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Sunday, March 3, 2019

How prostate cancer becomes treatment resistant

The development of effective anti-androgen therapies for prostate cancer is a major scientific advance. However, some men who receive these targeted treatments are more likely to develop a deadly treatment-resistant prostate cancer subtype called neuroendocrine prostate cancer (NEPC). No effective treatment for NEPC exists.
Now, scientists from Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified how prostate cancer transforms into aggressive NEPC following treatment with anti-androgen therapy. Their findings — which include the metabolic rewiring and the epigenetic alteration that drives this switch — reveal that an FDA-approved drug holds potential as a NEPC treatment. The research also uncovers new therapeutic avenues that could prevent this transformation from occurring. The study was published in Cancer Cell.
“Acquired treatment resistance is a major concern for every oncologist. Eventually, over enough time, cancer patients who receive a targeted therapy can become resistant to treatment,” says Darren Sigal, M.D., an oncologist at Scripps Clinic and Scripps MD Anderson Cancer Center who worked with the scientists on the study. “This study is an important advance that helps us understand why targeted treatments for prostate cancer may promote the development of a more aggressive tumor. These insights could lead to better treatments that help fathers, sons and grandfathers around the world who are fighting prostate cancer.”
Prostate cancer is the second-leading cause of cancer death for American men, according to the American Cancer Society. The cancer grows in response to hormones called androgens. Targeted therapies that block these hormones have extended survival for many patients. However, nearly all men eventually develop resistance to these treatments. In 2019, more than 30,000 men in the U.S. are expected to die from prostate cancer.
“Similar to bacteria that gain resistance to antibiotics, tumors can become resistant to anti-cancer drugs by ‘remodeling’ their environment and developing strategies to evade targeted therapies. As targeted therapies become more potent, putting more stress on tumors, we expect to see drug resistance become more common,” says Maria Diaz-Meco, Ph.D., the senior author of the paper and a professor in the Cancer Metabolism and Signaling Networks Program at SBP. “Our study shows that in a form of treatment-resistant prostate cancer, a tumor suppressor gene called protein kinase C lambda/iota is downregulated. We subsequently identified metabolic and epigenetic vulnerabilities which are possible routes to prevent treatment resistance from arising.”
In the study, the scientists analyzed tissue samples from men with metastatic NEPC, prostate cancer cell lines and a new mouse model of NEPC, created by the researchers, to identify the molecular switch that triggers prostate cancer to become treatment-resistant NEPC following targeted treatment. In addition to detecting the downregulation of protein kinase C lambda/iota, the scientists found that the NEPC cells upregulate the synthesis of a metabolite called serine. Because serine is a non-essential amino acid, treatments aimed at blocking serine production may be devised that could impact the tumor with minimal or no effect on the normal cells, thereby reducing potential toxicities. Additionally, the researchers discovered that the cancer cells used a communication pathway called mTORC1/ATF4 to accelerate the synthesis of serine, allowing the tumor to grow faster and to epigenetically switch to the NEPC mode. A protein that regulates the positions of lysosomes, the cell’s degradation machinery, was also involved in the tumor’s transformation. Together, these tumor characteristics represent novel approaches that could prevent prostate cancer from transforming into NEPC.
A new identity
“NEPC is essentially a new cancer. From what it ‘eats’ to how it looks, the tumor cells are completely reprogrammed. The tumor even loses the receptor that is targeted by current treatments, which is why it is so difficult to treat,” says Jorge Moscat, Ph.D., a study author and director and professor in SBP’s Cancer Metabolism and Signaling Networks Program. “Identifying the switch that drives the transformation from prostate cancer to NEPC is a critical first step toward developing treatments that prevent treatment resistance in men with prostate cancer before it begins.”
The scientists also identified epigenetic patterns — molecular tags that modify our DNA — associated with NEPC, linked to the expression of an enzyme, phosphoglycerate dehydrogenase (PHGDH), which could be a treatment target for NEPC. Next, the scientists plan to work with SBP’s drug discovery center, the Conrad Prebys Center for Chemical Genomics (Prebys Center), to try to identify a drug that can block PHGDH. The findings also indicated that an FDA-approved drug that inhibits epigenetic changes, called decitabine, could hold promise as a treatment for NEPC.
“Luckily, prostate cancer is a cancer type that is well characterized, which helps us better understand the mechanisms behind treatment resistance,” says Diaz-Meco. “With more research, one day we hope that no man dies of prostate cancer.”
Story Source:
Materials provided by Sanford Burnham Prebys Medical Discovery InstituteNote: Content may be edited for style and length.

Journal Reference:
  1. Miguel Reina-Campos, Juan F. Linares, Angeles Duran, Thekla Cordes, Antoine L’Hermitte, Mehmet G. Badur, Munveer S. Bhangoo, Phataraporn K. Thorson, Alicia Richards, Tarmo Rooslid, Dolores C. Garcia-Olmo, Syongh Y. Nam-Cha, Antonio S. Salinas-Sanchez, Ken Eng, Himisha Beltran, David A. Scott, Christian M. Metallo, Jorge Moscat, Maria T. Diaz-Meco. Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate CancerCancer Cell, 2019; DOI: 10.1016/j.ccell.2019.01.018

Amazon’s got milk

Amazon is getting into the milk business through privately owned brand Happy Belly.
The Happy Belly dairy items, spotted by brand tracker TJI, include various kinds of lactose-free milk (1%, 2%, whole, fat free), half and half, and whipping cream. “If you like Lactaid, we invite you to try Happy Belly,” reads a description on a product page, which also identifies Happy Belly as “an Amazon brand.”
The prices compare favorably to Lactaid. A half gallon of Happy Belly 2% reduced fat milk, for example, is currently priced at $3.29. A half gallon of the comparable Lactaid product sells for $3.88 at Walmart.
The catch is that Happy Belly dairy products have limited availability. You can order them in some markets through Prime Now, Amazon’s on-demand delivery service, or buy them at an Amazon Go store, Amazon’s chain of automated convenience stores. You can also purchase Happy Belly dairy products by subscribing to Amazon Fresh, Amazon’s $14.99-a-month grocery delivery subscription that can be purchased on top of a regular Prime membership.
Amazon seems to be hoping Happy Belly’s dairy products will help attract new users to Fresh. Where Amazon’s buy button would usually be for a regular Amazon shopper or Prime customer, the product pages for Happy Belly milk and other dairy items instead feature an avocado-green button to “Try Prime Fresh,” which leads to a page where you can sign up for a free 30-day Fresh trial.
SCREENSHOT FROM AMAZON
Amazon spokeswoman Nell Rona told Quartz in an email that Happy Belly is the first of its brands to offer milk and dairy products, excluding private brands it gained in June 2017 with its purchase of Whole Foods Market. Happy Belly started selling eggs in 2016 and milk and cheese in 2018, Rona said. Its cheese offerings include sliced provolone, blocks of cheddar, and a Mexican four-cheese blend.
Grocery has proven a white whale for Amazon, which has tried to break into the delivery of fresh foods for more than a decade, largely unsuccessfully. Amazon first unveiled Fresh on Mercer Island, a Seattle suburb, in 2007. The program expanded slowly but never caught on the way Amazon’s flagship Prime membership did, perhaps because the idea of spending $180 a year for grocery delivery on top of an annual Prime subscription was unattractive to the typical Prime user.
Amazon’s acquisition of Whole Foods prompted speculation that the company would overhaul its grocery delivery model using Whole Foods’ more than 400 stores as delivery hubs. A few months after the deal closed, Amazon partially shut down Fresh delivery in at least nine states.
Grocery delivery is a perilous line of business because the margins are so thin. The typical grocery keeps just $1 to $3 of every $100 that shoppers spend. Money is made not by getting customers to order groceries once, but many times over a month or year. How does this relate to milk? Well, dairy products like milk and eggs are a staple for many households. That means grocery shoppers are more likely to order from your site or shop at your store if they can buy those products there along with everything else.
Grocers online and offline are leaning heavily on private labels to set their stores apart, according to research from Food Marketing Institute, and milk or non-dairy substitutes top the list of categoriesfrom which shoppers say they purchase private-label goods. Amazon has been pushing into private- and exclusive labels for the better part of a year, not only in grocery but also clothing, furniture, electronics, and healthcare and beauty, among other things. According to TJI, Amazon at last count owned 137 private-label brands.

Saturday, March 2, 2019

Toward a blood test for early-stage liver disease

One in four people in Western and Asian societies develop a build-up of fat in the liver as a result of an unhealthy diet. This disease – referred to as non-alcoholic fatty liver disease (NAFLD) – causes no symptoms initially but can develop into end-stage liver cirrhosis with limited treatment options. A discovery, published today in Molecular Systems Biology, paves the way for a simple blood test to detect early stages of NAFLD, opening up the possibility of preventing the development of liver cirrhosis through lifestyle changes or pharmaceutical intervention.
The liver is an important organ, filtering  from the body and producing proteins required for digestion, blood clotting, and other important physiological functions.
“The liver is very resilient and capable of regenerating itself, which may be the reason why liver damages due to excessive fat deposition can go undetected for a long time,” says EMBO Member Matthias Mann of the University of Copenhagen, Denmark, and the Max Planck Institute of Biochemistry in Martinsried, Germany, who led the study. However, when damage accumulates liver function eventually starts to fail.
To date, the standard procedure for diagnosing NAFLD is liver biopsy – a cumbersome and costly procedure that can lead to complications. Non-invasive methods that reliably detect early stage NAFLD are therefore urgently required.
Mann and his colleagues investigated the plasma proteome – the entire set of proteins present in the  – of NAFLD patients. Using sophisticated mass spectrometry technologies, they uncovered a set of proteins that accumulate in the plasma of patients with non-symptomatic NAFLD.
In a first set of experiments, they determined that the blood proteome of patients in a late stage of the disease differed considerably from that of healthy controls. Many proteins that were altered in the patients’ blood proved to be associated with known aspects of the disease, such as thrombosis, vitamin A and D deficiency, or defects in glucose metabolism. These observations show the validity of the procedure to find new disease-related proteins.
In the next step, comparing the proteome of patients in early stage NAFLD with that of healthy individuals, the researchers found only minor differences. They did, however, succeed in identifying six proteins that were significantly associated with early stage NAFLD.
“One of the proteins we uncovered, termed PIGR, is of special interest,” says Mann. “Individuals with NAFLD who do not show any symptoms have increased levels of PIGR in their blood. And the concentration of the  increases the further the disease progresses, making PIGR an interesting biomarker candidate for the inclusion in liver damage tests.”
While current  tests only detect  damage at a late stage in disease development, the present study is an important step towards developing new diagnostic tools to identify patients with NAFLD in a much earlier, pre-symptomatic phase.
More information: Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. Molecular Systems BiologyDOI: 10.15252/msb.20188793

Early stage cancer biotech Precision BioSciences files for a $100 million IPO

Precision BioSciences, an early stage cancer biotech developing gene-edited Car T Cell therapies, filed on Friday with the SEC to raise up to $100 million in an initial public offering.
The Durham, NC-based company was founded in 2006 and booked $11 million in collaboration revenue for the 12 months ended December 31, 2018. It plans to list on the Nasdaq under the symbol DTIL. Precision BioSciences filed confidentially on October 19, 2018. J.P. Morgan, Goldman Sachs, Jefferies and Barclays are the joint bookrunners on the deal. No pricing terms were disclosed.

Macquarie seen leading bidder for Bayer’s chemical park operator

Macquarie has emerged as the leading bidder for Bayer’s 60 percent stake in chemical park operator Currenta, which the German drugmaker has put on the block to reduce its debt pile, people close to the matter said.

Talks between Bayer and the Australian bank’s Macquarie Infrastructure and Real Assets (MIRA) arm will likely continue for a few more weeks and the deal could still fall apart given the complexity of the negotiations, they added.
If no deal emerges, Bayer may fall back on runner-ups DWS and KKR, the sources said, adding that it was unclear whether the Ontario Municipal Employees Retirement System, which also made a final bid in January, was still interested.
Bayer, Macquarie, KKR and DWS declined to comment, while Omers had no immediate comment.
Currenta is expected to be valued at well above 2 billion euros(1.72 billion pounds), including debt, the sources said.
Bayer initially planned to sell the Currenta stake – a legacy asset with little benefit for its core drugs and agriculture businesses – to its former industrial chemicals subsidiary Covestro, but could not reach an agreement on valuation.
Covestro and Lanxess, both former Bayer businesses, are Currenta’s main customers.
Lanxess, a maker of additives, drug ingredients and leather-tanning chemicals, holds the remaining 40 percent in Currenta. It has a right of first refusal for the remaining shares but has said it would keep its current holding unchanged.
Bayer has launched a slew of asset sales to reduce debt after the $63 billion takeover of U.S. seed maker Monsanto.
Currenta runs the infrastructure at western German chemical complexes in Leverkusen, Dormagen and Krefeld-Uerdingen, which were once dominated by Bayer.
Talks with Macquarie are focusing on a slew of topics such as the exact size of the asset, the status of the property and future dividend policy, the people said.
It is competing with larger pharma rivals as it bids for the rights to promising new treatments from biotech firms to try to strengthen its drugs development pipeline.
Currenta serves more than 70 customers with 3,200 staff, providing electricity, steam and natural gas as well as services such as transportation, maintenance and waste management.

Geisinger, Johns Hopkins Testing Liquid Biopsy Assay for Early Cancer Detection

Geisinger Health and Johns Hopkins University have teamed up to study whether a liquid biopsy test that combines targeted circulating tumor DNA analysis with a number of protein markers can detect cancer early in healthy individuals.
At the Advances in Genome Biology and Technology meeting here last night, Joshua Cohen, a researcher at Johns Hopkins University who was involved in developing the test, called CancerSEEK, said that the study aims to recruit 50,000 healthy individuals. Cohen pointed out that for many types of cancer, early detection is associated with a better chance of survival, and for some, such as pancreatic or ovarian cancer, no good screening tests exist.
According to Geisinger’s website, the Detecting Cancers Earlier Through Elective Mutation-Based Blood Collection and Testing (DETECT) study is currently recruiting 10,000 women between the ages of 65 and 75 with no personal history of cancer for the study by March of this year and had enrolled 7,600 as of January.
The blood test used in the study, which was described about a year ago in a study in Science, looks for mutations in 16 genes in cell-free DNA and will assess the levels of 11 protein markers.
The Science study, which was retrospective and tested samples from patients with eight different types of cancer at various stages, as well as from healthy controls, had shown that the assay was only 40 percent sensitive for stage I cancer. Also, sensitivity differed between cancer types, with the test performing best for ovarian and liver cancer and worst for breast cancer. Specificity was high, with only seven false positives in the 812 healthy controls.
In his presentation last night, Cohen said that the Hopkins team has also developed an algorithm that can help predict the tissue of origin of the cancer in those testing positive. Again, performance differs by cancer type, with the top prediction being 80 percent correct for colorectal cancer, for example, and less accurate for other cancers.
He said that in the DETECT study, patients with a positive result in the initial blood test and a confirmatory second sample will undergo additional testing based on the localization prediction, for example, a colonoscopy if the assay predicts colorectal cancer. If the origin of the cancer cannot be predicted, they will undergo a PET-CT scan.
According to the Geisinger website, patients with two positive blood tests will talk to a genetic counselor and receive a recommendation for a PET-CT scan that will be paid for by the study.
In an interview with ABC last month, Andrew Faucett, co-chair of the Genetic Counseling Professional Council at Geisinger, said that while the current phase of the study, which has been ongoing for about a year, is recruiting only women, who are often more willing to see a doctor and more engaged, the study will expand to include men if successful. All participants will be followed for two years to see if they develop cancer.
He said the test has already detected cancer, including colon and ovarian cancer, in nine study participants.

Excessive daily TV at older age tied to poorer memory

Older people who want to preserve their faculties may wish to consider rationing their TV time. A large new study of older adults found that those who spent at least 3.5 hours per day watching TV experienced a greater decline in verbal memory.
Researchers at University College London in the United Kingdom analyzed data from the English Longitudinal Study of Ageing (ELSA) on 3,662 adults aged 50 and older.
In 2008–2009, and again in 2014–2015, the ELSA participants had answered questions about the time they spent watching TV.
At these times, they also completed tests of verbal memory and fluency.
The analysis revealed that those who watched TV for 3.5 hours or more per day had an average decline of 8–10 percent in word- and language-related memory over the 6 years the study covered. This is compared with a lower 4–5 percent average decline in those who watched fewer hours of TV per day over the same period.
The study, which now features in the journal Scientific Reports, found no such links between TV viewing time and differences in “semantic fluency.”
The verbal memory tests asked the participants to memorize and then recall lists of words within a given time, while the semantic fluency tests asked them to list as many examples of a category (such as a type of animal) as they could think of within a given time.
The study authors note that while there has been a lot of research into the effects of watching TV on cognition, most of it has focused on children.
“Much less attention,” says study co-author Dr. Daisy Fancourt, who works in the Department of Behavioural Science and Health, “has been paid to the effects of television viewing at the other end of the lifespan, despite it being hypothesized for over 25 years that watching excessive television could contribute to the development of dementia.”

Watching TV is a ‘passive activity’

An interesting point about the new study is the fact that the link between extensive TV viewing and greater verbal memory decline remained even after the researchers adjusted the results for how much time people spent sitting.
In considering potential reasons for their findings, they discuss the nature of TV viewing compared with other sedentary activities.
“Television,” explain the study authors, “has been described as a unique cultural activity in that it combines strong, rapidly changing fragmentary dense sensory stimuli on the one hand with passivity from the viewer on the other.”
Many studies that have tied sedentary time to cognitive decline in older adults have not considered this unique “alert-passive” nature of TV viewing, but they have treated it as a “proxy for sedentary behavior.”
The authors draw comparisons with research on other screen-based sedentary behaviors that has not linked them to cognitive decline.
Some studies, for example, have suggested that using the internet and playing video games — both sedentary activities that involve use of a screen — may even preserve, if not enhance, cognitive skills such as those necessary for problem-solving.

Watching TV and ‘cognitive stress’

The researchers suggest that watching TV could impact verbal memory through “cognitive stress.” Such stress, they argue, might arise from the alert-passive nature of TV viewing coupled with the psychological effects of witnessing violent, suspenseful, and graphic scenes.
Another explanation for the study findings could be that the more time people spend watching TV, the less opportunity they have to engage in “cognitively beneficial activities,” such as reading, playing board games, and cultural pursuits.
This could imply that the potentially negative impact of TV viewing is not just a result of its direct effects, but also because it displaces activities that preserve cognitive ability, even though they may also be sedentary.
“However,” note the study authors, “this remains to be explored further in future studies.”

Study does not deny benefits of TV

Finally, the researchers point out that their findings do not suggest that TV viewing in older age has no benefits at all. There is evidence, for instance, that adults who watch dramas as opposed to documentaries do better in tests that indicate a greater ability to understand others.
Some studies have also revealed that when “designed appropriately,” educational TV programs are efficient vehicles for learning.
TV also offers a means to escape from life at times of difficulty, and many people consider it a form of relaxation.
The British Heart Foundation part-funded this research. Chris Allen, a senior cardiac nurse for the charitable organization, explains that “it’s important to remember that cognitive decline is not the same as dementia.”