumor's natural growth history. Therefore, active surveillance should not be considered an equivalent alternative to definitive surgical therapy, but it can be used as an initial short-term option for select patients who are poor surgical candidates.

"There is a perception that all cancers, once detected, should be treated immediately because they are all equally lethal, but what we've seen in this study is that small, asymptomatic kidney cancers can be managed through active surveillance," says Robert G. Uzzo, M.D., F.A.C.S., chairman of the department of surgery at Fox Chase and member of the AUA Guidelines Council. "As a medical community, we need to recognize this shift and begin to risk stratify patients and counsel them based on criteria other than the presence of small renal masses on scans."

While more research is necessary, this study suggests that growth kinetics may be the best measurement currently available for determining which patients should undergo immediate intervention and which should not. As a supplement to radiographic data, future biomarker discovery in conjunction with percutaneous -- or renal biopsy -- might ultimately influence management decisions on an individual patient basis. Based on these findings patients should seek out urologic oncology experts to help them understand the implications of small kidney cancers and avoid overtreatment.

Co-authors on the study include Fox Chase researchers Alexander Kutikov, Daniel J. Canter, Brian L. Egleston, Rosalia Viterbo, David Y.T. Chen, Richard E. Greenberg and Robert G. Uzzo.

Statistical analysis for this research was supported by Fox Chase Cancer Center's Keystone Program in Personalized Kidney Cancer Therapy. Established in 2008, this collaborative program brings researchers and clinicians from multiple disciplines together to investigate the biological mechanisms that lead to kidney cancer metastasis and to uncover the molecular signals that predict how an individual patient's kidney tumor will respond to therapies. Ultimately, the research supported by this privately-funded program will allow clinicians to optimize therapies for a given patient based on the unique molecular characteristics of his or her tumor.

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Breast cancer: New treatment avenue identified

ScienceDaily (May 17, 2011) — Researchers at the CHUM Research Centre (CRCHUM) and the Peter MacCallum Cancer Centre in Australia have identified a new avenue for treating breast cancer.

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In 20 to 30% of breast cancer patients, the over-expression of a particular protein (human epidermal growth factor-2) is the main cause of the proliferation of cancer cells. Over the past few years Herceptin® (trastuzumab) has become the standard treatment for this kind of cancer. While it is known that it blocks the activity of this protein, its exact mechanism of action has remained a mystery.

Professor John Stagg, a CRCHUM researcher, Professor Mark J. Smyth, with the Peter MacCallum Cancer Centre in Australia, and their colleagues have discovered that in addition to blocking cell proliferation, Herceptin also stimulates the production of interferons, which in turn activate immune cells called lymphocytes.

This study further supports the view that the presence of lymphocytes in tumours enhances treatment success. In addition to revealing the precise workings of Herceptin, this study also showed that combining Herceptin with a therapy that stimulates lymphocytes greatly increases its efficacy in animals.

"These findings open another avenue for breast cancer treatment for nearly a third of all women who are affected," notes Professor Stagg, who is also affiliated with the Faculty of Pharmacy at the University of Montreal and with the Institut du Cancer de Montréal. Clinical trials could get underway in the near future and pave the way for more targeted therapies.

This study was conducted in collaboration with the Peter MacCallum Cancer Centre, East Melbourne, Australia; Jules Bordet Institute, Brussels, Belgium; University of Melbourne, Australia; and Juntendo University, Tokyo, Japan;

The study was funded by the National Health and Medical Research Council of Australia, the Susan Komen Breast Cancer Foundation and the Victoria Breast Cancer Research Consortium (Australia).

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New treatment regimen shows clinical benefit in advanced colon cancer

ScienceDaily (May 21, 2011) — A new treatment regimen for patients with metastatic colon cancer appears to offer clinical benefit even when used after multiple other treatments have failed, say research physicians at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center.

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The research team found that combining a PARP inhibitor with chemotherapy (temozolomide) offers significant benefit in patients who had no further treatment options. However, the study is small, and does not include a comparison arm, so further investigation is needed, they add. The study will be presented in an oral session on Saturday, June 4th, at the 2011 annual meeting of the American Society of Clinical Oncology in Chicago.

PARP, short for "poly (ADP-ribose) polymerase" is a key part of a cell's DNA repair apparatus, and is important for protecting our normal cells against DNA damage. However, cancer cells become resistant to chemotherapy in part by increasing PARP expression and thus rapidly repairing DNA damage intentionally caused by chemotherapy. PARP inhibitors are designed to overcome a cancer cell's ability to repair the damaged DNA. (They are showing promise in both breast and ovarian cancers, and are being studied in a variety of other cancer types).

In this clinical study, doctors administered a potent DNA-damaging chemotherapy, temozolomide, with a PARP inhibitor called ABT-888. The theory is that ABT-888 will diminish the ability of these cancer cells to fix the damage that was just inflicted by the temozolomide, pushing the cancer into a death spiral.

"This is a classic one-two punch: the chemotherapy damages the cancer cells and the PARP inhibitor prevents it from fixing itself, leaving the cell to die," says lead author, Michael Pishvaian, M.D., Ph.D., an assistant professor at Georgetown Lombardi.

This single-arm, phase II study enrolled 49 patients with metastatic disease who were not eligible for surgery and had exhausted all of the standard therapies currently used. Despite having advanced cancer, all study participants were still active at work or home. Researchers found the drug combination controlled cancer growth for nearly six months in 23 percent of the patients, with two patients having a significant reduction in their tumor burden (partial response).

Pishvaian explains, "The treatment was extremely well tolerated, so to have a period of six months with no tumor growth, but also no significant side effects was really meaningful for the patients."

In addition, researchers were able to collect samples of the patients' tumors for further molecular analysis. "By testing tissue samples and identifying their molecular fingerprints, perhaps we can identify which patient subgroups are most likely to respond to this new therapeutic combination," concludes Pishvaian.

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Ex-Dallas Maverick survives rare form of leukemia thanks to experimental drug treatment

ScienceDaily (May 19, 2011) — Ray Johnston's goal in three years is for his band to sell out at the 1,600-seat House of Blues in Dallas. In eight years, he wants to pack the 6,400-seat Verizon Theatre in Grand Prairie, and by 2030, to play to tens of thousands of fans at Cowboys Stadium in Arlington.

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Mr. Johnston's unmentioned goal, though, is to live another year after battling leukemia for the past seven. Despite four relapses, the former Dallas Mavericks basketball player is enjoying life as a rising musician in The Ray Johnston Band.

Although he credits God for his recovery, Mr. Johnston also gives thanks to Dr. Robert Collins, director of the Bone Marrow Transplantation/Hematologic Malignancies Program at UT Southwestern Medical Center, and the experimental drug that has killed his rare, stubborn form of cancer called acute promyelocytic leukemia.

"It's got to be inspiring to Dr. Collins to see that I'm alive because I'm supposed to be done by now," Mr. Johnston said of his painful yet rewarding journey, which was chronicled last year in an HDNet series called "Ray Johnston Band: Road Diaries."

Today, Mr. Johnston's self-described "happy rock" Dallas band is working on its second CD and booking about 100 shows a year. "My primary goal is to keep playing," Mr. Johnston said.

Tamibarotene, the drug that's kept the 32-year-old musician alive, is a retinoid drug that induces cancer cells to differentiate into mature cells and eventually die. Available only in clinical trials in the U.S., tamibarotene was sought for Mr. Johnston under a compassionate use protocol since he did not qualify for those studies and other treatments had been exhausted. The drug, approved only in Japan for cancer treatment, is being developed domestically by CytRx.

"It's amazing that he's still doing so well," said Dr. Collins, professor of internal medicine and senior author of a report on this case published online April 11 in the Journal of Clinical Oncology. "This drug happens to be just right for him."

Mr. Johnston's treatment with tamibarotene, which is considered 10 times more potent than all-trans retinoic acid, another retinoid commonly used to treat this type of leukemia, began in December 2009. He took the drug twice daily for 56 days, followed by a two-week break. Since then, Mr. Johnston has been taking the drug 28 days on, 28 off.

On April 18, he returned to UT Southwestern for a positron emission tomography (PET) scan, which showed his cancer had not relapsed for the fifth time.

"The type of acute leukemia he has is very rare. It's usually curable with current therapies, but as it relapses it becomes more resistant and harder to treat," said Dr. Collins.

Gambling on life, and success as a musician, doesn't scare the Alabama native who once dreamed of a professional basketball career. But cancer ended his NBA stint, which began when he won a spot on the Dallas Mavericks summer league roster during a Hoop It Up tournament in 2004.

Mr. Johnston didn't even know he had leukemia until that August, when he injured his leg in a pick-up game. He was diagnosed with compartment syndrome, a condition in which pressure in the muscle builds to dangerous levels. Following surgery, doctors were unable to control bleeding. They soon discovered that Mr. Johnston's body was riddled with advanced leukemia.

His treatment included chemotherapy, surgery and a bone marrow transplant. Mr. Johnston's type of leukemia, which affects soft tissues rather than blood and bone marrow, represents just 5 percent to 8 percent of acute myelogenous leukemia, the most common form of the disease.

Discouraged by failing treatments and the thought of his first bone marrow transplant, he nearly gave up hope. In 2006, a recommendation from a friend led him to Dr. Collins and UT Southwestern.

"When you achieve a life milestone that you're not supposed to, when you hug it out, you can see and feel Dr. Collins drop a tear on your shoulder. That's life. That's real," said Mr. Johnston.

Reality for this cancer survivor also means getting serious about music. Mr. Johnston has a lot of work ahead after launching the six-member band in September 2009. Some of the band's performances raise money for The Ryan Gibson Foundation, a Dallas-based nonprofit dedicated to leukemia research.

One of the songs on the band's first CD, "Sweet Tooth," is Rise & Go, based on a verse in the Bible, Luke 17:19. Mr. Johnston said it sums up "my last seven years."

"Wake up and I go outside, I see my blue sky, I'm happy to be alive … I got a tough upper lip, but a bottom little broken heart. When I look into the sky, I see my Maker's eyes. That's when I know my Plan B for eternity is strong as gold, so I rise and go.

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Curcumin compound improves effectiveness of head and neck cancer treatment, study finds

ScienceDaily (May 19, 2011) — A primary reason that head and neck cancer treatments fail is the tumor cells become resistant to chemotherapy drugs. Now, researchers at the University of Michigan Comprehensive Cancer Center have found that a compound derived from the Indian spice curcumin can help cells overcome that resistance.

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When researchers added a curcumin-based compound, called FLLL32, to head and neck cancer cell lines, they were able to cut the dose of the chemotherapy drug cisplatin by four while still killing tumor cells equally as well as the higher dose of cisplatin without FLLL32.

The study appears this week in the Archives of Otolaryngology -- Head and Neck Surgery.

"This work opens the possibility of using lower, less toxic doses of cisplatin to achieve an equivalent or enhanced tumor kill. Typically, when cells become resistant to cisplatin, we have to give increasingly higher doses. But this drug is so toxic that patients who survive treatment often experience long-term side effects from the treatment," says senior study author Thomas Carey, Ph.D., professor of otolaryngology and pharmacology at the U-M Medical School and co-director of the Head and Neck Oncology Program at the U-M Comprehensive Cancer Center.

That tumors become resistant to cisplatin is a major reason why head and neck cancer patients frequently see their cancer return or spread. It also plays a big role in why five-year survival for head and neck cancer has not improved in the past three decades.

FLLL32 is designed to sensitize cancer cells at a molecular level to the antitumor effects of cisplatin. It targets a key type of protein called STAT3 that is seen at high levels in about 82 percent of head and neck cancers. High levels of STAT3 are linked to problems with normal cell death processes, which allow cancer cells to survive chemotherapy treatment. STAT3 activation has been associated with cisplatin resistance in head and neck cancer.

Curcumin is known to inhibit STAT3 function, but it is not well-absorbed by the body. FLLL32 was developed by researchers at Ohio State University to be more amenable to use in people. The current study used the compound only in cell lines in the laboratory.

In the current study, researchers compared varying doses of cisplatin alone with varying doses of cisplatin plus FLLL32 against two sets of head and neck cancer cells: one line that was sensitive to cisplatin and one line that was resistant.

They found that FLLL32 decreased the activation levels of STAT3, sensitizing both resistant and sensitive tumor cells to cisplatin. Further, lower doses of cisplatin with FLLL32 were equally effective at killing cancer cells as the higher doses of cisplatin alone.

Separate studies suggest FLLL32 may not be well-absorbed by the body and researchers are developing a next generation compound that they hope improves on that. The U-M team plans to further study this newer compound for its potential as part of head and neck cancer treatment. Clinical trials using this compound are not currently available.

Additional authors include Waleed M. Abuzeid, M.B.B.S.; Samantha Davis, B.S., M.D.; Alice L. Tang, B.A., M.D.; Lindsay Saunders, B.S.; J. Chadwick Brenner, M.S.E.; Emily Light, M.S.; Carol R. Bradford, M.D.; and Mark E.P. Prince, M.D., all from U-M; Jiayuh Lin, Ph.D., from the Nationwide Children's Hospital, Columbus, Ohio; James R. Fuchs, Ph.D., from The Ohio State University.

Funding was provided by the National Institute of Dental and Craniofacial Research, Head and Neck Specialized Program of Research Excellence (SPORE) grant, National Cancer Institute, American Cancer Society

Head and neck cancer statistics: 36,540 Americans will be diagnosed with head and neck cancer this year and 7,880 will die from the disease, according to the American Cancer Society.

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