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Precision Medicine: What Is Cancer, Really? Scientists overview here.

Monday, May 22nd, 2017

The men and women who are trying to bring down cancer are starting to join forces rather than work alone. Together, they are winning a few of the battles against the world’s fiercest disease. For this unprecedented special report, we visited elite cancer research centers around the country to find out where we are in the war.

I. Precision Medicine: What Is Cancer, Really?

When you visit St. Jude Children’s Research Hospital in Memphis, Tennessee, you expect to feel devastated. It starts in the waiting room. Oh, here we go with the little red wagons, you think, observing the cattle herd of them rounded up by the entrance to the Patient Care Center. Oh, here we go with the crayon drawings of needles. The itch begins at the back of your throat, and you start blinking very fast and mentally researching how much money you could donate without starving. Near a row of arcade games, a preteen curls his face into his mother’s shoulder while she strokes his head. Oh, here we go.

But the more time you spend at St. Jude, the more that feeling is replaced with wonder. In a cruel world you’ve found a free hospital for children, started by a Hollywood entertainer as a shrine to the patron saint of lost causes. There is no other place like this. Corporations that have nothing to do with cancer—nothing to do with medicine, even—have donated vast sums of money just to be a part of it. There’s a Chili’s Care Center. The cafeteria is named for Kay Jewelers.

Scott Newman’s office is in the Brooks Brothers Computational Biology Center, where a team of researchers is applying computer science and mathematics to the question of why cancer happens to children. Like many computer people, Newman is very smart and a little quiet and doesn’t always exactly meet your eyes when he speaks to you. He works on St. Jude’s Genomes for Kids project, which invites newly diagnosed patients to have both their healthy and tumor cells genetically sequenced so researchers can poke around.

“Have you seen a circle plot before?” Newman asks, pulling out a diagram of the genes in a child’s cancer. “If I got a tattoo, it would be one of these.” Around the outside of the circle plot is something that looks like a colorful bar code. Inside, a series of city skylines. Through the center are colored arcs like those nail-and-string art projects students make in high school geometry class. The diagram represents everything that has gone wrong within a child’s cells to cause cancer. It’s beautiful.

A Genetic Disaster: This circular visualization shows real gene mutations found in 3,000 pediatric cancers at St. Jude Children’s Research Hospital. Genes with sequence mutations are labeled in blue; those with structural variations are in red; and those

“These are the genes in this particular tumor that have been hit,” Newman says in a Yorkshire accent that emphasizes the t at the end of the word hit in a quietly violent way. “And that’s just one type of thing that’s going on. Chromosomes get gained or lost in cancer. This one has gained that one, that one, that one, that one,” he taps the page over and over. “And then there are structural rearrangements where little bits of genome get switched around.” He points to the arcs sweeping across the page. “There are no clearly defined rules.”

It’s not like you don’t have cancer and then one day you just do. Cancer—or, really, cancers, because cancer is not a single disease—happens when glitches in genes cause cells to grow out of control until they overtake the body, like a kudzu plant. Genes develop glitches all the time: There are roughly twenty thousand genes in the human body, any of which can get misspelled or chopped up. Bits can be inserted or deleted. Whole copies of genes can appear and disappear, or combine to form mutants. The circle plot Newman has shown me is not even the worst the body can do. He whips out another one, a snarl of lines and blocks and colors. This one would not make a good tattoo.

“As a tumor becomes cancerous and grows, it can accumulate many thousands of genetic mutations. When we do whole genome sequencing, we see all of them,” Newman says. To whittle down the complexity, he applies algorithms that pop out gene mutations most likely to be cancer-related, based on a database of all the mutations researchers have already found. Then, a genome analyst manually determines whether each specific change the algorithm found seems likely to cause problems. Finally, the department brings its list of potentially important changes to a committee of St. Jude’s top scientists to discuss and assign a triage score. The mutations that seem most likely to be important get investigated first.

It took thirteen years and cost $2.7 billion to sequence the first genome, which was completed in 2003. Today, it costs $1,000 and takes less than a week. Over the last two decades, as researchers like Newman have uncovered more and more of the individual genetic malfunctions that cause cancer, teams of researchers have begun to tinker with those mutations, trying to reverse the chaos they cause. (The first big success in precision medicine was Gleevec, a drug that treats leukemias that are positive for a common structural rearrangement called the Philadelphia chromosome. Its launch in 2001 was revolutionary.) Today, there are eleven genes that can be targeted with hyperspecific cancer therapies, and at least thirty more being studied. At Memorial Sloan Kettering Cancer Center in New York City, 30 to 40 percent of incoming patients now qualify for precision medicine studies.

Charles Mullighan,a tall, serious Australian who also works at St. Jude, is perhaps the ideal person to illustrate how difficult it will be to cure cancer using precision medicine. After patients’ cancer cells are sequenced, and the wonky mutations identified, Mullighan’s lab replicates those mutations in mice, then calls St. Jude’s chemical library to track down molecules—some of them approved medicines from all over the world, others compounds that can illuminate the biology of tumors—to see if any might help.

New York: Britta Weigelt and Jorge Reis-Filho use police forensics techniques to repair old tumor samples at Memorial Sloan Kettering so the samples can be genetically profiled.

If Mullighan is lucky, one of the compounds he finds will benefit the mice, and he’ll have the opportunity to test it in humans. Then he’ll hope there are no unexpected side effects, and that the cancer won’t develop resistance, which it often does when you futz with genetics. There are about twenty subtypes of the leukemia Mullighan studies, and that leukemia is one of a hundred different subtypes of cancer. This is the kind of precision required in precision cancer treatment—even if Mullighan succeeds in identifying a treatment that works as well as Gleevec, with the help of an entire, well-funded hospital, it still will work for only a tiny proportion of patients.

Cancer is not an ordinary disease. Cancer is the disease—a phenomenon that contains the whole of genetics and biology and human life in a single cell. It will take an army of researchers to defeat it.

Luckily, we’ve got one.

Interlude

“I used to do this job out in L.A.,” says the attendant at the Hertz counter at Houston’s George Bush Intercontinental Airport. “There, everyone is going on vacation. They’re going to the beaach or Disneyland or Hollywood or wherever.

“Because of MD Anderson, I see more cancer patients here. They’re so skinny. When they come through this counter, they’re leaning on someone’s arm. They can’t drive themselves. You think, there is no way this person will survive. And then they’re back in three weeks, and in six months, and a year. I’m sure I miss some, who don’t come through anymore because they’ve died. But the rest? They come back.”

II. Checkpoint Inhibitor Therapy: You Have the Power Within You!

On a bookshelf in Jim Allison’s office at MD Anderson Cancer Center in Houston (and on the floor surrounding it) are so many awards that some still sit in the boxes they came in. The Lasker-DeBakey Clinical Medical Research Award looks like the Winged Victory statue in the Louvre. The Breakthrough Prize in Life Sciences, whose benefactors include Sergey Brin, Anne Wojcicki, and Mark Zuckerberg, came with $3 million.

“I gotta tidy that up sometime,” Allison says.

Allison has just returned to the office from back surgery that fused his L3, L4, and L5 vertebrae, which has slightly diminished his Texas rambunctiousness. Even on painkillers, though, he can explain the work that many of his contemporaries believe will earn him the Nobel Prize: He figured out how to turn the immune system against tumors.

“One day, the miracles won’t be miracles at all. They’ll just be what happens.”

Allison is a basic scientist. He has a Ph.D., rather than an M.D., and works primarily with cells and molecules rather than patients. When T-cells, the most powerful “killer cells” in the immune system, became better understood in the late 1960s, Allison became fascinated with them. He wanted to know how it was possible that a cell roaming around your body knew to kill infected cells but not healthy ones. In the mid-1990s, both Allison’s lab and the lab of Jeffrey Bluestone at the University of Chicago noticed that a molecule called CTLA-4 acted as a brake on T-cells, preventing them from wildly attacking the body’s own cells, as they do in autoimmune diseases.

Allison’s mother died of lymphoma when he was a child and he has since lost two uncles and a brother to the disease. “Every time I found something new about how the immune system works, I would think, I wonder how this works on cancer?” he says. When the scientific world discovered that CTLA-4 was a brake, Allison alone wondered if it might be important in cancer treatment. He launched an experiment to see if blocking CTLA-4 would allow the immune system to attack cancer tumors in mice. Not only did the mice’s tumors disappear, the mice were thereafter immune to cancer of the same type.

Ipilimumab (“ipi” for short) was the name a small drug company called Medarex gave the compound it created to shut off CTLA-4 in humans. Early trials of the drug, designed just to show whether ipi was safe, succeeded so wildly that Bristol Myers Squibb bought Medarex for $2.4 billion. Ipilimumab (now marketed as Yervoy) became the first “checkpoint inhibitor”: It blocks one of the brakes, or checkpoints, the immune system has in place to prevent it from attacking healthy cells. Without the brakes the immune system can suddenly, incredibly, recognize cancer as the enemy.

“You see the picture of that woman over there?” Allison points over at his desk. Past his lumbar-support chair, the desk is covered in papers and awards and knickknacks and frames, including one containing a black card with the words “Never never never give up” printed on it. Finally, the photo reveals itself, on a little piece of blue card stock.

That’s the first patient I met,” Allison says. “She was about twenty-four years old. She had metastatic melanoma. It was in her brain, her lungs, her liver. She had failed everything. She had just graduated from college, just gotten married. They gave her a month.”

The woman, Sharon Belvin, enrolled in a phase-two trial of ipilimumab at Memorial Sloan Kettering, where Allison worked at the time. Today, Belvin is thirty-five, cancer- free, and the mother of two children. When Allison won the Lasker prize, in 2015, the committee flew Belvin to New York City with her husband and her parents to see him receive it. “She picked me up and started squeezing me,” Allison says. “I walked back to my lab and thought, Wow, I cure mice of tumors and all they do is bite me.” He adds, dryly, “Of course, we gave them the tumors in the first place.”

After ipi, Allison could have taken a break and waited for his Nobel, driving his Porsche Boxster with the license plate CTLA-4 around Houston and playing the occasional harmonica gig. (Allison, who grew up in rural Texas, has played since he was a teenager and once performed “Blue Eyes Crying in the Rain” onstage with Willie Nelson.) Instead, his focus has become one of two serious problems with immunotherapy: It only works for some people.

So far, the beneficiaries of immune checkpoint therapy appear to be those with cancer that develops after repeated genetic mutations—metastatic melanoma, non-small-cell lung cancer, and bladder cancer, for example. These are cancers that often result from bad habits like smoking and sun exposure. But even within these types of cancer, immune checkpoint therapies improve long-term survival in only about 20 to 25 percent of patients. In the rest the treatment fails, and researchers have no idea why.

Lately, Allison considers immune checkpoint therapy a “platform”—a menu of treatments that can be amended and combined to increase the percentage of people for whom it works. A newer drug called Keytruda that acts on a different immune checkpoint, PD-1, knocked former president Jimmy Carter’s metastatic melanoma into remission in 2015. Recent trials that blocked both PD-1 and CTLA-4 in combination improved long-term survival in 60 percent of melanoma patients. Now, doctors are combining checkpoint therapies with precision cancer drugs, or with radiation, or with chemotherapy. Allison refers to this as “one from column A, and one from column B.”

The thing about checkpoint inhibitor therapy that is so exciting—despite the circumscribed group of patients for whom it works, and despite sometimes mortal side effects from the immune system going buck-wild once the brakes come off—is the length of time it can potentially give people. Before therapies that exploited the immune system, response rates were measured in a few extra months of life. Checkpoint inhibitor therapy helps extremely sick people live for years. So what if it doesn’t work for everyone? Every cancer patient you can add to the success pile is essentially cured.

Jennifer Wargo and team remove lymph nodes from a melanoma patient.

Diabetes cured in mice. What next? Human Trials

Tuesday, May 9th, 2017

The new technique cures diabetes in mice by bypassing the immune system that attacks beta cells

According to the Center for Disease Control, 1.25 million people suffer from type 1 diabetes in the US alone. So far, it can only be managed with diet and regular doses of insulin, but scientists at UT Health San Antonio have invented a way of curing the disease in mice that may one day do the same for humans even with type 2 diabetes.

Type 1 diabetes is a particularly unpleasant condition. It occurs when the pancreas ceases to produce the insulin needed by the body to metabolize sugar and, until the invention of artificial insulin injections, it was as deadly as cancer. Type 2 is the less severe form of the disease, where the body produces insufficient insulin; it can often be managed through diet alone.

Surprisingly, diabetes is an autoimmune disease. Insulin is made by specialized cells in the pancreas, called beta cells, and sometimes the body’s immune system turns against itself and attacks these beta cells, destroying them. Diabetes results when this destruction is over 80 percent.

Invented by Bruno Doiron and Ralph DeFronzo, the UT Health technique uses gene transfer to alter cells in the pancreases of mice to make them think they’re beta cells and start making insulin. This involves taking selected genes from external beta cells and using viruses as carriers to move them into the new host cells, in the diabetic pancreas.

Bruno Doiron (left), and Ralph DeFronzo co-invented a technique that has cured diabetes in mice for one year without side effects (Credit: UT Health)

According to DeFronzo, the altered cells then produce insulin, but only in the presence of sugar, which is how a functioning beta cell is supposed to work. Otherwise, the cells would just keep cranking out the hormone, metabolizing all the sugar in the bloodstream and causing hypoglycemia.

Only about 20 percent of the lost cells need to be replaced, but if new beta cells are simply introduced, it’s likely that the body would attack and destroy them as well. One big advantage of this technique is that it works around the autoimmune system, which ignores the altered cells.

“If a type 1 diabetic has been living with these cells for 30, 40 or 50 years, and all we’re getting them to do is secrete insulin, we expect there to be no adverse immune response,” says DeFronzo.

The team emphasizes that there is a large gap between curing diabetic mice and achieving the same in human beings. They say that they’d like to start clinical trials in three years, but more animal testing is needed first at a cost of about US$5 million, as well as making an application to the US Food and Drug Administration for investigational new drug approval.

“It worked perfectly,” says Doiron. “We cured mice for one year without any side effects. That’s never been seen. But it’s a mouse model, so caution is needed. We want to bring this to large animals that are closer to humans in physiology of the endocrine system.”

Source: UT Health

Henry Sapiecha

Potent Plant powder power prevents malaria victims from dying

Monday, May 8th, 2017

So what is this plant?

Weathers has made several high-producing versions of the plant using tissue cultures  (Credit: Worcester Polytechnic Institute)

When 18 malaria patients in the Congo failed to respond to conventional treatments and instead continued to head toward terminal status, doctors knew they had to act fast – and try something different. So instead of turning to more synthetic drugs, they turned instead to nature and found a solution that delivered remarkable results.

The patients were first treated with the regimen described by the World Health Organization (WHO): artemisinin-based combination therapy (ACT). This drug combines an extract from a plant known as Artemisia annua, with other drugs that launch a multi-pronged attack on the malaria parasite. But just as is the case with antibiotic-resistant bacteria, the malaria parasite is evolving to resist the drugs designed to kill it. In fact, according to the WHO, three of the five malarial parasites that infect humans have shown drug resistance.

As the patients continued to decline, with one five-year-old even entering into a coma, the doctors administered a drug called artesunate intravenously, which is the preferred course of action when treating severe malaria. The treatment didn’t work.

Finally, doctors turned to the Artemisia annua plant itself. Also called sweet wormwood or sweet Annie, the plant is the source of the chemical artemisinin, which is used in ACT therapy. The plant has been used since ancient times in Chinese medicine to treat fevers, although this bit of knowledge was lost until 1970 when the Chinese Handbook of Prescriptions for Emergency Treatments (340 AD) was rediscovered. In 1971 it was found that extracts from the plant could fight malaria in primates.

Pamela Weathers, professor of biology and biotechnology at Worcester Polytechnic Institute began researching Artemisia annua over 25 years ago. Along with postdoctoral fellow Melissa Towler, Weathers created a pill made from nothing more than the dried and powdered leaves of the plant. When the pills were given to the 18 dying patients over the course of five days, all of them completely recovered, with no trace of the malaria parasite remaining in their blood.

“These 18 patients were dying,” Weathers said. “So to see 100 percent recover, even the child who had lapsed into a coma, was just amazing. It’s a small study, but the results are powerful.”

Weathers had previously shown that the dried leaves of the Artemisia annua plant (DLA) could deliver 40 times more Artemisia annua to the blood than extracts of the plant alone. In a later experiment, she showed that not only could the leaves beat drug-resistant bacteria in mice, but that after passing the malaria parasite through 49 generations of mice, the parasite still showed no resistance to the plant.

While the exact mechanism through which DLA operates is unclear, Weathers says it’s likely due to the intricate chemical dance that occurs between the phytochemicals in the leaves.

Weathers with the Artemisia plant (Credit: Worcester Polytechnic Institute)

Because the drug is inexpensive and relatively simply to produce, Weathers also says that it could be a source of industry for people living in the areas where malaria is a problem, such as Ghana, Kenya and Malawi where it was recently announced that the first malaria vaccines will be deployed. “This simple technology can be owned, operated, and distributed by Africans for Africans,” said Weathers, who has already established a supply chain on the continent for the leaves using local producers.

Weathers also said that further research into DLA could lead to effective ways to combat other maladies.

“We have done a lot of work to understand the biochemistry of these compounds, which include a number of flavonoids and terpenes, so we can better understand the role they play in the pharmacological activity of the dried leaves,” Weathers said. “The more we learn, the more excited we become about the potential for DLA to be the medication of choice for combatting malaria worldwide. Artemisia annua is known to be efficacious against a range of other diseases, including other tropical maladies and certain cancers, so in our lab we are already at work investigating the effectiveness of DLA with other diseases.”

The results of the case in the Congo have been described in the journal Phytomedicine. You can hear more from Weathers in the video below.

Source: Worcester Polytechnic Institute

www.pythonjungle.com

Henry Sapiecha

 

Mayne pharma company shares plunge on revised sales

Monday, May 1st, 2017

Mayne Pharma buried its bad news a long way back in its presentation to investors on Monday, but when shareholders caught on their reaction was sharp.

Mayne Pharma’s shares plunged more than 10 per cent after it revealed sales for a flagship suite of US generic drugs would not meet guidance.

The news was buried on on page 107 of a 110-page update released to coincide with an investor day the company was holding on Monday.

The company said in the investor update that tougher generic drug pricing was behind the revised guidance for the suite of drugs called the Teva portfolio.

“The US generics market is facing a tough price deflation cycle, there’s no doubt about that, and Mayne Pharma is not immune,” chief executive Scott Richards told investors.

“This is probably as tough as it’s been.”

Mayne bought the portfolio of drugs from pharmaceutical giant Teva Pharmaceuticals last year for $845 million. The aquisition saw Mayne’s first-half profit soar 278 per cent to $72.7 million in February.

Shares were trading at $1.20 on Monday afternoon and was down almost 11 per cent for the day wiping about $200 million off the market capitalisation of the company.

Shares closed at $1.20.

Mayne, which is worth more than $1.8 billion, re-affirmed its full-year profit guidance during its first half results in February.

Chief executive Scott Richards said at the time that the outlook for the group “continues to be positive” with significant growth opportunities from recent acquisitions and new product launches.

He said the generic product division would benefit in the second half from a full six months’ contribution from the Teva product acquisition.

But on Monday Mayne raised several threats to its pharma pricing including the fact that US President Donald Trump had accused the industry of “getting away with murder”.

The company has been under fire on multiple fronts in the US. Its shares dived in December on the back of news of a US price fixing lawsuit.

The civil complaint – originally filed by 20 US states, now 40 – accuses six companies including Teva and Mayne of conspiring to artificially inflate prices on an antibiotic and a diabetes drug.

It is also facing three civil class actions over the matter.

Mr Richards said on Monday the lawsuits would not have a material impact on the business.

“We still don’t believe that under any reasonable case we can see based on our knowledge that it’s going to be a material event in any fiscal year,” Mr Richards said.

A spokesperson for the company said nothing material had changed in terms of its full year earnings guidance for Teva.

“Teva sales are expected to be down due to increasing price deflation in the US generics market,” the spokesperson said.

“However, notwithstanding that, the FY17 Teva earnings before interest, tax, depreciation and amortization (EBITDA) is broadly in line with the guidance we gave at the time of the Teva acquisition.”

www.druglinks.info

Henry Sapiecha