Bukowski, Butcher Billy
Not only will you be too terrified to ever get a job after watching this 1994 United Safety Council workplace safety video called Will You Be Here Tomorrow?, there’s also a good chance you’ll be too scared to ever actually leave your home. Neither Freddy Krueger nor Jason were ever as scary as the apparent horrors lurking in the average factory.
Here’s the classic science experiment of mixing fire and alcohol in a large empty jug. It’s always fun to see the perfect layer of flames slowly dance its way down the cylinder, like a slow drip of fire as the alcoholic vapors combust. Of course, the best part is that ‘whoosh’ sound it makes.
Some weeks can leave you feeling like you don’t want to live on this planet anymore. For one hour and 34 blissful minutes you can move to the marshy forests of Dagobah, and leave your earthly problems behind you.
Really hope they make this movie.
For years now we’ve been reporting on the on-again, off-again development of The Jim Henson Company’s The Happytime Murders, a puppet noir described as “Avenue Q meets L.A. Confidential.” The project got a shot in the arm last year when STX Entertainment scooped it up, and now it’s taking another big step forward by casting its first human. Jamie Foxx is in early talks to play the human half of the detective duo investigating a streak of puppet murders.
The Hollywood Reporter, which broke the Jamie Foxx Happytime Murders casting news. Brian Henson, son of Jim Henson and director of The Muppet Christmas Carol and Muppet Treasure Island, is on board to direct, as he has been since 2008. Erich and Jon Hoeber (Red, Battleship) wrote the latest version of the script, following earlier drafts by Todd Berger (It’s a Disaster) and Dee Robertson.
The trade describes the project as a “dark, R-rated” action comedy and explains the plot as follows:
Happytime takes place in a world where humans and puppets coexist, with the puppets viewed as second-class citizens. When the puppet castmembers of 1980s children’s TV show The Happytime Gang begin turning up dead, an alcoholic, disgraced LAPD detective-turned-private eye puppet takes the case with his former human partner.
Deadline has a little more to add, describing Foxx’s character as a “type-A, take-no-prisoners human with a secret” and his partner as “a crass, hard-drinking puppet with a connection to one of the victims.” The similarities to Avenue Q and L.A. Confidential are obvious, but The Happytime Murders also sounds a bit like Who Framed Roger Rabbit?, only with puppets instead of cartoons and an edgy R-rating instead of a family-friendly PG.
Foxx seems like a pretty great choice for the role. Not only is he the kind of big-name actor that could help a long-developing project like this pick up some steam, he’s a versatile talent who can switch between serious and silly. He was last seen in Annie and Horrible Bosses 2 (and The Amazing Spider-Man 2, about which the less said the better), and is now shooting Edgar Wright’s Baby Driver with Ansel Elgort and Kevin Spacey. Also on his to-do list is Robin Hood: Origins, a gritty retelling of the classic legend.
The post Jamie Foxx May Solve Crimes With a Puppet in The Jim Henson Company’s ‘The Happytime Murders’ appeared first on /Film.
Even before the Punisher made his Marvel Cinematic Universe debut in the second season of Daredevil, rumors abounded about the possibility of a Punisher spinoff. He’s a popular character to begin with, after all, and Jon Bernthal couldn’t be a better choice to play him. Then the character actually appeared on the show, and proved to be everything fans had hoped for. The calls for a Punisher spinoff only got louder. And now, Marvel is finally ready to make its move.
A Punisher spinoff has reportedly been ordered by Marvel, with Bernthal set to return as the vigilante character. Steve Lightfoot (Hannibal) will write, executive produce, and serve as showrunner.
Entertainment Weekly broke the news of the Punisher spinoff. This makes Punisher the sixth Marvel series at Netflix, after Daredevil, Jessica Jones, and the upcoming Luke Cage, Iron Fist, and The Defenders. As of now, it’s unclear whether Bernthal’s Punisher will appear in The Defenders, an Avengers-style team-up which brings together Netflix’s other four street-level heroes (Charlie Cox’s Daredevil, Krysten Ritter’s Jessica Jones, Mike Colter’s Luke Cage, and Finn Jones’ Iron Fist).
We’ve been hearing for a while that Netflix was eyeing the possibility of a Punisher solo series, though Marvel has insisted that nothing is official yet. According to Entertainment Weekly’s sources, they’ll make the official announcement later today. Vigilante Frank Castle definitely has enough of a following to lead his own project, and his grim and deadly antihero persona is a perfect fit for this darker, grittier corner of the Marvel Cinematic Universe.
Lightfoot is a veteran of British TV whose credits include Casualty and Hannibal. He began writing for the latter series in season 1 and was promoted to executive producer in season 2.
There’s no word yet on when the Punisher series will get going, but while we wait for updates you can check out the first teaser image below:
IT’S FUCKING WEDNESDAY. DID YOU KNOW THE ACCEPTANCE RATE FOR NASA’S LATEST ASTRONAUT JOB OPENINGS WILL COME IN AT .08%?
WORDS OF WISDOM OF THE FUCKING DAY:
DON’T WAIT FOR GANDALF TO SHOW UP AT YOUR DOOR AND TAKE YOU ON A GRAND ADVENTURE. BE GANDALF.
PERSON OF THE FUCKING DAY:
MOTHERFUCKING EINSTEIN’S COUSIN/WIFE. more>>
EDUCATE YOUR IGNORANT ASS:
HOW TO STOP GIVING A FUCK ABOUT WHAT OTHER PEOPLE THINK. more>>
FUCKING MIND-BLOWING BOOK OF THE DAY:
THE GREATEST SHIT NEVER TOLD. more>>
USEFUL SHIT OF THE GODDAMN DAY:
FOR ADULTS WHO REFUSE TO GROW THE FUCK UP. more>>
WEBSITE OF THE FUCKING DAY:
LEARN YOUR DAMN AFRICAN COUNTRIES. more>>
AWESOME-AS-SHIT VIDEO OF THE DAY:
ARE WE ALONE IN THE FUCKING UNIVERSE? more>>
SWEET-ASS PICTURE OF THE DAY:
FUCKING TAIPEI. more>>
IT’S FUCKING THURSDAY. DID YOU KNOW IN 1838 THE GOVERNOR OF MISSOURI MADE IT LEGAL TO KILL MORMONS?
WORDS OF WISDOM OF THE FUCKING DAY:
IF IT SCARES YOU, THEN IT MIGHT BE A GOOD THING TO TRY.
PERSON OF THE FUCKING DAY:
WASHINGTON’S RIVAL AND AN ASSHOLE GENERAL. more>>
EDUCATE YOUR IGNORANT ASS:
FUCKING JOB INTERVIEW PREP 101. more>>
FUCKING MIND-BLOWING BOOK OF THE DAY:
HOW TO SEE SHIT DIFFERENTLY. more>>
USEFUL SHIT OF THE GODDAMN DAY:
HAPPY FUCKING WHATEVER. more>>
WEBSITE OF THE FUCKING DAY:
POLISH YOUR SHITTY WRITING. more>>
AWESOME-AS-SHIT VIDEO OF THE DAY:
HOW TO COUNT PAST FUCKING INFINITY. more>>
SWEET-ASS PICTURE OF THE DAY:
GLACIER NATIONAL FUCKING PARK. more>>
Deadline reports that The Weinstein Company backed series will follow Stallone as the “last great American don” Raymonde Aprile and his adopted nephew Astorre Viola. Chosen to succeed Aprile, Astorre comes to control the don’s banking interests in a plot line that seems fairly reminiscent of The Godfather Part III.
While Stallone has produced and appeared in a number of reality TV series, this will be his first significant recurring dramatic role.
Magnificent Seven remake director Antonie Fuqua will direct and executive produce with Stallone. The production is also currently looking for a showrunner, a lead actress and a network to take on the event series.
In honor of the best backfire & comeuppance episode in South Park history, Kidrobot brings you a figure like no other. A.W.E.S.O.M.-O, a collectible that is fully-sculpted, and 6 inches of awesome design, for $59.99.
Here’s what Kidrobot has to say:
“Technically known as A.W.E.S.O.M.-O 4000, hijinks ensue when Cartman does what Cartman does and acts like a choade. Disguising himself to learn Butters’ deepest secrets…”
A.W.E.S.O.M.-O even comes with a removable head that reveals the half-starved face of Eric Cartman with only his toothpaste accessory for sustenance. I can safely say, this looks like one of the coolest collectibles I’ve seen, especially South Park wise. Since it’s made its return to Kidrobot.com, I wouldn’t wait to grab one. The uniqueness and detailed design will surely make it sell out again.
Makes me like Keanu more.
The kidnapped kitten at the center of the new comedy Keanu is obviously named after Keanu Reeves, the seemingly immortal star of Speed, Point Break, The Matrix, and John Wick, but we now know that the actor himself has a tiny cameo in the film. Keanu Reeves plays Keanu the cat. Well, technically he voices Keanu the cat in a scene where a character hallucinates during a crazy drug trip. However, this cameo almost didn’t happen and we have Mr. Reeves’ sister to thank for its existence.
Keanu, which is the big screen debut of beloved comedy duo Keegan-Michael Key and Jordan Peele, follows two best friends, one a lazy stoner and the other a boring suburbanite, who infiltrate the local criminal underworld when a beloved kitten is abducted by a dangerous gangster. Naturally, all kinds of mayhem ensues. The work-in-progress cut that screened at SXSW earlier this year was inconsistent, but funny enough to warrant a second round with the finished version. And yes, that cut did feature a scene where Keanu the kitten speaks with the voice of Keanu Reeves, but at the time, it wasn’t clear if it was the man himself or a skilled imitator.
Speaking with the LA Times, director Peter Atencio explained that he initially reached out to Reeves’ representatives, but he didn’t get very far. However, the arrival of the film’s trailer changed everything:
Yeah, they politely declined. Who knows if he ever even heard about the offer. But then we got a call after the trailer came out — apparently, his sister showed him the trailer and said, ‘Hey, you gotta see this. You’re gonna love this!’ He flipped out and got in touch with us directly to say ‘If there’s anything I can do, let’s make this work.’
Before he signed on, Reeves wanted to speak with Atencio to make sure the movie wasn’t making fun of him. Atencio has nothing but nice things to say about his conversation with the man who gave his movie its title:
He wanted to talk to me before he agreed to make sure that wasn’t the case. So I told him about the movie and talked him through the story. His personality has just transcended life, in a lot of ways. You wouldn’t have ever guessed that the guy from Bill and Ted’s Excellent Adventure would turn out to be this thoughtful, kind man.
So Reeves recorded his cameo in Rome, where he was filming John Wick: Chapter 2 and the rest is history. You can watch Keanu Reeves play Keanu in Keanu when the movie hits theaters this Friday.
UPDATE: Page Six has learned that Reagan is no longer on Will Ferrell’s docket, and there’s a chance it may never have been. A representative told Page Six, “The ‘Reagan’ script is one of a number of scripts that had been submitted to Will Ferrell which he had considered. While it is by no means [an] ‘Alzheimer’s comedy’ as has been suggested, Mr. Ferrell is not pursuing this project.”
It’s not clear if Ferrell was possibly involved and some outcry about the project changed his mind, but either way, he’s not starring in the movie, nor is he producing it. So the project will have to find some other talent to bring it to life, if anyone else out there dares to make it happen. Our original story from yesterday follows below
Will Ferrell is no stranger to political satire. The comedian garnered a huge following while on Saturday Night Live for his iconic portrayal of President George W. Bush, which he eventually reprised for a one-man stage show. Plus, he also starred in the comedy feature The Campaign, not to mention skewering cable news in Anchorman 2: The Legend Continues. Now Ferrell will bring another Republican president to life, this time on the big screen.
The Black List comedy script Reagan has just landed Will Ferrell to star as President Ronald Reagan. However, at least one member of the president’s family is already unhappy with the project. Find out why below.
The movie that will have Will Ferrell playing Ronald Reagan takes place at the start of the ex-president’s second term, when the Commander in Chief started to develop Alzheimer’s disease. In the film, an intern is tasked with convincing Ronald Reagan that he’s an actor playing the president in the movie. That sounds like a hilarious concept, which is probably why the script from Mike Rosolio made the Black List last year. But Ronald Reagan’s son Michael Reagan doesn’t agree. He took to Twitter to gripe about the comedy:
— Michael Reagan (@ReaganWorld) April 27, 2016
What an Outrag….Alzheimers is not joke…It kills..You should be ashamed all of you. https://t.co/GNzqR5vjrX
— Michael Reagan (@ReaganWorld) April 27, 2016
One can’t really slight Michael Reagan for being mad about a satire that aims to make jokes out of a debilitating disease that his father had. It’s a tough ailment to deal with both for the one who has the disease and for their family. There have been plenty of other people echoing Reagan’s sentiments regarding both the disrespect for Ronald Reagan and for Alzheimer’s patients in general.
But this is satire we’re talking about, and sometimes comedy is the best way to deal with painful subject matter. Personally, I don’t find this comedic concept to be disrespectful of Ronald Reagan or Alzheimer’s patients. It’s a fabricated story that uses real-life tragedy as a jumping off point for comedy, and it’s no more disrespectful than anything that was done on Saturday Night Live to mock Ronald Reagan, or any other president for that matter.
Plus, when you consider how much time has passed, it doesn’t seem like all that insensitive of a comedic concept. Tragedy plus time equals comedy. Plenty of people make jokes about Abraham Lincoln or John F. Kennedy being assassinated, and one could argue that getting shot in the head is probably much worse than Alzheimer’s disease.
Satire is often meant to be provocative, so this kind of controversy is nothing new. But since Variety says the movie doesn’t have a distributor just yet, any potential outrage or adversity may stop the film from getting off the ground. The film doesn’t have a director yet, but with Ferrell also producing through his Gary Sanchez Productions banner, they shouldn’t have a problem finding one.
What do you think of this Ronald Reagan comedy?
The post Will Ferrell Not Starring in Presidential Comedy ‘Reagan’ After All [UPDATED] appeared first on /Film.
The featherweight bout opened up the main card of the UFC 197 event at MGM Grand Garden Arena in Las Vegas. It aired on pay-per-view following prelims on FOX Sports 1 and UFC Fight Pass.
Fili (15-4 MMA, 3-3 UFC) was on his toes from the first second with Rodriguez (7-1 MMA, 4-0 UFC) whipping flashy kicks at his legs, body and head. Making matters worse for the Team Alpha Male fighter was Rodriguez’s ability to score takedowns and work from top position.
After managing to get the fight back to the feet, Fili found himself on the receiving end of a knockout that will become a staple of UFC advertising for years to come. Rodriguez launched himself into the air and landed a switch kick to the face of Fili, knocking him stiff and ending the bout at the 2:15 mark of Round 2.
Check out the video highlights above.
Crusoe the Celebrity Dachshund (previously at Neatorama) and his brother Oakley don ridiculous little uniforms to play a game of street hockey. They’re not very good players, but no one cares because they are so funny!
These dogs have little trouble aiming their sticks, and tend to succumb to temptation and eat the puck. But you won’t find better dachshund hockey players anywhere! -via Tastefully Offensive
Kiss cams are old hat! Besides, it can be truly embarrassing when the camera focuses in and you’re sitting there with your brother, or even worse, your side-dude. Last night, the Denver Nuggets hosted the San Antonio Spurs, and unveiled a new crowd-cam idea that everyone immediately understood and took to: The Lion King Cam!
During a timeout, the camera finds a baby in the crowd, focuses in, and plays the opening lines from “The Circle of Life.” The object of the focus immediately understands what to do. All new parents, and even aunts and granddads, know they are supposed to hold the baby up just like Rafiki presenting Simba to the Pride Rock residents (or, for those of us of a certain age, the infancy of Kunta Kinte). We hope Denver keeps this idea going, and it may spread to other arenas. -via Uproxx
2CELLOS are back with a little number that blends Beethoven’s Fifth Symphony with “Whole Lotta Love” from Led Zeppelin. By the time they are finished, it’s four cellos.
Luka Sulic and Stjepan Hauser were once rivals for the title of hottest best cello player in Croatia, and then teamed up to form 2CELLOS. Which was a great move. Hear more of their music in previous posts at Neatorama.
That's fucked up.
...I'd try it.
The bad news is that Elliot was not able to rescue E.T. and ensure that he got back home.
The good news is that E.T. is delicious!
(Photos: Bengt Pettersson and Helga Steppan)
Eating E.T. is an occasional project by Terje Östling and Unsworn Industries, a design firm in Malmö, Sweden. They crafted an E.T. sculpture out of vegan-friendly foods and roasted it at the Exploring the Animal Turn symposium in Lund, Sweden in 2014. Later they made another E.T. and roasted him at the Foodycle festival in Helsinki, Finland.
The purpose of the project, beyond eating good barbecue, is to explore how being human impacts ethical food choices:
What would it feel like to eat an alien? How can we dearly love and grieve some non-human species while accepting the industrialised slaughter of others? How can we cater to the needs of eaters who seek a surrogate for the sacrificial and ritual aspects of convivial, meat-based, barbecues? What are our ethical responsibilities towards fictional organisms?
Octopuses1 are complicated creatures: vulnerable but strong; slimy, but also kitten-like. And they're full of remarkable secret powers.
(Image credit: Flickr user Aoife Cahill)
Aside from its beak and braincase, an octopus is entirely squishy, meaning that a 100-pound giant Pacific octopus can squeeze through a hole about the size of a cherry tomato. They can also undo latches, untie knots, and open locks, all of which makes them extremely difficult to keep in captivity. In his 1973 book Octopus and Squid: The Soft Intelligence, Jacques Cousteau tells this charming story: “Our friend Gilpatric ... brought an octopus home and put it in an aquarium, which he then covered with a heavy lid. A short time later, the aquarium was empty, and Gilpatric found the octopus going through his library, book by book, turning the pages with its arms.”
Given their love of libraries, it’s no surprise that octopuses are the smartest invertebrates. They can solve puzzles, recognize human faces, navigate mazes, and even open childproof Tylenol bottles. In the 1990s, biologist Roland Anderson gave plastic pill bottles to the octopuses in his lab. Once they learned the bottles weren’t edible, all of the octopuses lost interest- except for one. A female octopus used her funnel2 to push the bottle to the opposite end of her tank. The water current pushed it back, and again, she pushed the bottle away. After repeating the move 18 times, Anderson had no doubt: The octopus was playing a game of bouncy ball.
Since they move around to find prey, an octopus must find a new home every few days. The ideal pad is hidden, dark, and just a little larger than the octopus’s body, so octopuses will often hide in the crevice of a rock, an old seashell, the hull of a shipwreck, or a stubby brown bottle. (“If you’re determined to litter at sea but still want to keep the little octopus in mind, I suppose Red Stripe bottles might be the way to go,” writes Katherine Harmon Courage in her book, Octopus!) Once the octopus selects a house, it uses its funnel to blow debris out of the den, and then barricades the entrance with rocks to keep out unwanted visitors.
(Image credit: Sylke Rohrlach)
Octopuses are careful housekeepers and spend time each day cleaning the sand, gravel, and the remains of last night’s dinner from their house. Divers have learned to spot octopus dens by looking for a trash pile just outside the entrance. Female octopuses are also skilled interior decorators: They lay their eggs in long strings and attach them to the ceiling like translucent beaded curtains.
(Image credit: Brocken Inaglory)
Some shallow-water species occasionally come ashore to hunt. Some have even been caught eating seagulls. But walking is just the beginning: To the chagrin of some scientists, these cephalopods can run. As a pre-veterinary student, Alexa Warburton had the tricky task of scooping octopuses out of their tanks. The stubborn animals would hide or squeeze into the tank’s cracks to avoid being removed. As a last-ditch effort, some octopuses would trampoline off the net, leap to the floor, and take off zig-zagging around the lab. It’s “like chasing a cat,” Warburton told Orion magazine.
In less than 0.3 seconds, octopuses can change their color, texture, and shape to blend in with their surroundings—transforming their skin to mimic algae-covered rocks, a sandy seabed, or fronds of kelp. (Special cells let them display different pigments, while bumps on their skin called papillae can create textures.) It’s astonishing, considering that scientists believe octopuses are colorblind. But that’s just the first act: If a predator still isn’t fooled, some species can deploy a pseudomorph—a life-size self-portrait made from a cloud of ink and mucus. The specter distracts and irritates the predator and allows the octopus to jet away.
The mimic octopus, a smaller species that lives in the Indo-Pacific, uses its shape-shifting skills for a mind-boggling defense. Instead of convincing would-be predators that it has disappeared, T. mimicus instantly changes shape to look and act like venomous creatures, including flatfish, spiky lionfish, jellyfish, and sea snakes.
Concerned for the octopus’s safety, Seattle Aquarium staff were hesitant to house dogfish sharks and a giant Pacific octopus in the same tank in 2001. They did it anyway, and for a while, everything seemed calm. Then partially eaten sharks began turning up on the tank’s floor. A video camera captured the perpetrator—the octopus—following unhealthy sharks around the tank, grabbing them, and chowing down. Octopuses will also rip the stinging tentacles off a Portuguese man-o’-war and wield them like a weapon.
(Image credit: Делфина)
Deep inside its rubbery mantle, an octopus has a sharp beak and a toothed, tongue-like ribbon called a radula. When its super-strong arms aren’t enough to pry apart a tasty clam’s shell, the octopus uses its radula to drill a small hole in the shell, then injects a neurotoxin into the opening. The clam goes limp, the shell opens, and lunch is served.
The couch potato of the sea, octopuses will go to great lengths to avoid leaving the house. Fortunately, the male’s sex organ is at the end of one arm, so mating doesn’t have to be intimate. While some opt for the traditional mounted technique, others prefer what scientists call the “distance position.” Male and female Abdopus aculeatus adults will even find houses near one another so that the male only has to stretch his hectocotylus—or sex arm—out his front door and into the female’s house. Everybody stays safe indoors, and nobody has to buy dinner.
1. It's true! The most acceptable English plural is octopuses, not octopi. The classic Latin plural -which adds the i- is great for Latin-based words. Problem is, octopus isn't Latin! It's Greek. Octopodes, the Greek form, is also acceptable but a little archaic.
2. The funnel is nature's great jet propulsion system, helping some octopuses dart through the water at 25 mph.
The above article is reprinted with permission from the May 2015 issue of mental_floss magazine.
Dangerous Minds appropriately calls this outfit the "holy grail" of fashion. Fashion designers might as well pack it in because the long quest for the perfect, every day, all day outfit is now finally complete. Rage On sells an adult onesie covered with faces of actor Steve Buscemi's movie characters.
Minor problem: there's no flap in the back. You could probably cut one, though.
Vince Gilligan and Peter Gould like to include Easter Eggs in their shows for observant fans to find, and viewers enjoyed finding secret stuff on Breaking Bad so much Vince and Peter decided to keep the Eggs rolling in Better Call Saul. (Spoiler-ish material ahead)
For the second season of Saul they decided to go beyond the visual and play with words by including an anagram in the episode titles, so they put the puzzle in place and didn't give it a second thought.
But a fan named Shaquita discovered the Easter Egg faster than a tweeker on Blue Sky, posting her findings on Twitter with the caption “on vacation this week, and have nothing but time lol".
The creators confirmed Shaquita's findings and were blown away by how fast she found it:
“We had this—to us—this very bright idea of encoding the words “Fring’s Back” in the episode titles,” Gould told Vanity Fair. “And we thought we’d be revealing it maybe sometime over the summer. I guess we really underestimated the genius and hard work of our fans.”
“And their attention to detail, and God bless them for it,” Gilligan chimed in.
Gould concluded: “It’s hard to complain about people paying attention to every aspect of the show. It certainly reminds us again that we better keep all our i’s dotted and our t’s crossed in every aspect of the show.”
A photo posted by julie b. (@julie_b_xyz) on Jun 26, 2015 at 8:39pm PDT
Every year since 2008, cyclists in Portland, Oregon, have taken part in a ride called Bowie vs. Prince. They sign up for either Team Bowie or Team Prince, and then dress like them for the ride. Founder Lillian Karabaic had considered changing the event in the wake of Bowie’s death.
"Me and my co-leader, with Bowie's death this year, were considering making the ride Bowie vs. Bowie," said Karabaic. "We felt like a lot of people wouldn't want to be Prince in light of it. I guess for better or worse, it's now going to be Bowie vs. Prince again."
Karabaic was thinking about ending the annual ride even before the stars' deaths. She's hoping some other event can take its place next year, but thinks it's fitting this year's bike ride will be the last.
"Bowie vs. Prince is going to be a totally different type of ride this year," she said. "It's going to be a memorial ride."
Somehow, I think that this year’s event may be the biggest of all, even if it is the last one. -via Uproxx
This is awesome.
It sounds like a headline out of Warren Ellis‘s Iron Man run.
Isaac Perlmutter, the billionaire CEO of Marvel and one of Disney’s largest shareholders has, along with his wife Laura Perlmutter, donated an additional $9 million to the NYU Langone Medical Center and the Technion-Israel Institute of Technology in addition to a 2014 donation of $50 million that set up the Perlmutter Cancer Center.
The first $3 million of that will be used to finance six joint research projects, with co-investigators on each project will receive a two-year, $500,000 grant–$250,000 for each site.
While the remaining $6 million will establish a state-of-the-art research facility on the Technion campus in Israel to support these and other research projects, primarily in the emerging field of cancer metabolomics, the systematic study of the unique chemical fingerprints that cellular processes leave behind. These processes are both affected by, and can influence, a variety of human diseases, including cancer.
In the first joint collaboration, NYU Langone and Technion researchers will test the ability of a nanotechnology based on stem cell “nanoghosts” to deliver to the brain a promising treatment for metastatic melanoma, skin cancer that has spread or metastasized, and is often incurable.
In earlier studies, researchers at the Technion took a stem cell, removed its contents, and then shaped a piece of the cell’s outer membrane into a vehicle to deliver treatments into the brain. The idea was to borrow the stem cell’s outer membrane ability to home in on cancer cells. As a fragment of the former stem cell’s membrane, the nanoghost encompasses particular mechanisms that slow it enough to traverse the barrier that filters blood flowing into the brain, and which keeps most drugs from entering.
The nanoghost’s cargo is a microRNA (miR), a stretch of genetic material that fine-tunes genetic messages by blocking the conversion of genes into proteins. First applied by NYU researchers to metastatic melanoma, miR-124a, in particular, blocks the expression of cancer-promoting genes. The joint team’s experiments will seek to determine the feasibility of encapsulating miR-124a in the nanoghost, and study how the vehicle reaches its target in mouse models of the disease.
“Our studies should provide important information on nanoghosts’ general value as drug and gene carriers to the brain, and create potential for new treatment approaches against brain tumors and metastases,” said Professor Marcelle Machluf, PhD, head of the Laboratory for Cancer Drug Delivery & Cell Based Technologies at the Technion, and inventor of the nanoghost with her colleagues there. “The difficulty of delivering agents to the brain represents a major impediment to improving outcomes in patients suffering from brain tumors. Our state-of-the-art nanovehicle promises safer, simpler and more clinically relevant treatments than existing vehicles, which are comprised of polymers or synthetic vesicles which largely lack the ability to enter the brain and to target evolving and changing pathologies.”
“It is much harder to secure funding for this type of high risk, high reward research,” said Eva Hernando-Monge, PhD, associate professor in the Department of Pathology at NYU Langone, a member of the Perlmutter Cancer Center, and leader of the NYU team that first identified miR-124 as a suppressor of the growth of brain metastases. “The Perlmutters’ generous gift gives us the ability to be bold.”
Like the stem cells they are based on, nanoghosts are invisible to the immune system, which means they could potentially be made from donated stem cells, expanded to large numbers in the lab, and not just from the patient’s own supply. In the future, this could enable the stockpiling of nanoghost treatments used off the shelf without fear of immune reactions to treatments based on “foreign” cells.
The second joint project will investigate whether an enzyme called heparanase can be used to diagnose and treat mesothelioma, a rare cancer that develops in the mesothelium, the protective lining of the lungs and other internal organs of the body. Malignant pleural mesothelioma (MPM), the most common form of the disease, often occurs after exposure to asbestos and is resistant to most therapies.
Heparanase was first identified as a treatment target in 2004 by a team led by Israel Vlodavsky, PhD, one of the project’s co-investigators and professor at the Rappaport Faculty of Medicine. Past studies found that patients with high levels of this enzyme in their tumors have lower survival rates after surgery, and that related tumors in mice respond to treatment with heparanase-inhibiting compounds.
The enzyme breaks up molecular chains of heparan sulfate, a building block of the scaffolds that give organs shape and support. Cancer cells use the enzyme to break down tissue barriers around a growing tumor, providing new pathways for the cancer to spread and for the building of blood vessels that supply tumors. In addition, breaking up extracellular matrices releases pro-growth proteins stored there to further drive disease. Furthermore, the joint team has developed the novel theory that heparanase secreted by tumor cells primes local microenvironments in a “vicious” cycle where inflammation and tumor growth drive each other.
The co-investigators at NYU Langone — led by Harvey I. Pass, MD, the Stephen E. Banner Professor of Thoracic Surgery and vice chair for research, Department of Cardiothoracic Surgery, at NYU Langone, also a member of its Perlmutter Cancer Center — will use tissue samples from its Thoracic Oncology Archives to validate Dr. Vlodavsky’s findings in hopes of eventually evaluating the treatment potential of heparanase-inhibiting compounds in mesothelioma clinical trials. Dr. Pass has been collecting tissue samples from his surgical patients since 1989, when he was head of thoracic oncology at the National Cancer Institute (NCI). The collection now houses frozen specimens from more than 350 mesothelioma patients.
“This project, supported through the generosity of the Perlmutters, enables us to collaborate with one of the world’s leading experts on the role of heparanase in cancer, and is crucial in developing new strategies,” Dr. Pass says. “We hope that these experiments can be translated into applications for ongoing funding from the NCI, and enable Phase I trials with new therapeutics that influence heparanase pathways.”
“Our collaboration represents the first attempt to focus on heparanase as a major risk factor in mesothelioma and a valid target for the development of heparanase-inhibiting drugs,” Dr. Vlodavsky says. “In fact, applying a potent inhibitor of the heparanase enzyme we have already demonstrated a most prominent inhibition of tumor progression in mouse models of human mesothelioma, resulting in a pronounced extension of mouse survival. This joint effort provides an opportunity to make important strides in both our fundamental understanding of mesothelioma and in translating this knowledge into therapeutics.”
Much has been made of the Perlmutter’s financial support for the Republican Party Presidential candidates with two million to promote Marco Rubio‘s Presidential campaign, and one million to Donald Trump‘s veteran campaign. Rubio has stated that he does not support human embryonic stem cell research while Trump stated he is undecided. Technion however was the place that first harvested human embryonic stem cells and are likely to form the basis for this research. It may demonstrates that the Perlmutter are a little more nuanced when it comes to putting their money where their mouths are.