Artificial intelligence to generate new cancer drugs on demand

December 18, 2016

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Summary:

  • Clinical trial failure rates for small molecules in oncology exceed 94% for molecules previously tested in animals and the costs to bring a new drug to market exceed $2.5 billion
  • There are around 2,000 drugs approved for therapeutic use by the regulators with very few providing complete cures
  • Advances in deep learning demonstrated superhuman accuracy in many areas and are expected to transform industries, where large amounts of training data is available
  • Generative Adversarial Networks (GANs), a new technology introduced in 2014 represent the “cutting edge” in artificial intelligence, where new images, videos and voice can be produced by the deep neural networks on demand
  • Here for the first time we demonstrate the application of Generative Adversarial Autoencoders (AAEs), a new type of GAN, for generation of molecular fingerprints of molecules that kill cancer cells at specific concentrations
  • This work is the proof of concept, which opens the door for the cornucopia of meaningful molecular leads created according to the given criteria
  • The study was published in Oncotarget and the open-access manuscript is available in the Advance Open Publications section
  • Authors speculate that in 2017 the conservative pharmaceutical industry will experience a transformation similar to the automotive industry with deep learned drug discovery pipelines integrated into the many business processes
  • The extension of this work will be presented at the “4th Annual R&D Data Intelligence Leaders Forum” in Basel, Switzerland, Jan 24-26th, 2017

Thursday, 22nd of December Baltimore, MD – Scientists at the Pharmaceutical Artificial Intelligence (pharma.AI) group of Insilico Medicine, Inc, today announced the publication of a seminal paper demonstrating the application of generative adversarial autoencoders (AAEs) to generating new molecular fingerprints on demand. The study was published in Oncotarget on 22nd of December, 2016. The study represents the proof of concept for applying Generative Adversarial Networks (GANs) to drug discovery. The authors significantly extended this model to generate new leads according to multiple requested characteristics and plan to launch a comprehensive GAN-based drug discovery engine producing promising therapeutic treatments to significantly accelerate pharmaceutical R&D and improve the success rates in clinical trials.

Since 2010 deep learning systems demonstrated unprecedented results in image, voice and text recognition, in many cases surpassing human accuracy and enabling autonomous driving, automated creation of pleasant art and even composition of pleasant music.

GAN is a fresh direction in deep learning invented by Ian Goodfellow in 2014. In recent years GANs produced extraordinary results in generating meaningful images according to the desired descriptions. Similar principles can be applied to drug discovery and biomarker development. This paper represents a proof of concept of an artificially-intelligent drug discovery engine, where AAEs are used to generate new molecular fingerprints with the desired molecular properties.

“At Insilico Medicine we want to be the supplier of meaningful, high-value drug leads in many disease areas with high probability of passing the Phase I/II clinical trials. While this publication is a proof of concept and only generates the molecular fingerprints with the very basic molecular properties, internally we can now generate entire molecular structures according to a large number of parameters. These structures can be fed into our multi-modal drug discovery pipeline, which predicts therapeutic class, efficacy, side effects and many other parameters. Imagine an intelligent system, which one can instruct to produce a set of molecules with specified properties that kill certain cancer cells at a specified dose in a specific subset of the patient population, then predict the age-adjusted and specific biomarker-adjusted efficacy, predict the adverse effects and evaluate the probability of passing the human clinical trials. This is our big vision”, said Alex Zhavoronkov, PhD, CEO of Insilico Medicine, Inc.

Previously, Insilico Medicine demonstrated the predictive power of its discovery systems in the nutraceutical industry. In 2017 Life Extension will launch a range of natural products developed using Insilico Medicine’s discovery pipelines. Earlier this year the pharmaceutical artificial intelligence division of Insilico Medicine published several seminal proof of concept papers demonstrating the applications of deep learning to drug discovery, biomarker development and aging research. Recently the authors published a tool in Nature Communications, which is used for dimensionality reduction in transcriptomic data for training deep neural networks (DNNs). The paper published in Molecular Pharmaceutics demonstrating the applications of deep neural networks for predicting the therapeutic class of the molecule using the transcriptional response data received the American Chemical Society Editors’ Choice Award. Another paper demonstrating the ability to predict the chronological age of the patient using a simple blood test, published in Aging, became the second most popular paper in the journal’s history.

“Generative AAE is a radically new way to discover drugs according to the required parameters. At Pharma.AI we have a comprehensive drug discovery pipeline with reasonably accurate predictors of efficacy and adverse effects that work on the structural data and transcriptional response data and utilize the advanced signaling pathway activation analysis and deep learning. We use this pipeline to uncover the prospective uses of molecules, where these types of data are available. But the generative models allow us to generate completely new molecular structures that can be run through our pipelines and then tested in vitro and in vivo. And while it is too early to make ostentatious claims before our predictions are validated in vivo, it is clear that generative adversarial networks coupled with the more traditional deep learning tools and biomarkers are likely to transform the way drugs are discovered”, said Alex Aliper, president, European R&D at the Pharma.AI group of Insilico Medicine.

Recent advances in deep learning and specifically in generative adversarial networks have demonstrated surprising results in generating new images and videos upon request, even when using natural language as input. In this study the group developed a 7-layer AAE architecture with the latent middle layer serving as a discriminator. As an input and output AAE uses a vector of binary fingerprints and concentration of the molecule. In the latent layer the group introduced a neuron responsible for tumor growth inhibition index, which when negative it indicates the reduction in the number of tumour cells after the treatment. To train AAE, the authors used the NCI-60 cell line assay data for 6252 compounds profiled on MCF-7 cell line. The output of the AAE was used to screen 72 million compounds in PubChem and select candidate molecules with potential anti-cancer properties.

“I am very happy to work alongside the Pharma.AI scientists at Insilico Medicine on getting the GANs to generate meaningful leads in cancer and, most importantly, age-related diseases and aging itself. This is humanity’s most pressing cause and everyone in machine learning and data science should be contributing. The pipelines these guys are developing will play a transformative role in the pharmaceutical industry and in extending human longevity and we will continue our collaboration and invite other scientists to follow this path”, said Artur Kadurin, the head of the segmentation group at Mail.Ru, one of the largest IT companies in Eastern Europe and the first author on the paper.

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About Insilico Medicine, Inc

Insilico Medicine, Inc. is a bioinformatics company located at the Emerging Technology Centers at the Johns Hopkins University Eastern campus in Baltimore with Research and Development (“R&D”) resources in Belgium, UK and Russia hiring talent through hackathons and competitions. The company utilizes advances in genomics, big data analysis, and deep learning for in silico drug discovery and drug repurposing for aging and age-related diseases. The company pursues internal drug discovery programs in cancer, Parkinson’s Disease, Alzheimer’s Disease, sarcopenia, and geroprotector discovery. Through its Pharma.AI division, the company provides advanced machine learning services to biotechnology, pharmaceutical, and skin care companies. Brief company video: https://www.youtube.com/watch?v=l62jlwgL3v8

From: https://eurekalert.org/pub_releases/2016-12/imi-ait122016.php

Microsoft will ‘solve’ cancer within 10 years by ‘reprogramming’ diseased cells

November 14, 2016

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Microsoft has vowed to “solve the problem of cancer” within a decade by using ground-breaking computer science to crack the code of diseased cells so they can be reprogrammed back to a healthy state.

In a dramatic change of direction for the technology giant, the company has assembled a “small army” of the world’s best biologists, programmers and engineers who are tackling cancer as if it were a bug in a computer system.

This summer Microsoft opened its first wet laboratory where it will test out the findings of its computer scientists who are creating huge maps of the internal workings of cell networks.

Microsoft opened its first wet laboratory this summer
Microsoft opened its first ‘wet’ laboratory this summer

The researchers are even working on a computer made from DNA which could live inside cells and look for faults in bodily networks, like cancer. If it spotted cancerous chances it would reboot the system and clear out the diseased cells.

Chris Bishop, laboratory director at Microsoft Research, said: “I think it’s a very natural thing for Microsoft to be looking at because we have tremendous expertise in computer science and what is going on in cancer is a computational problem.

“It’s not just an analogy, it’s a deep mathematical insight. Biology and computing are disciplines which seem like chalk and cheese but which have very deep connections on the most fundamental level.”

The biological computation group at Microsoft are developing molecular computers built from DNA which act like a doctor to spot cancer cells and destroy them.

Andrew Philips, head of the group, said: “It’s long term, but… I think it will be technically possible in five to 10 years time to put in a smart molecular system that can detect disease.”

Andrew Philips, head of the group
Andrew Philips, head of the group Credit: Ed Miller

The programming principles and tools group has already developed software that mimics the healthy behavior of a cell, so that it can be compared to that of a diseased cell, to work out where the problem occurred and how it can be fixed.

The Bio Model Analyser software is already being used to help researchers understand how to treat leukemia more effectively.

Dr Jasmin Fisher
Dr Jasmin Fisher believes scientists may be able to control and regulate cancer ‘within a decade’

Dr Jasmin Fisher, senior researcher and an associate professor at Cambridge University, said: “If we are able to control and regulate cancer then it becomes like any chronic disease and then the problem is solved.”

“I think for some of the cancers five years, but definitely within a decade. Then we will probably have a century free of cancer.”

She believes that in the future smart devices will monitor health continually and compare it to how the human body should be operating, so that it can quickly detect problems.

“My own personal vision is that in the morning you wake up, you check your email and at the same time all of our genetic data, our pulse, our sleep patterns, how much we exercised, will be fed into a computer which will check your state of well-being and tell you how prone you are to getting flu, or some other horrible thing,” she added.

“In order to get there we need these kind of computer models which mimic and model the fundamental processes that are happening in our bodies.

“Under normal development cells divide and they die and there is a certain balance, the problems start when that balance is broken and that’s how we had uncontrolled proliferation and tumours.

“If we could have all of that sitting on your personal computer and monitoring your health state then it will alert us when something is coming.”

Improved scanning technology offers hope

Patients undergoing radiotherapy could see treatment slashed from hours to just minutes with a new innovation to quickly map the size of a tumour.

 consultant studying a mammogram showing a womans breast in order check for breast cancer, as experienced radiologists can spot subtle signs of breast cancer in mammogram images in just half a second, a study has found
Experienced radiologists can spot subtle signs of breast cancer in mammogram images in just half a second, a study has found Credit: PA

Currently radiologists must scan a tumour and then painstakingly draw the outline of the cancer on dozens of sections by hand to create a 3D map before treatment, a process which can take up to four hours.

They also must outline nearby important organs to make sure they are protected from the blast of radiation.

But Microsoft engineers have developed a programme which can delineate a tumour within minutes, meaning treatment can happen immediately.

The programme can also show doctors how effective each treatment has been, so the dose can be altered depending on how much the tumour has been shrunk.

“Eyeballing works very well for diagnosing,” said Antonio Criminisi, a machine learning and computer vision expert who heads radiomics research in Microsoft’s Cambridge, UK, lab.

“Expert radiologists can look at an image – say a scan of someone’s brain – and be able to say in two seconds, ‘Yes, there’s a tumor. No, there isn’t a tumor. But delineating a tumour by hand is not very accurate.”

The system could eventually evaluate 3D scans pixel by pixel to tell the radiologist exactly how much the tumor has grown, shrunk or changed shape since the last scan.

It also could provide information about things like tissue density, to give the radiologist a better sense of whether something is more likely a cyst or a tumor. And it could provide more fine-grained analysis of the health of cells surrounding a tumor.

“Doing all of that by eye is pretty much impossible,” added Dr Criminisi.

The images could also be 3D printed so that surgeons could practice a tricky operation, such as removing a hard-to -reach brain tumour, before surgery.

http://www.telegraph.co.uk/science/2016/09/20/microsoft-will-solve-cancer-within-10-years-by-reprogramming-dis/

Have researchers really discovered a ‘new miracle drug to cure nine in 10 cancers’? No, but the research is fascinating

October 18, 2015

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You may have seen some of the headlines today reporting a new ‘miracle drug’ that could cure nine out of 10 cancers. It sounds amazing, but is it true?

Unfortunately, the answer is no. At least for now. But that’s not to say this isn’t important, promising new research.

The reports centre on the supposedly serendipitous discovery of a link between an experimental malaria vaccine for pregnant women and a molecule that sits on the surface of cancer cells.

So what did the study – published in the journal Cancer Cell – actually show?

What they did

The researchers – based at the University of Copenhagen – had been studying malaria in pregnant women, and the role a particular type of sugar molecule, called chondroitin sulphate, plays in the disease.

They already knew that the molecule, which is found on the surface of cells in the placenta, sticks to a protein – called VAR2CSA – that’s produced by the malaria parasite Plasmodium falciparum. And the team have been working on an experimental vaccine that uses the sticky interaction between chondroitin sulphate and VAR2CSA as a possible way to prevent malaria in pregnant women.

But the latest study behind today’s headlines showed something new – the specialised sugar molecule can also be found on the surface of some cancer cells. So the researchers decided to see if tweaking their experimental malaria vaccine might turn it into something that could kill cancer cells.

To test this, they added a toxin designed to kill cancer cells to the VAR2CSA protein, and added the modified vaccine to cancer cells grown in the lab. They also tested the vaccine by treating mice with prostate cancer, melanoma and a type of lymphoma.

Their experiments showed that the VAR2CSA was able to stick to the chondroitin sulphate on the cancer cells, delivering the deadly toxin that killed the cancer cells, but left healthy cells alone.

It’s exciting stuff. But did this research show that this modified malaria vaccine could be a ‘cure’ for nine in 10 cancers?

The short answer is no. (We think this press release might be where that misleading figure came from).

Not nine in 10

What the researchers actually showed was that in the group of cancer cells they studied – which didn’t include all types of cancer – the majority (95 per cent) of them also produced chondroitin sulphate on their surface.

This means that the malaria vaccine could potentially be used to target these cancers in the future. But not without a lot more research.

This study was done in mice, meaning before this modified malaria vaccine can be used to treat cancer in people we need to understand more about it, and whether it’s safe to be used in humans.

This would also require larger studies to see if the vaccine kills cancer cells in the same way in people, while leaving healthy cells alone and which patients with which cancers could benefit.

Only more research and clinical trials will be able to answer these questions.

So while this certainly is exciting research that could one day help cancer patients in the future, at the moment, it is not a ‘miracle’ drug that will cure nine out of 10 cancers.

http://scienceblog.cancerresearchuk.org/2015/10/14/have-researchers-really-discovered-a-new-miracle-drug-to-cure-nine-in-10-cancers-no-but-the-research-is-fascinating/

Discovery of new code makes reprogramming of cancer cells possible

August 27, 2015

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Cancer researchers dream of the day they can force tumor cells to morph back to the normal cells they once were. Now, researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.

The finding, published in Nature Cell Biology, represents “an unexpected new biology that provides the code, the software for turning off cancer,” says the study’s senior investigator, Panos Anastasiadis, Ph.D., chair of the Department of Cancer Biology on Mayo Clinic’s Florida campus.

That code was unraveled by the discovery that adhesion proteins — the glue that keeps cells together — interact with the microprocessor, a key player in the production of molecules called microRNAs (miRNAs). The miRNAs orchestrate whole cellular programs by simultaneously regulating expression of a group of genes. The investigators found that when normal cells come in contact with each other, a specific subset of miRNAs suppresses genes that promote cell growth. However, when adhesion is disrupted in cancer cells, these miRNAs are misregulated and cells grow out of control. The investigators showed, in laboratory experiments, that restoring the normal miRNA levels in cancer cells can reverse that aberrant cell growth.

“The study brings together two so-far unrelated research fields — cell-to-cell adhesion and miRNA biology — to resolve a long-standing problem about the role of adhesion proteins in cell behavior that was baffling scientists,” says the study’s lead author Antonis Kourtidis, Ph.D., a research associate in Dr. Anastasiadis’ lab. “Most significantly, it uncovers a new strategy for cancer therapy,” he adds.

That problem arose from conflicting reports about E-cadherin and p120 catenin — adhesion proteins that are essential for normal epithelial tissues to form, and which have long been considered to be tumor suppressors. “However, we and other researchers had found that this hypothesis didn’t seem to be true, since both E-cadherin and p120 are still present in tumor cells and required for their progression,” Dr. Anastasiadis says. “That led us to be believe that these molecules have two faces — a good one, maintaining the normal behavior of the cells, and a bad one that drives tumorigenesis.”

Their theory turned out to be true, but what was regulating this behavior was still unknown. To answer this, the researchers studied a new protein called PLEKHA7, which associates with E-cadherin and p120 only at the top, or the “apical” part of normal polarized epithelial cells. The investigators discovered that PLEKHA7 maintains the normal state of the cells, via a set of miRNAs, by tethering the microprocessor to E-cadherin and p120. In this state, E-cadherin and p120 exert their good tumor suppressor sides.

However, “when this apical adhesion complex was disrupted after loss of PLEKHA7, this set of miRNAs was misregulated, and the E-cadherin and p120 switched sides to become oncogenic,” Dr. Anastasiadis says.

“We believe that loss of the apical PLEKHA7-microprocessor complex is an early and somewhat universal event in cancer,” he adds. “In the vast majority of human tumor samples we examined, this apical structure is absent, although E-cadherin and p120 are still present. This produces the equivalent of a speeding car that has a lot of gas (the bad p120) and no brakes (the PLEKHA7-microprocessor complex).

“By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to re-establish the brakes and restore normal cell function,” Dr. Anastasiadis says. “Initial experiments in some aggressive types of cancer are indeed very promising.”

The study was supported by the National Institutes of Health grants R01 CA100467, R01 NS069753, P50 CA116201, R01 GM086435, R01CA104505, R01CA136665; the Florida Department of Health, Bankhead-Coley grants 10BG11; the Breast Cancer Research Foundation; the Swiss Cancer League; and the Jay and Deanie Stein Career Development Award for Cancer Research at Mayo Clinic.


Story Source:

The above post is reprinted from materials provided by Mayo Clinic. Note: Materials may be edited for content and length.


Journal Reference:

  1. Siu Ngok, Ryan Feathers; Lomeli Carpio; Tiffany Baker; Jennifer Carr; Irene Yan; Sahra Borges, Edith Perez, Peter Storz, John Copland, Tushar Patel, E. Aubrey Thompson, Pamela Pulimeno, Sandra Citi. Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120-catenin activity. Nature Cell Biology, 2015 DOI: 10.1038/ncb3227

http://www.sciencedaily.com/releases/2015/08/150824064916.htm

Immune System Drugs Melt Tumors In New Study, Leading A Cancer Revolution

April 27, 2015

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“I’ve been in immunotherapy for a long time, and we’ve talked and fantasized about reactions like this, but I’ve never seen anything this quickly,” he says. She has no detectable melanoma – amazing for a disease that has long been considered close to untreatable.

The 49-year-old woman had had three melanoma growths removed from her skin, but now the disease was spreading further. A several-centimeter-sized growth under her left breast went deep into her chest wall. Some of the tissue in the tumor was dying because of lack of blood flow.

Doctors at Memorial Sloan Kettering Cancer Center offered her an experimental combination of two drugs: Opdivo and Yervoy, both manufactured by Bristol-Myers Squibb, both among a vanguard of new medicines that boost the immune system to attack tumors. Three weeks later she came back for her second dose.

“She didn’t say anything and when I examined her, I said, ‘Wait a minute!’” says Paul Chapman, the doctor who was treating her. “She said,  ‘Yeah, it kind of just dissolved.’”

Where the tumor was before was, literally, a hole – a wound doctors hope will heal with time. Chapman took some fluid from it, and found there were no melanoma cells there. “I’ve been in immunotherapy for a long time, and we’ve talked and fantasized about reactions like this, but I’ve never seen anything this quickly,” he says. He skipped her next dose, and gave her two more before she stopped treatment because of the diarrhea the drug combination was causing. She has no detectable melanoma – amazing for a disease that has long been considered close to untreatable.

The story, published as a case report this morning in the New England Journal of Medicine, alongside a 142-patient study that tested the combination of Opdivo and Yervoy against Yervoy alone. The results show that the anonymous woman’s case was anything but a fluke, as the combination of the two drugs had unprecedented cancer-fighting potency, but also caused toxicity: 50% of patients had side effects that were severe or life-threatening. But an amazing 22% of patients – 16 of them – had what’s called a complete response. As with Chapman’s patient, all their cancer seemed to melt away.

“To me it’s a really graphic demonstration that the immune system is sitting there, waiting,” says Jedd Wolchok, Director, Ludwig Collaborative Laboratory at Memorial Sloan Kettering and lead author of the new study. “And there are immune cells which are fully prepared to get rid of these tumors. But they are being held in check.”

These new drugs release the body’s own weapons: killer white blood cells called T cells. And that approach is one of several bringing a huge amount of excitement to the field of cancer research, one that can be palpably felt here at the annual meeting of the American Association for Cancer Research in Philadelphia, where researchers are unveiling advances large and small. They are priming the immune system not only with drugs but also with genetically engineered cells and viruses. And they are using powerful genetic sequencing technologies not only to classify tumors and pick drugs, but to create blood tests that will allow doctors to monitor cancer in real time, catching it early and knowing rapidly which medicines will prove effective.

Analysts at Piper Jaffray were swept up in the excitement. “We are attending the AACR cancer meeting in Philadelphia, and are awestruck by the speed at which the oncology field is evolving,” they wrote. The combination of immune-boosting and genetic tools, they argue, could in 20 years make the market for cancer treatment as big as all of health care is now: half a trillion dollars a year.

That could, in part, be the wishful thinking of Wall Streeters who don’t want the current biotech boom (the Nasdaq iShares Biotechnology Index is up 116% in two years) to end. In fact, part of the worry about all these new technologies is their cost: the combination of Opdivo and Yervoy could have a wholesale cost of $270,000 if the patient stays on Opdivo for a full year. How we’re going to pay for all this innovation remains a big question. Other immune therapies that use a patient’s own genetically modified cells could cost even more.

But the innovation is real. Here’s a roundup:

Immune-boosting drugs

The combination of Opdivo and Yervoy had stunning efficacy. Yesterday, Merck announced that its Keytruda, a PD-1 blocker much like Opdivo, beat Yervoy as a melanoma treatment. In both trials, Yervoy caused tumors in about 11% of patients to shrink. Keytruda caused tumors in 33% of patients to shrink. The Opdivo-Yervoy combination caused tumor shrinkage in 66% of patients. It’s not clear how long patients live on the new treatment – the study hasn’t gone on long enough – but it’s much longer than the average 4.4-month survival on Yervoy alone.

Doctors will debate whether this treatment should be used for all melanoma patients or whether the side effects mean patients should try Keytruda or Opdivo alone first. But Wolchok says the standard treatment he offers melanoma patients is an expanded access clinical trial providing the combination. A larger trial testing the combo is expected in a few months. Bristol-Myers Squibb would not say when it will ask the Food and Drug Administration to approve the new therapy.

Meanwhile, advances have come so fast that they’re hard to catalogue. Merck and Bristol have both announced positive results for Keytruda and Opdivo in non-small cell lung cancer, and Keytruda has shown benefit in mesothelioma, the rare cancer that can be caused by asbestos. In an early trial, a similar AstraZeneca drug caused tumors to shrink in 19% of patients with the hard-to-treat triple-negative form of breast cancer.

Killer cells

Some of the most dramatic stories in immunotherapy have come from the field of CAR-T, in which a protein chimeric antigen receptor (CAR) is used to modify a white blood cell (or T-cell) so that it attacks tumors. This has led to stories of patients with blood cancer where tumors literally melt away through an immune response that, like the complete responses seen with the Opdivo-Yervoy combination, could actually be dangerous. (You can hear one such story here.) The excitement around these cells has resulted in the formation of a number of biotechnology startups, including Juno Therapeutics and Kite Pharma.

But so far CARTs have only worked in blood cancer, which is in many ways an easier target. Today, researchers at the University of Pennsylvania, who are working with Novartis, presented data on a CART that targets mesothelin, a protein on the surface of many tumor cells, in two patients with serous ovarian cancer, two with epithelial mesothelioma, and one with pancreatic cancer.

The good news is that nothing particularly terrible happened when the cells were infused (although these patients were sick, and developed conditions including sepsis, fluid in the lung, and anemia). There were no cases of the cytokine release syndrome – the extreme, potentially deadly immune response that occurred in some blood cancer patients.

The CART cells seemed to go to where the tumors were, including in the fluid around the heart, without causing damage and inflammation. It’s still too early, though, to know whether the CART cells are damaging the tumors. All researchers could say was that four of the patients had remained stable – there are no melting tumors this time.

Michel Sadelain, a researcher at Memorial Sloan Kettering and one of the co-founders of Juno Therapeutics, was hopeful but cautious. “With advanced stable disease at four weeks, it’s encouraging but you can’t over-interpret that,” he said. Still, he holds out hope for meso-CARTs, which JUNO is developing to. “If the toxicities are manageable I believe it’s going to be something big,” he says.

Researchers also presented data on using T-cells to treat a rare condition called Epstein-Barr Virus-associated lymphoproliferative disorder. This disease occurs when the virus that causes mononucleosis causes a kind of secondary cancer in patients after a transplant, often a bone marrow transplant. This is a rare disease, but perfect for cell therapy: white blood cells are great at attacking cells infected with viruses, and the patients don’t have immune systems. Using T-cells donated from other patients, researchers were able to reduce or eliminate the cancer cells in 63% of patients. The treatment has received breakthrough designation from the Food and Drug Administration, but has not yet been licensed by a drug company. Atara Biotherapeutics has an exclusive option to license it.

A blood test for cancer?

Another big idea is what’s called a liquid biopsy, in which free bits of cancer DNA are detected via a blood test. Here at AACR, researchers from the Department of Radiation Sciences at Umeå University in Sweden used the technique to determine when patients with lung cancer would stop responding to Xalkori, a Pfizer lung cancer drug. But the implications of the test are much bigger.

Last year at the Forbes Healthcare Summit in New York, Richard Klausner, the chief medical officer of DNA sequencing leader Illumina and the former head of the National Cancer Institute, gave an early look at the promise of this technology.

“There’s a phenomena that we now know that tumors put out, at very early stages, their DNA into the circulation,” Klausner said. “We can now measure that with incredible precision. I think one of the biggest breakthroughs we can see in cancer in the next few years is this possibility that there could be a blood test or a urine test that detects early stage cancer.”

Many of these advances could be years away from the market. And doctors’ ardor is predicated partly on how grim things have been in the past. Even in the Opdivo-Yervoy study, 126 of 142 patients did not see their cancer vanish entirely. And even with the best studies of CART therapy in leukemia, two or three out of every ten patients are not helped, and are likely to die. But in the world of cancer research, where it often seemed that arduous research was only adding mere months to patients lives, this counts as reason for hope.

“We are in the middle of a revolution,” said Louis Weiner, of Georgetown University, at an AACR press conference about the immunotherapies. “I don’t think that is hyperbolic. Those are the kinds of observations that we’ve rarely seen in our business. What really makes it exciting is that it is not just one disease.”

http://www.forbes.com/sites/matthewherper/2015/04/20/immune-system-drugs-melt-tumors-leading-a-cancer-revolution/

Video

The Future of Healthcare: Medicine 2064

November 22, 2014

Curing half of the world’s known cancers, granting movement to the paralyzed, preventing Alzheimer’s. Visionary medical expert Dr. Daniel Kraft believes all of this and more can happen by 2064. In this first film in our “Conversations with Tomorrow” series, take a glimpse at the future of medicine and its impact on our lives.

 

http://ieet.org/index.php/IEET/more/kraft20141117

Highly effective new anti-cancer drug shows few side effects in mice

November 2, 2014

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A new drug, known as OTS964, can eradicate aggressive human lung cancers transplanted into mice, according to a report in Science Translational Medicine. The drug, given as a pill or by injection, inhibits the action of a protein that is overproduced by several tumor types, including lung and breast, but is rarely expressed in healthy adult tissues. Without this protein, cancer cells fail to complete the cell-division process and die.

When taken by mouth, the drug was well tolerated with limited toxicity. An intravenous form, delivered within a liposome, was just as effective with fewer side effects. Both approaches — described in the October 22, 2014 issue of Science Translational Medicine — led to complete regression of transplanted tumors.

“We identified the molecular target for this drug ten years ago, but it took us nearly a decade to find an effective way to inhibit it,” said study author Yusuke Nakamura, MD, PhD, professor of medicine at the University of Chicago and deputy director of the University’s Center for Personalized Therapeutics. “We initially screened 300,000 compounds and then synthesized more than 1,000 of them, and found a few that were likely to work in humans. We focused on the most effective. We think we now have something very promising.”

OTS964 targets TOPK (T — lymphokine-activated killer cell — originated protein kinase), a protein that is produced by a wide range of human cancers and is believed to promote tumor growth. High TOPK expression correlates with poor prognosis in patients with breast and lung cancer.

Initial studies of the drug, and a precursor called OTS514, found they were effective in killing cancer cells. But they could disrupt the production of new red and white blood cells, causing hematopoietic toxicity such as mild anemia and increasing the risk of infection. At the same time, the drugs increased the production of platelets, which help in blood clotting.

When the researchers encapsulated the drugs in liposomes — microscopic bubbles similar to a cell membrane, commonly used to transport drugs within the body — the drug no longer caused this decrease in red and white blood cells. This approach “completely eliminated the hematopoietic toxicity,” the researchers wrote.

They tested OTS964 alone and in liposomes in mice with a highly aggressive human lung tumor known as LU-99. They allowed the tumors to grow to 150 cubic millimeters — about the size of a raisin — and then administered the drug intravenously to six mice, twice a week for three weeks. The tumors shrank rapidly and continued to shrink even after treatment stopped. In five of the six mice, the tumors completely disappeared — three within 25 days of the first treatment and two within 29 days. Mice that received the liposome-coated drug had no detectable toxicity.

Caption: This is an illustration depicting liposomal OTS964 entering cancer cells where it blocks the enzyme TOPK, preventing the final stage of cell division.                                     Credit: Jae-Hyun Park D.V.M., Ph.D., Research Associate/Assistant Professor, Section of Hematology/Oncology, The University of Chicago

The drug also proved effective when taken in larger doses by mouth. Six mice with LU-99 lung tumors were fed 100 milligrams per kilogram of OTS964 every day for two weeks. Again, continuous tumor shrinkage was observed after the final dose of the drug. In all six mice the tumors completely regressed. All of the mice had low white-blood-cell counts after treatment, but they recovered within two weeks.

Although this was a small study, the outcome was dramatic. Seeing these results was a “quite exciting moment,” said Nakamura, who stepped down from his role as Director in the Japanese Government’s Office of Medical Innovation to join the faculty at the University of Chicago in April 2012. “It is rare to see complete regression of tumors in a mouse model,” he said. “Many drugs can repress the growth, but it is uncommon to see them eradicated. This has rarely been reported.”

Similar studies of the drug’s effects on tumor cells growing outside the body enabled the researchers to videotape the process as the cancer cells died. TOPK appears to play a central role late in cytokinesis, the final stage in cell division. Dividing cancer cells would begin to separate into two new cells, but were unable to fully disconnect, retaining an intercellular bridge.

“Without TOPK the cells can’t seem to divide; they can’t make the break,” Nakamura said. “They can’t complete the process. Instead they remain tethered by a tiny bridge. When that finally breaks apart, they can’t close the membrane. Everything within the cells spills out, they suffer and then die.”

TOPK may provide a good drug target for several types of cancer. This study involved primarily lung cancers, but the gene is frequently upregulated in breast, brain, liver, bladder and other solid tumors as well as certain types of leukemia. The researchers are working with oncologists at the University to begin a phase-1 clinical trial as soon as the fall of 2015.


Story Source:

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


Journal Reference:

  1. Yo Matsuo, Jae-Hyun Park, Takashi Miyamoto, Shinji Yamamoto, Shoji Hisada, Houda Alachkar, and Yusuke Nakamura. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. Science Translational Medicine, October 2014 DOI:10.1126/scitranslmed.3010277

Viewing cancer on the move: New device yields close-up look at metastasis

November 1, 2014

This dish houses a lab chip that Johns Hopkins engineers built to gain an unprecedented close-up view of how cancer cells enter the bloodstream to spread the disease. (Credit: Will Kirk/Johns Hopkins University)

Johns Hopkins engineers have invented a lab device to give cancer researchers an unprecedented microscopic look at metastasis, the complex way that tumor cells spread through the body, causing more than 90 percent of cancer-related deaths. By shedding light on precisely how tumor cells travel, the device could uncover new ways to keep cancer in check.
The inventors, from the university’s Whiting School of Engineering and its Institute for NanoBioTechnology (INBT), published details and images from their new system recently in the journal Cancer Research. Their article reported on successful tests that captured video of human breast cancer cells as they burrowed through reconstituted body tissue material and made their way into an artificial blood vessel.
Johns Hopkins | Researchers captured this video of human breast cancer cells (red) as they burrowed through reconstituted body tissue material and made their way into an artificial blood vessel (this is an animated GIF created from the original video)

 

“There’s still so much we don’t know about exactly how tumor cells migrate through the body, partly because, even using our best imaging technology, we haven’t been able to see precisely how these individual cells move into blood vessels,” said Andrew D. Wong, a Department of Materials Science and Engineering doctoral student who was lead author of the journal article. “Our new tool gives us a clearer, close-up look at this process.”

With this novel lab platform, Wong said, the researchers were able to record video of the movement of individual cancer cells as they crawled through a three-dimensional collagen matrix. This material resembles the human tissue that surrounds tumors when cancer cells break away and try to relocate elsewhere in the body. This process is called invasion.

Wong also collected video of single cancer cells prying and pushing their way through the wall of an artificial vessel lined with human endothelial cells, the same kind that line human blood vessels. By entering the bloodstream through this process, called intravasion, cancer cells are able to hitch a ride to other parts of the body and begin to form deadly new tumors.

To view these important early stages of metastasis, Wong replicated these processes in a small transparent chip that incorporates the artificial blood vessel and the surrounding tissue material. A nutrient-rich solution flows through the artificial vessel, mimicking the properties of blood. The breast cancer cells, inserted individually and in clusters in the tissue near the vessel, are labeled with fluorescent tags, enabling their behavior to be seen, tracked and recorded via a microscopic viewing system.

Wong’s doctoral advisor, Peter Searson, the Joseph R. and Lynn C. Reynolds Professor of Materials Science and Engineering and director of the INBT, said his graduate student took on this challenging project nearly five years ago — and ultimately produced impressive results.

“Andrew was able to build a functional artificial blood vessel and a microenvironment that lets us capture the details of the metastatic process,” said Searson, who was the corresponding author of the Cancer Research article. “In the past, it’s been virtually impossible to see the steps involved in this process with this level of clarity. We’ve taken a significant leap forward.”

This improved view should give cancer researchers a much clearer look at the complex physical and biochemical interplay that takes place when cells leave a tumor, move through the surrounding tissue and approach a blood vessel. For example, the new lab device enabled the inventors to see detailed images of a cancer cell as it found a weak spot in the vessel wall, exerted pressure on it and squeezed through far enough so that the force of the passing current swept it into the circulating fluid.

“Cancer cells would have a tough time leaving the original tumor site if it weren’t for their ability to enter our bloodstream and gain access to distant sites,” Wong said. “So it’s actually the entry of cancer cells into the bloodstream that allows the cancer to spread very quickly.”

Knowing more about this process could unearth a key to thwarting metastasis.

“This device allows us to look at the major steps of metastasis as well as to test different treatment strategies at a relatively fast pace,” Wong said. “If we can find a way to stop one of these steps in the metastatic cascade, we may be able to find a new strategy to slow down or even stop the spread of cancer.”

Next, the researchers plan to use the device to try out various cancer-fighting drugs within this device to get a better look at how the medications perform and how they might be improved.


Story Source:

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


Journal Reference:

  1. A. D. Wong, P. C. Searson. Live-Cell Imaging of Invasion and Intravasation in an Artificial Microvessel Platform. Cancer Research, 2014; 74 (17): 4937 DOI:10.1158/0008-5472.CAN-14-1042

Google X is working on nanoparticles that swim through your blood, identifying cancer and other diseases

October 30, 2014

http://www.extremetech.com/extreme/193083-google-x-is-working-on-nanoparticles-that-swim-through-your-blood-identifying-cancer-and-other-diseases

New ‘lab-on-a-chip’ could revolutionize early diagnosis of cancer

October 11, 2014

exosome-chip

A new miniaturized biomedical “lab-on-a-chip” testing device for exosomes — molecular messengers between cells — promises faster, earlier, less-invasive diagnosis of cancer, according to its developers at the University of Kansas Medical Center and the University of Kansas Cancer Center.

“A lab-on-a-chip shrinks the pipettes, test tubes and analysis instruments of a modern chemistry lab onto a microchip-sized wafer,” explained Yong Zeng, assistant professor of chemistry at the University of Kansas.

Zeng and his fellow researchers developed the lab-on-a-chip initially for early detection of lung cancer — the number-one cancer killer in the U.S.

Lung cancer is currently detected mostly with an invasive biopsy, after tumors are larger than 3 centimeters in diameter and even metastatic. Using the lab-on-a-chip, lung cancer could be detected much earlier, using only a small drop of a patient’s blood, according to Zeng.

How it works

The prototype lab-on-a-chip is made of a widely used silicone rubber called   polydimethylsiloxane and uses a technique called “on-chip immunoisolation

“We used magnetic beads of 3 micrometers in diameter to pull down the exosomes in plasma samples,” Zeng said. “To avoid other interfering species present in plasma, the bead surface was chemically modified with an antibody that recognizes and binds with a specific target protein — for example, a protein receptor — present on the exosome membrane. The plasma containing magnetic beads then flows through the microchannels on the diagnostic chip in which the beads can be readily collected using a magnet to extract circulating exosomes from the plasma.”

“Our technique provides a general platform to detecting tumor-derived exosomes for cancer diagnosis,” he said. “We’ve also tested for ovarian cancer in this work. In theory, it should be applicable to other types of cancer. Our long-term goal is to translate this technology into clinical investigation of the pathological implication of exosomes in tumor development. Such knowledge would help develop better predictive biomarkers and more efficient targeted therapy to improve the clinical outcome.”

The research by Zeng and his KU colleagues was described in a paper published in the Royal Society of Chemistry journal, and has been awarded a  $640,000 grant from the National Cancer Institute at the National Institutes of Health, intended to further develop the lab-on-a-chip technology.

http://www.kurzweilai.net/new-lab-on-a-chip-could-revolutionize-early-diagnosis-of-cancer?utm_source=KurzweilAI+Weekly+Newsletter&utm_campaign=062176e44c-UA-946742-1&utm_medium=email&utm_term=0_147a5a48c1-062176e44c-282129417