DNA Robots Target Cancer

May 17, 2018

DNA nanorobots that travel the bloodstream, find tumors, and dispense a protein that causes blood clotting trigger the death of cancer cells in mice, according to a study published today (February 12) in Nature Biotechnology.

The authors have “demonstrated that it’s indeed possible to do site-specific drug delivery using biocompatible, biodegradable, DNA-based bionanorobots for cancer therapeutics,” says Suresh Neethirajan, a bioengineer at the University of Guelph in Ontario, Canada, who did not participate in the study. “It’s a combination of diagnosing the biomarkers on the surface of the cancer itself and also, upon recognizing that, delivering the specific drug to be able to treat it.”

The international team of researchers started with the goal of “finding a path to design nanorobots that can be applied to treatment of cancer in human[s],” writes coauthor Hao Yan of Arizona State University in an email to The Scientist.

Yan and colleagues first generated a self-assembling, rectangular, DNA-origami sheet to which they linked thrombin, an enzyme responsible for blood clotting. Then, they used DNA fasteners to join the long edges of the rectangle, resulting in a tubular nanorobot with thrombin on the inside. The authors designed the fasteners to dissociate when they bind nucleolin—a protein specific to the surface of tumor blood-vessel cells—at which point, the tube opens and exposes its cargo.

Nanorobot design. Thrombin is represented in pink and nucleolin in blue.S. LI ET AL., NATURE BIOTECHNOLOGY, 2018

The scientists next injected the nanorobots intravenously into nude mice with human breast cancer tumors. The robots grabbed onto vascular cells at tumor sites and caused extensive blood clots in the tumors’ vessels within 48 hours, but did not cause clotting elsewhere in the animals’ bodies. These blood clots led to tumor-cell necrosis, resulting in smaller tumors and a better chance for survival compared to control mice. Yan’s team also found that nanorobot treatment increased survival and led to smaller tumors in a mouse model of melanoma, and in mice with xenografts of human ovarian cancer cells.

The authors are “looking at specific binding to tumor cells, which is basically the holy grail for . . . cancer therapy,” says the University of Tennessee’s Scott Lenaghan, who was not involved in the work. The next step is to investigate any damage—such as undetected clots or immune-system responses—in the host organism, he says, as well as to determine how much thrombin is actually delivered at the tumor sites.

The authors showed in the study that the nanorobots didn’t cause clotting in major tissues in miniature pigs, which satisfies some safety concerns, but Yan agrees that more work is needed. “We are interested in looking further into the practicalities of this work in mouse models,” he writes.

Going from “a mouse model to humans is a huge step,” says Mauro Ferrari, a biomedical engineer at Houston Methodist Hospital and Weill Cornell Medical College who did not participate in the study. It’s not yet clear whether targeting nucleolin and delivering thrombin will be clinically relevant, he says, “but the breakthrough aspect is [that] this is a platform. They can use a similar approach for other things, which is really exciting. It’s got big implications.”

S. Li et al., “A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo,Nature Biotechnology, doi:10.1038/nbt.4071, 2018.

This article was originally published by: https://www.the-scientist.com/?articles.view/articleNo/51717/title/DNA-Robots-Target-Cancer/

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Cancer ‘vaccine’ eliminates tumors in mice

May 17, 2018

Ronald Levy (left) and Idit Sagiv-Barfi led the work on a possible cancer treatment that involves injecting two immune-stimulating agents directly into solid tumors. Steve Fisch

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.

The approach works for many different types of cancers, including those that arise spontaneously, the study found.

The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

“When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”

One agent is already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma. (Information about the trial is available online.)

Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which was published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.

‘Amazing, bodywide effects’

Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anti-cancer treatment in humans.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides — from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.

“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”

Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

Levy’s method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.

Cancer-destroying rangers

Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.

Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span, the researchers found.

Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

The study’s other Stanford co-authors are senior research assistant and lab manager Debra Czerwinski; professor of medicine Shoshana Levy, PhD; postdoctoral scholar Israt Alam, PhD; graduate student Aaron Mayer; and professor of radiology Sanjiv Gambhir, MD, PhD.

Levy is a member of the Stanford Cancer Institute and Stanford Bio-X.

Gambhir is the founder and equity holder in CellSight Inc., which develops and translates multimodality strategies to image cell trafficking and transplantation.

The research was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation and the Phil N. Allen Foundation.

Stanford’s Department of Medicine also supported the work.

This article was originally published by: http://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html

Cancer ‘vaccine’ eliminates tumors in mice

February 05, 2018

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.

The approach works for many different types of cancers, including those that arisespontaneously, the study found.

The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

“When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”

One agent is currently already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma.

Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which was published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.

‘Amazing, bodywide effects’

Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anticancer treatment in humans.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides — from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.

“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”

Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

Levy’s method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.

Cancer-destroying rangers

Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.

Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span, the researchers found.

Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

The study’s other Stanford co-authors are senior research assistant and lab manager Debra Czerwinski; professor of medicine Shoshana Levy, PhD; postdoctoral scholar Israt Alam, PhD; graduate student Aaron Mayer; and professor of radiology Sanjiv Gambhir, MD, PhD.

Levy is a member of the Stanford Cancer Institute and Stanford Bio-X.

Gambhir is the founder and equity holder in CellSight Inc., which develops and translates multimodality strategies to image cell trafficking and transplantation.

The research was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation and the Phil N. Allen Foundation.

Stanford’s Department of Medicine also supported the work.

This article was originally published by:
https://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html

Suicide molecules kill any cancer cell

January 05, 2018

CHICAGO – Small RNA molecules originally developed as a tool to study gene function trigger a mechanism hidden in every cell that forces the cell to commit suicide, reports a new Northwestern Medicine study, the first to identify molecules to trigger a fail-safe mechanism that may protect us from cancer.

The mechanism — RNA suicide molecules — can potentially be developed into a novel form of cancer therapy, the study authors said.

Cancer cells treated with the RNA molecules never become resistant to them because they simultaneously eliminate multiple genes that cancer cells need for survival.

“It’s like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time,” said Northwestern scientist and lead study author Marcus Peter. “You cannot survive.”

The inability of cancer cells to develop resistance to the molecules is a first, Peter said.

“This could be a major breakthrough,” noted Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  

Peter and his team discovered sequences in the human genome that when converted into small double-stranded RNA molecules trigger what they believe to be an ancient kill switch in cells to prevent cancer. He has been searching for the phantom molecules with this activity for eight years.

“We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old,” he said. “It could be a fail safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer.”

This study, which will be published Oct. 24 in eLife, and two other new Northwestern studies in Oncotarget and Cell Cycle by the Peter group, describe the discovery of the assassin molecules present in multiple human genes and their powerful effect on cancer in mice.

Looking back hundreds of millions of years

Why are these molecules so powerful?

“Ever since life became multicellular, which could be more than 2 billion years ago, it had to deal with preventing or fighting cancer,” Peter said. “So nature must have developed a fail safe mechanism to prevent cancer or fight it the moment it forms. Otherwise, we wouldn’t still be here.”

Thus began his search for natural molecules coded in the genome that kill cancer.

“We knew they would be very hard to find,” Peter said. “The kill mechanism would only be active in a single cell the moment it becomes cancerous. It was a needle in a haystack.”

But he found them by testing a class of small RNAs, called small interfering (si)RNAs, scientists use to suppress gene activity. siRNAs are designed by taking short sequences of the gene to be targeted and converting them into double- stranded RNA. These siRNAs when introduced into cells suppress the expression of the gene they are derived from.Peter found that a large number of these small RNAs derived from certain genes did not, as expected, only suppress the gene they were designed against. They also killed all cancer cells. His team discovered these special sequences are distributed throughout the human genome, embedded in multiple genes as shown in the study in Cell Cycle.

When converted to siRNAs, these sequences all act as highly trained super assassins. They kill the cells by simultaneously eliminating the genes required for cell survival. By taking out these survivor genes, the assassin molecule activates multiple death cell pathways in parallel.

The small RNA assassin molecules trigger a mechanism Peter calls DISE, for Death Induced by Survival gene Elimination.

Activating DISE in organisms with cancer might allow cancer cells to be eliminated. Peter’s group has evidence this form of cell death preferentially affects cancer cells with little effect on normal cells.

To test this in a treatment situation, Peter collaborated with Dr. Shad Thaxton, associate professor of urology at Feinberg, to deliver the assassin molecules via nanoparticles to mice bearing human ovarian cancer. In the treated mice, the treatment strongly reduced the tumor growth with no toxicity to the mice, reports the study in Oncotarget. Importantly, the tumors did not develop resistance to this form of cancer treatment. Peter and Thaxton are now refining the treatment to increase its efficacy.

Peter has long been frustrated with the lack of progress in solid cancer treatment.

“The problem is cancer cells are so diverse that even though the drugs, designed to target single cancer driving genes, often initially are effective, they eventually stop working and patients succumb to the disease,” Peter said. He thinks a number of cancer cell subsets are never really affected by most targeted anticancer drugs currently used.

Most of the advanced solid cancers such as brain, lung, pancreatic or ovarian cancer have not seen an improvement in survival, Peter said.

“If you had an aggressive, metastasizing form of the disease 50 years ago, you were busted back then and you are still busted today,” he said. “Improvements are often due to better detection methods and not to better treatments.”

Cancer scientists need to listen to nature more, Peter said. Immune therapy has been a success, he noted, because it is aimed at activating an anticancer mechanism that evolution developed. Unfortunately, few cancers respond to immune therapy and only a few patients with these cancers benefit, he said.

“Our research may be tapping into one of nature’s original kill switches, and we hope the impact will affect many cancers,” he said. “Our findings could be disruptive.”

Northwestern co-authors include first authors William Putzbach, Quan Q. Gao, and Monal Patel, and coauthors Ashley Haluck-Kangas, Elizabeth T. Bartom, Kwang-Youn A. Kim, Denise M. Scholtens, Jonathan C. Zhao and Andrea E. Murmann.

The research is funded by grants T32CA070085, T32CA009560, R50CA211271 and R35CA197450 from the National Cancer Institute of the National Institutes of Health.

This article was originally published by:
https://news.northwestern.edu/stories/2017/october/suicide-molecules-kill-any-cancer-cell/

King cancer: The top 10 therapeutic areas in biopharma R&D

July 23, 2017

It’s not going to come as a surprise to anyone who’s been paying attention to drug R&D trends that cancer is the number 1 disease in terms of new drug development projects. But it is amazing to see exactly how much oncology dominates the industry as never before.

At a time the first CAR-T looks to be on the threshold of a pioneering approval and the first wave of PD-(L)1 drugs are spurring hundreds of combination studies, cancer accounted for 8,651 of the total number of pipeline projects counted by the Analysis Group, crunching the numbers in a new report commissioned by PhRMA. That’s more than a third of the 24,389 preclinical through Phase III programs tracked by EvaluatePharma, which provided the database for this review.

That’s also more than the next 5 disease fields combined, starting with number 2, neurology — a field that includes Parkinson’s and Alzheimer’s. Psychiatry, once a major focus for pharma R&D, didn’t even make the top 10, with 468 projects.

Moving downstream, cancer studies are overwhelmingly in the lead. Singling out Phase I projects, cancer accounted for 1,757 out of a total of 3,723 initiatives, close to half. In Phase II it’s the focus of 1,920 of 4,424 projects. Only in late-stage studies does cancer start to lose its overwhelming dominance, falling to 329 of 1,257 projects.

PhRMA commissioned this report to underscore just how much the industry is committed to R&D and significant new drug development, a subject that routinely comes into question as analysts evaluate how much money is devoted to developing new drugs instead of, say, marketing or share buybacks.

The report makes a few other points to underscore the nature of the work these days.

— Three out of four projects in the clinic were angling for first-in-class status, spotlighting the emphasis on advancing new medicines that can make a difference for patients. Me-too drugs are completely out of fashion, unlikely to command much weight with payers.

— Of all the projects in clinical development, 822 were for orphan drugs looking to serve a market of 200,000 or less. Orphan drugs have performed well, able to command high prices and benefiting from incentives under federal law.

— There were 731 cell and gene therapy projects in the clinic, with biopharma looking at pioneering approvals in CAR-T, with Novartis and Kite, as well as the first US OK for a gene therapy, with the first application accepted this week for a priority review of a new therapy from Spark Therapeutics.


Distribution of products and projects by therapeutic area and phase


Source: Analysis Group, using EvaluatePharma data


Unique NMEs in development by stage (August 2016)

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.

###

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/