sid_melo blogreen: 06/01/14

domingo, 1 de junho de 2014

Drop in global malnutrition depends on agricultural productivity, climate change

May 29, 2014

Purdue University

Global malnutrition could fall 84 percent by the year 2050 as incomes in developing countries grow -- but only if agricultural productivity continues to improve and climate change does not severely damage agriculture, researchers say. According to the researchers' models, income growth coupled with projected increases in agricultural productivity could raise more than half a billion people out of extreme hunger by mid-century.

Click to enlarge

Agricultural economists Uris Baldos, left, and Thomas Hertel.

"The prevalence and severity of global malnutrition could drop significantly by 2050, particularly in the poorest regions of the world," said Thomas Hertel, Distinguished Professor of Agricultural Economics. "But if productivity does not grow, global malnutrition will worsen even if incomes increase. Climate change also adds a good deal of uncertainty to these projections."

Hertel and doctoral student Uris Baldos developed a combination of economic models -- one that captures the main drivers of crop supply and demand and another that assesses food security based on caloric consumption -- to predict how global food security from 2006 to 2050 could be affected by changes in population, income, bioenergy, agricultural productivity and climate.

According to the models, income growth coupled with projected increases in agricultural productivity could raise more than half a billion people out of extreme hunger by mid-century.

Income is also set to eclipse population as the dominant driver of food security, a "historical first," said Baldos.

"We expect that the population driver will diminish relative to per capita income in the coming decades, especially in the developing world," he said.

Growth in income will allow people to increase the amount of food they consume and "upgrade" their diets by adding more meat and processed foods to staples such as crops and starches. The shift toward a diet higher in calories and richer in protein could lift many in hunger-stricken regions such as sub-Saharan Africa, South Asia, China and Mongolia above the malnutrition line.

Globally, the volume of food consumed per capita could increase by about 31 percent. In developing regions with strong growth in income and population, consumption could rise by about 56 to 75 percent.

But these projections depend heavily on corresponding increases in agricultural productivity, Hertel said. Productivity is a measure of crop yields relative to the inputs used in producing them such as land, labor and fertilizers. Increased global productivity improved the availability of food over the last 50 years, but this trend must continue between now and 2050 to buttress food security.

"There is a clear link between productivity growth in agriculture and the number of malnourished people," Hertel said. "Boosting productivity tends to lower food prices, and declines in the cost of food in turn can allow for better nutrition. Income growth alone will not be enough to solve the malnutrition problem."

Historically, agricultural productivity has been driven by investments in agricultural research and development. The researchers said improvements in food security depend on increasing research spending, especially over the next two decades.

"The decisions we make now about funding for agricultural research will have implications for a number of malnourished people in 2050," Hertel said. "If agricultural productivity stagnates, there will be far more malnourished people in the future, particularly in regions where chronic hunger is already present."

The researchers also cautioned that the impacts of a changing climate on crop yields remain uncertain.

Rising temperatures could extend the growing season in northern latitudes, and an increase in carbon dioxide in the atmosphere could benefit some crops by improving water efficiency. But climate change is complicated, Hertel said.

"Up to 2050, there could be some pluses for agriculture," he said. "But in the longer run, adverse temperatures will likely become overwhelming, and rising carbon dioxide concentrations won't help after a certain point. Eventually, you drop off a cliff."

The models show that climate change is a less influential driver of global food security than income, population and productivity -- but it could still pose a significant risk to the nutrition levels of people living in the world's poorest regions, Baldos said.

"People living in the most hunger-stricken areas will be the most vulnerable to climate change."

Story Source:

The above story is based on materials provided by Purdue University. The original article was written by Natalie van Hoose. Note: Materials may be edited for content and length.

Journal Reference:

Uris Lantz C. Baldos, Thomas W. Hertel. Global food security in 2050: the role of agricultural productivity and climate change. Australian Journal of Agricultural and Resource Economics, 2014; DOI: 10.1111/1467-8489.12048

Graphene's multi-colored butterflies

June 1, 2014

University of Manchester

Combining black and white graphene can change the electronic properties of the one-atom thick materials, researchers have found. One of the major challenges for using graphene in electronics applications is the absence of a band gap, which basically means that graphene's electrical conductivity cannot be switched off completely. Whatever researchers tried to do with the material so far, it remained highly electrically conductive.

Writing in Nature Physics, a large international team led by Dr Artem Mishchenko and Sir Andre Geim from The University of Manchester shows that the electronic properties of graphene change dramatically if graphene is placed on top of boron nitride, also known as 'white graphite'.

One of the major challenges for using graphene in electronics applications is the absence of a band gap, which basically means that graphene's electrical conductivity cannot be switched off completely. Whatever researchers tried to do with the material so far, it remained highly electrically conductive.

A new direction that has recently emerged in graphene research is to try to modify graphene's electronic properties by combining it with other similar materials in multilayered stacks. This creates an additional landscape for electrons moving through graphene and, therefore, its electronic properties can change strongly.

The University of Manchester scientists have used capacitance measurements to probe these changes. They found that in combination with a magnetic field this creates numerous replicas of the original graphene spectrum. This phenomenon is known as the Hofstadter butterfly but it is the first time that well developed replica spectra have been observed.

The researchers found a wealth of unexpected physics in this new system. For example, the Hofstadter butterflies turned out to be strongly contorted, very different from the theoretical predictions. This happens because electrons feel not only the landscape but also each other, which modifies the butterfly.

Another phenomenon that the Manchester paper reports is that graphene starts behaving at very low temperatures like a tiny ferromagnet. Usually, the higher the magnetic field, the more magnetic graphene become. The Hofstadter butterfly in Manchester's capacitors leads to an unexpected oscillating behaviour of the ferromagnetism. As new replica spectra emerge and disappear, so does the ferromagnetism.

Dr Mishchenko said: "It is really a new nice electronic system both similar to and different from graphene. We expect many more surprises. Let us first understand what it is and then we start talking about possible applications."

Story Source:

The above story is based on materials provided by University of Manchester. Note: Materials may be edited for content and length.

Osteoporosis: Genetic researchers take major step towards better diagnosis, treatment

May 30, 2014

European Society of Human Genetics (ESHG)

A new target that may be critical for the treatment of osteoporosis, a disease which affects about 25% of post-menopausal women, has been discovered by a group of researchers. New studies in zebrafish and mice have shown that injection of human plastin 3 (PLS3) or related proteins in zebrafish where PLS3 action has been suppressed can replace its loss and repair the bone development anomalies associated with this deficiency.

A new target that may be critical for the treatment of osteoporosis, a disease which affects about 25% of post-menopausal women, has been discovered by a group of researchers in The Netherlands and in Germany.

Professor Brunhilde Wirth, Head of the Institute of Human Genetics, University of Cologne, Germany, will tell the annual conference of the European Society of Human Genetics tomorrow (Sunday) that new studies in zebrafish and mice have shown that injection of human plastin 3 (PLS3) or related proteins in zebrafish where PLS3 action has been suppressed can replace its loss and repair the bone development anomalies associated with this deficiency. Furthermore, overexpression of human (PLS3) in normal mice had a significant impact on bone development and maintenance, making them more resistant to fractures.

The discovery that PLS3 mutations could cause osteoporosis was published last year in The New England Journal of Medicine. The results came as a surprise to the researchers, since mutations in the PLS3 gene had not previously been known to be related to osteoporosis and fractures, or to play a role in bone formation. “In our most recent research, we started out by using zebrafish embryos in which PLS3 was knocked-out and studying their development at the three and five day-old stage,” says Professor Wirth, “and we found that they had massive impairment of craniofacial skeletal development. However, this was fully restored when we added human PLS3. The same thing happened when we added two other proteins, actinin 1 and actinin 4, F-actin proteins2 which are involved in ‘bundling’ or building the ‘scaffolding’ for cells, and it seems that these proteins can compensate for the loss of PLS3. Thus we have been able to verify the essential role of actin in bone development and maintenance.”

The subsequent mouse studies confirmed the findings in zebrafish, the researchers say, and open up possibilities for new treatments. They now intend to use PLS3 knock-out mice, where the PLS3 gene has been removed, in the search for the disease-causing mechanism involved. PLS3 is expressed in three different types of cells - osteocytes and osteoclasts, both involved in bone growth and remodelling, as well as in muscle cells. Using a transgenic mouse that overexpresses PLS3, they will also investigate whether this overexpression could be effective in other diseases involving in bone weakness.

“Since we know that about five percent of the human population expresses higher than normal levels of PLS3, we can hypothesise that these people may be protected against osteoporosis,” says Professor Wirth.

Once the researchers understand the exact disease-causing mechanism, it may be possible to translate the knowledge into therapy, they say. PLS3 overexpression is also protective against spinal muscular atrophy, the second most frequent autosomal recessive disorder in humans.3 This implies that understanding the protective role of PLS3 is crucial in both disorders. “We are currently trying to unravel the whole protein network and, once we have understood the signalling pathways influencing PLS3 expression, we should be able to identify drugs or molecules that influence PLS3 expression or actin proteins,” she says.

Osteoporosis affects not only post-menopausal women, but also older men, and the condition currently causes more than 8.9 million fractures per year or an osteoporitic fracture every three seconds. Worldwide one in three women over 50 will experience fractures due to osteoporosis, as will one in five men. Currently, emphasis for sufferers is on the prevention of falls that can cause broken bones. Although bisphosphonates are useful in decreasing the risk of future fractures in those who have already sustained an osteoporotic fracture, they are otherwise of little use.

“Osteoporosis poses an urgent health problem that is going to become more important as years go with the numbers of elderly people in the community continuing to increase,” says Professor Wirth. “Although in itself it is not a fatal illness, large numbers of people die prematurely as a result of health complications following falls. We believe that our work has led to a better understanding of the condition and has pointed the way towards improved diagnosis and prevention, and, we hope, an effective treatment in the future.”

Story Source:

The above story is based on materials provided by European Society of Human Genetics (ESHG). Note: Materials may be edited for content and length.

Journal Reference:

Fleur S. van Dijk, M. Carola Zillikens, Dimitra Micha, Markus Riessland, Carlo L.M. Marcelis, Christine E. de Die-Smulders, Janine Milbradt, Anton A. Franken, Arjan J. Harsevoort, Klaske D. Lichtenbelt, Hans E. Pruijs, M. Estela Rubio-Gozalbo, Rolf Zwertbroek, Youssef Moutaouakil, Jaqueline Egthuijsen, Matthias Hammerschmidt, Renate Bijman, Cor M. Semeins, Astrid D. Bakker, Vincent Everts, Jenneke Klein-Nulend, Natalia Campos-Obando, Albert Hofman, Gerard J. te Meerman, Annemieke J.M.H. Verkerk, André G. Uitterlinden, Alessandra Maugeri, Erik A. Sistermans, Quinten Waisfisz, Hanne Meijers-Heijboer, Brunhilde Wirth, Marleen E.H. Simon, Gerard Pals. PLS3Mutations in X-Linked Osteoporosis with Fractures. New England Journal of Medicine, 2013; 369 (16): 1529 DOI: 10.1056/NEJMoa1308223

'Often and early' gives children a taste for vegetables

Exposing infants to a new vegetable early in life encourages them to eat more of it compared to offering novel vegetables to older children, new research from the University of Leeds suggests.

The researchers, led by Professor Marion Hetherington in the Institute of Psychological Sciences, also found that even fussy eaters are able to eat a bit more of a new vegetable each time they are offered it.

The research, involving babies and children from the UK, France and Denmark, also dispelled the popular myth that vegetable tastes need to be masked or given by stealth in order for children to eat them.

Professor Hetherington said: "For parents who wish to encourage healthy eating in their children, our research offers some valuable guidance.

"If you want to encourage your children to eat vegetables, make sure you start early and often. Even if your child is fussy or does not like veggies, our study shows that 5-10 exposures will do the trick."

In the study, which was funded by the EU, the research team gave artichoke puree to 332 children from three countries aged from weaning age to 38 months. During the experiment each child was given between five and 10 servings of at least 100g of the artichoke puree in one of three versions: basic; sweetened, with added sugar; or added energy, where vegetable oil was mixed into the puree.

There was also little difference in the amounts eaten over time between those who were fed basic puree and those who ate the sweetened puree, which suggests that making vegetables sweeter does not make a significant difference to the amount children eat.

Younger children consumed more artichoke than older children. This is because after 24 months children become reluctant to try new things and start to reject foods -- even those they previously liked. Among the children, four distinct groups emerged. Most children (40%) were "learners" who increased intake over time. Of the group, 21% consumed more than 75% of what was offered each time and they were called "plate-clearers." Those who ate less than 10g even by the fifth helping were classified as "non-eaters," amounting to 16% of the cohort, and the remainder were classified as "others" (23%) since their pattern of intake varied over time. Non-eaters, who tended to be older pre-school children, were the most fussy, the research found.

Globe artichoke was chosen as the sample vegetable because, as part of the research, parents were surveyed and artichoke was one of the least-offered vegetables. NHS guidelines are to start weaning children onto solid foods at six months.

The research has been published in the journal PLOS ONE.

Story Source:

The above story is based on materials provided by University of Leeds. Note: Materials may be edited for content and length.

Journal Reference:

Samantha J. Caton, Pam Blundell, Sara M. Ahern, Chandani Nekitsing, Annemarie Olsen, Per Møller, Helene Hausner, Eloïse Remy, Sophie Nicklaus, Claire Chabanet, Sylvie Issanchou, Marion M. Hetherington. Learning to Eat Vegetables in Early Life: The Role of Timing, Age and Individual Eating Traits. PLoS ONE, 2014; 9 (5): e97609 DOI: 10.1371/journal.pone.0097609

Prevalence of new genetic driver in lung cancer shown in study

May 31, 2014

University of Colorado Cancer Center

A line has been drawn from mutation of the gene NTRK1, to its role as an oncogene in non-small cell lung cancer, to treatment that targets this mutation. "Everything we know about lung cancer points to the idea that when we find one of these genetic drivers and can target it with a drug, patients will respond and tend to have a good amount of time on drug before it becomes ineffective. Obviously we can't guarantee the effectiveness of targeting the NTRK1 mutation at this point, but everything we know about these kinds of genes makes us extremely hopeful," says one researcher.

A University of Colorado Cancer Center study presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO) draws a line from mutation of the gene NTRK1, to its role as an oncogene in non-small cell lung cancer, to treatment that targets this mutation. The current study reports the prevalence of the NTRK1 mutation in an unselected population of 450 lung cancer samples, with >1% percent of patients testing positive. This and other work from Dr. Doebele's group forms the basis of a phase 1 clinical trial targeting NTRK1 mutations in advanced solid tumors (NCT02122913).

"Everything we know about lung cancer points to the idea that when we find one of these genetic drivers and can target it with a drug, patients will respond and tend to have a good amount of time on drug before it becomes ineffective. Obviously we can't guarantee the effectiveness of targeting the NTRK1 mutation at this point, but everything we know about these kinds of genes makes us extremely hopeful," says Robert C. Doebele, MD, PhD, investigator at the CU Cancer Center and associate professor of Medical Oncology at the CU School of Medicine.

Previous work in collaboration with Pasi A. Jänne, MD, PhD from the Dana-Farber Cancer Institute, examined lung cancer tumor samples from 36 "pan-negative" patients, meaning that no other driver oncogene had been identified. Next-gen sequencing at Foundation Medicine (Cambridge, MA) identified NTRK1 gene fusions as the potential driver in two of these samples.

Doebele and colleagues took the finding back to CU labs, where Marileila Varella-Garcia, PhD, developed a specific test for NTRK1 fusions based on fluorescence in situ hybridization (FISH), similar to what is currently used for ALK, ROS1 and RET fusions. This test would allow rapid detection of NRTK1 oncogenes in patient samples. "But no one had ever looked for NTRK1 mutations in a large series of unbiased patient samples," Doebele says. "The point of this study was to get a better sense of how many lung cancer patients are likely to be positive for NTRK1 mutations and what these patients are likely to look like."

Of 450 evaluated patient samples of non-small cell lung cancer, 5 tested "positive" and another 12 are considered suspicious for the mutation. Next generation sequencing studies revealed 5 previously undescribed NTRK1 mutations. Ongoing work seeks to tease apart the subtleties of diagnosis to further refine the criteria used to decide which tumors are truly created by the NTRK1 mutation.

Again, just as the FDA-approved drug crizotinib targets ALK fusions in an affected subset of lung cancer, the goal of the current line of research is to identify patients whose cancers are caused by NTRK1 and similarly target these patients with a drug that silences the problem gene. Toward that goal, Array BioPharma (Boulder, CO) provided candidate drugs to inhibit mutated NTRK1. Loxo Oncology, Inc. has managed further testing of the leading drug candidate, now known as LOXO-101. A phase 1a/1b clinical trial of the drug in advanced solid tumors is now recruiting patients.

"We found the mutation in a patient sample in 2012, published a manuscript in 2013 describing NTRK1 as a driver of lung cancer, and now here we are in May 2014 laying the groundwork for a clinical trial of drugs targeting this mutation," Doebele says. "Having seen this approach work well with other mutations in the past, the team is optimistic that this research could help control another important subset of lung cancers."

Story Source:

The above story is based on materials provided by University of Colorado Cancer Center. The original article was written by Garth Sundem. Note: Materials may be edited for content and length.

Patients with metastatic colon cancer respond to new combination therapy

May 31, 2014

University of Texas M. D. Anderson Cancer Center

In an aggressive disease known for poor response rates, researchers found patients with advanced colorectal cancer responded well to a combination therapy of the drugs vermurafenib, cetuximab and irinotecan. "What's promising is the fact that we're seeing these high response rates in early studies which suggests this could become a new standard of care down the line," one researcher said. "There's clearly some kind of synergistic activity with the combination."

In an aggressive disease known for poor response rates, researchers from The University of Texas MD Anderson Cancer Center found patients with advanced colorectal cancer responded well to a combination therapy of the drugs vermurafenib, cetuximab and irinotecan.

The Phase I trial, presented Saturday, May 31 in a poster discussion at the American Society of Clinical Oncology's 2014 Annual Meeting in Chicago, examines a specific mutation in the BRAF gene, which is present in 5 to 10 percent of colorectal cancer patients.

Previous research identified this mutation as a target for therapy, but response rates with single agent vemurafenib were poor, leading researchers to inquire about combining it with different drugs.

"Patients with a BRAF mutation in colorectal cancer are recognized for having aggressive disease that doesn't typically respond to standard chemotherapy," said David Hong, M.D., associate professor, Investigational Cancer Therapeutics and lead author. "So when BRAF inhibitors initially started, there was excitement this could become the new standard of care, however we found they didn't work very well."

In the trial, researchers combined escalating doses of vermurafenib (V), along with cetuximab (C) and irinotecan (I), two drugs previously used in the treatment of metastatic colorectal cancer. Twelve patients were enrolled at two dose levels including seven at dose level one (V-480 mg, C-250 mg and I-180 mg) and five at dose level two with vemurafenib increased to 720 mg.

Radiographic images were evaluated every four cycles over the course of a 14-day cycle of treatment. Patients were assessed for adverse events with the most common including rash, diarrhea and nausea.

Results Show Improved Responses

Of the nine evaluable patients, partial responses or stable disease was seen in all eight patients with colorectal cancer who underwent restaging scans following the beginning of their treatment. The response rate for the eight colorectal patients was 50 percent, whereas response rates with single agent vemurafenib are less than 10 percent.

"What's promising is the fact that we're seeing these high response rates in early studies which suggests this could become a new standard of care down the line," Hong said. "There's clearly some kind of synergistic activity with the combination."

A U.S. cooperative randomized Phase II trial of this combination in BRAF-mutated colorectal cancer will begin later this summer led by Scott Kopetz, M.D., Ph.D., in Gastrointestinal Medical Oncology who's the senior author on the Phase I study.

"While early, the exciting aspect is that we're seeing substantial response rates, but questions remain about the duration of these responses and what the mechanisms of resistance are," Kopetz said. "By expanding on our initial findings and moving to the cooperative group network we'll be able to rapidly perform studies that could lead to getting this combination approved."

Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.

One step closer to a breath test for lung cancer

May 31, 2014

University of Colorado Cancer Center

A test of organic compounds in exhaled breath can not only distinguish patients with lung cancer from patients with chronic obstructive pulmonary disease (COPD), but can also define the stage of any cancer present, new research shows. The device requires blowing up a balloon, which is then attached to an extremely sensitive gold nanoparticle sensor. The particles in the sensor trap and then help to analyze volatile organic compounds in the exhaled breath.

Results of a University of Colorado Cancer Center study presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO) show that a test of organic compounds in exhaled breath can not only distinguish patients with lung cancer from patients with chronic obstructive pulmonary disease (COPD), but can also define the stage of any cancer present.

"This could totally revolutionize lung cancer screening and diagnosis. The perspective here is the development of a non-traumatic, easy, cheap approach to early detection and differentiation of lung cancer," says Fred R. Hirsch, MD, PhD, investigator at the CU Cancer Center and professor of medical oncology at the University of Colorado School of Medicine.

The device requires blowing up a balloon, which is then attached to an extremely sensitive gold nanoparticle sensor. The particles in the sensor trap and then help to analyze volatile organic compounds in the exhaled breath. (A USB device has recently been developed, which can be plugged into a computer for rapid analysis).

"The metabolism of lung cancer patients is different than the metabolism of healthy people," Hirsch says, and it is these differences in metabolism that can define the signatures of healthy breath, COPD or lung cancer.

Hirsch points out the need for new lung cancer screening and diagnosis tools in the context of recent lung cancer screening guidelines by the U.S. Preventative Task Force showing that screening via low-dose computed tomography can reduce disease mortality by 20 percent. However, along with more sensitive screening comes a much higher incidence of false positives, primarily in the form of non-cancerous lung nodules.

"You detect many, many nodules in those screenings and unfortunately, around 90 percent of them are benign. So you need to find out how to better distinguish malignant from benign modules. The goal of this tool is to use breath biomarkers to distinguish malignant from benign screen-detected nodules," Hirsch says.

The developing device represents a collaboration between the University of Colorado Cancer Center and researchers from the Nobel-Prize-winning institution Technion University in Haifa, Israel.

The device's potential uses go beyond diagnosis.

"In addition to using levels of volatile organic compounds to diagnose lung cancer, we could eventually measure the change in patients' levels of VOCs across time with the intent of, for example, monitoring how well a patient responds to specific treatments," Hirsch says.

A breath now and a breath after treatment could define whether a patient should stay with a drug regimen or explore other options. In fact, a study with this goal was recently initiated at the University of Colorado Cancer Center.

Additionally, Hirsch points out that next generations of the device could potentially help doctors quickly, simply, and inexpensively define patients' lung cancer subtypes, allowing doctors to pair molecularly targeted therapies with subtypes early in the treatment process.

"If it works, you can imagine standing in the grocery store and having high risk people blow into a balloon or a USB device, and the profile of the organic compounds in their breath would tell you if they are at risk for developing or having lung cancer, which then could lead to further, focused tests," Hirsch says.

Story Source:

The above story is based on materials provided by University of Colorado Cancer Center. The original article was written by Garth Sundem. Note: Materials may be edited for content and length.

Results in Phase I Trial Targeting Cancer Stem Cells

May 31, 2014

University of Colorado Cancer Center

Results of a Phase I trial of OMP-54F28 (FZD8-Fc), an investigational drug candidate targeting cancer stem cells (CSCs) have been released. The drug was generally well tolerated, and several of the 26 patients with advanced solid tumors experienced stable disease for greater than six months. Three trials are now open in combinations with standard therapy for pancreatic, ovarian and liver cancers.

At the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO), University of Colorado Cancer Center researchers reported results of a Phase I trial of OMP-54F28 (FZD8-Fc), an investigational drug candidate discovered by OncoMed Pharmaceuticals targeting cancer stem cells (CSCs). The drug was generally well tolerated, and several of the 26 patients with advanced solid tumors experienced stable disease for greater than six months. Three trials are now open for OMP-54F28 (FZD8-Fc) in combinations with standard therapy for pancreatic, ovarian and liver cancers, being offered at the CU Cancer Center and elsewhere.

"These are optimistic results for one of the first targeted therapies for cancer stem cells," says Antonio Jimeno, MD, PhD, investigator at the CU Cancer Center, director of the university's Cancer Stem Cell-Directed Clinical Trials Program, and principal investigator of the clinical trial at the CU Cancer Center site. "And it is great to work with such a science-focused sponsor, whose vision aligns with ours: bringing to the clinic cutting-edge drugs and ideas that are focused on targeting CSCs. In the context of the collaboration between the Gates Center for Stem Cell Biology and the CU Cancer Center this was the second clinical trial we offered to our patients with the specific intent to eliminate the CSCs in their tumors."

OMP-54F28 (FZD8-Fc) is an antagonist of the Wnt pathway, a key CSC signaling pathway that regulates the fate of these cells. The Wnt pathway is known to be inappropriately activated in many major tumor types, including colon, breast, liver, lung and pancreatic cancers, and is critical for the function of CSCs. Because of this extensive validation, in the Jimeno lab and elsewhere, the Wnt pathway has been a major focus of anti-cancer drug discovery efforts. OMP-54F28 (FZD8-Fc) and a sister compound also developed by OncoMed, vantictumab (OMP-18R5), are two of the first therapeutic agents targeting this key pathway to enter clinical testing. In multiple preclinical models, OMP-54F28 (FZD8-Fc) has shown its effectiveness in reducing CSC populations, leading to associated anti-tumor activity, either as a single agent or when combined with chemotherapy.

"The ongoing line of work with this drug is an excellent example of the bench getting even closer to the bedside -- our lab work with the drug in patient-derived xenograft models of disease makes possible the clinical trials taking place at the University of Colorado Hospital next door," Jimeno says.

The Phase I clinical trial of OMP-54F28 (FZD8-Fc) is an open-label dose escalation study in patients with advanced solid tumors for which there was no remaining standard curative therapy. Patients are assessed for safety, immunogenicity, pharmacokinetics, biomarkers, and initial signals of efficacy. The trial is conducted at Pinnacle Oncology Hematology in Scottsdale, Arizona, the University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, and the CU Cancer Center under the direction of Principal Investigators Dr. Michael S. Gordon, Dr. David Smith and Dr. Antonio Jimeno, respectively.

The most common adverse events, mild to moderate and manageable, included dysgeusia (altered taste), fatigue, muscle spasms, decreased appetite, alopecia and nausea. One related Grade 3 or greater adverse event of Grade 3 increased blood phosphorus was reported. One moderate sacral insufficiency fracture occurred in one patient at the highest tested dose of 20 mg/kg every three weeks after 6 cycles.

"The drug is now being developed in combination with standard of care in three Phase 1b clinical trials, with the CU Cancer Center being one of the active sites," Jimeno says. "In pancreatic, ovarian and liver cancers, we hope that by adding anti-cancer stem cell drugs to standard of care, we can control proliferating cells within the tumor that could otherwise help the tumor regenerate in the face of existing chemotherapies."

Story Source:

The above story is based on materials provided by University of Colorado Cancer Center. Note: Materials may be edited for content and length.