Scott McNeil, director of the Nanotechnology Characterization Lab at the Frederick National Laboratory for Cancer Research

The protein tumor necrosis factor-alpha (TNF-alpha) is a powerful weapon in the arsenal to control cancer. Unfortunately, as is the case with many potent cancer therapies, the use of TNF-alpha as an anti-cancer therapy has been severely limited. “It was so toxic that it caused death,” and researchers gave up on it, explains Scott McNeil, director of the Nanotechnology Characterization Lab at the Frederick National Laboratory for Cancer Research.

That was back in the 1990s. Today, TNF-alpha is a prime example of how to safely and effectively deliver toxic substances to cancer cells through the use of nanotechnology.

McNeil’s lab, part of the federally funded research and development center operated by SAIC-Frederick for the National Cancer Institute, worked with a drug company to reformulate TNF-alpha by coupling it with gold nanoparticles. Using the nanotechnology-enhanced protein, it appears possible to safely inject up to three times the amount that had been lethal with previous versions. The modified drug has been through a Phase 1 clinical trial and is entering Phase 2.

In McNeil’s lab, and for other scientists using nanotechnology for drug delivery, stories like this one are increasingly common. Researchers are looking to accelerate the development of potential nanotechnology drugs for cancer by exploring ways to reduce side effects and make treatments hit their targets more effectively. This can mean using nanotechnology to reformulate drugs that may have failed in previous clinical trials. In some cases, by attaching a nanoparticle to an existing drug, researchers may not only be able to lower its toxicity, but they may also see significant life expectancy gains for patients.

Many cancer drugs are approved based on how long they delay the progression of disease. Some drugs on the market “only improve life expectancy by maybe five weeks,” says McNeil. He sees nanomedicine as a potential game-changer for cancer drugs in the future.

McNeil, both a chemist and biologist, has spent the majority of his career working in nanotechnology, but when he was asked to apply his expertise to find better drugs for cancer, he was skeptical. “My professional career was mostly military,” says the former Army officer. “I was using nanotech for military applications at SAIC, using quantum dots to see if you scatter things, where they land. I got a call out of the blue in December of 2003 and the message was, ‘We want to use nanotech for cancer applications.’ I thought, ‘What are they thinking? You are going to put a cadmium quantum dot in a human? There is no way!’ I discounted it at first and I actually ignored the emails, hoping it would go away.”

But it did not go away.  In fact, much has changed in the last 10 years. Now, nanopharmaceuticals are beginning to demonstrate their capacity to place the drugs directly in the tumor, where they will do the most good, rather than let them roam freely in the body. A drug is attached to a nanoparticle, which is often a tiny little sphere. To put it in perspective, a nanometer is one billionth of a meter; the width of a single strand of hair is about 10,000 nanometers. The nanoparticle is small enough to flow through blood vessels and into a tumor, where the particle dissociates, and the drug is released. In the end, the goal of nanomedicine is that the only part of the body affected by the drug is the tumor, the area of need.

McNeil’s Nanotechnology Characterization Lab was founded in 2004 in collaboration with the Food and Drug Administration and the National Institute of Standards and Technology. There is one thing the lab does not do: develop nanotechnology drugs. Instead, researchers there—ranging in expertise from cancer biology and toxicology to chemistry, immunology, and physics—help investigators from around the world create the best drugs possible. “We help investigators get from proof of concept, where they are generating a few tens of milligrams of material and get into clinical trials, where they are going to need kilograms of materials,” say McNeil. “That translational research, as we call it, is absolutely germane to getting into clinical trials.”

The majority of scientists who apply for assistance from the NCL are seeking FDA approval for their nanotech drugs but they don’t have the resources to optimize their formula. The NCL can help. “We help them understand what is involved with their particle because they don’t have the tools that we have to be able to characterize,” says McNeil. “They may have a nice picture or cartoon of it but until they see our electron micrographs, they don’t know what it looks like.”

The Nanotechnology Characterization Lab serves two purposes. After a molecule has been through the NCL’s assay cascade which consists of a set of tests that evaluate the preclinical toxicology, pharmacology, and efficacy of nanoparticles, the NCL is able to offer an evaluation. “The investigator is going to need $40 million dollars to get into Phase 2 trials. Investigators need to justify the investment. We help them generate data they need to further their work and then we serve as a third-party evaluation.” That is crucial, McNeil says, for an investigator seeking funding. “A venture capital company can come to us and say, ‘Well, what do you really think of this? Let’s see your data, and explain it and defend it.’ We, obviously, cannot endorse it but we can discuss the data in the context of what they are trying to do. That really holds a lot of weight.”

Consider the example of Abraxane (paclitaxel), which was approved for use by the FDA in 2005. Abraxane, a variably toxic but widely prescribed cancer drug, has been enhanced by attaching it to a nanoparticle, thereby creating a new, targeted treatment. “Because of the size and the binding to a different receptor, that drug now has decreased toxicity compared to the former drug. For the nanoparticle-Abraxane conjugate toxicity is very marginal, at least for immunotoxicity and hypersensitivity,” says McNeil.

Since 2005, the Nanotechnology Characterization Lab has characterized nearly 300 different particles. Six of them are in clinical trials. “Depending upon what community you are from, either that is a terrific ratio or that is a poor ratio,” explains McNeil. “We view it as a super terrific ratio. A pharmaceutical company can make hundreds of thousands of different drugs and only about one out of 100,000 gets into clinical trials.”

Nanotechnology’s place in the cancer treatment arsenal also appears secure. A new report from Infiniti Research Limited, a marketing research firm specializing in pharmaceuticals and health care, forecasts that the nanotechnology drug delivery market is on track to double within the next five years.

For more information about NCL, visit: http://ncl.cancer.gov/.

Anuradha Budhu, Ph.D.

Anuradha Budhu, Ph.D., heads a research team at the National Cancer Institute that recently  uncovered an imbalance between saturated and unsaturated fats (such as palmitic or fatty acids) that occur in patients with a common liver cancer called hepatocellular carcinoma, or HCC. Budhu’s team also determined that HCC patients with high unsaturated fat levels had poor survival rates, suggesting that a shift of balance toward saturated fats may be a novel therapeutic strategy in the treatment of aggressive liver cancer.

Budhu, who earned her doctorate at Cornell University, is a staff scientist at NCI’s Center for Cancer Research. She has been awarded CCR’s outstanding postdoctoral award as well as the NCI Director’s Innovation Award.

She has been in the Laboratory of Human Carcinogenesis since 2002 working to uncover molecular and genomic targets associated with liver cancer and its metastasis. Using these techniques in a unique way, she and her colleagues were able to link fatty acids with HCC patient outcome.

Past studies on HCC focused on the roles of either genes or metabolites, which are byproducts of metabolism such as fatty acids. Budhu’s group was the first to interweave these two distinct platforms to search for the key molecular drivers of HCC. As a result, they uncovered a set of cellular alterations in fat signaling pathways associated with HCC and discovered that an important transmitter of fatty acid flow—a gene called stearoyl CoA-desaturase, or SCD, that contributed to unfavorable outcomes for HCC patients. The study findings were published in Gastroenterology.

To profile metabolite and gene signals in HCC, Budhu and her colleagues worked with tissue samples taken from 386 HCC clinical patients that they divided into three sets—training, test and validation. Using the training set, they profiled paired tumor and non-tumor samples to identify the interdependent metabolites and genes in a HCC subtype that is most often associated with poor patient survival.

Once these molecular targets were identified, they searched for key pathways that connected these metabolites and genes, which they then confirmed in test and validation tissue sample sets for accuracy. As a result, they found that SCD and its associated metabolite—unsaturated fat—were associated with aggressive HCC outcomes. While these integrative results have shown that SCD and its related metabolites may one day be valuable as biomarkers and prognostic indicators for HCC, more work is needed to determine the mechanism underlying SCD’s role in HCC, said Budhu.

The 11 recipients will each receive $3 million for their outstanding work in the field of science; eight of them have received NCI grants to further their research:

• David Botstein Ph.D., director of the Lewis-Sigler Institute for Integrative Genomics and the Anthony B. Evnin professor of genomics at Princeton University, was recognized for linkage mapping of Mendelian disease in humans using variations in a DNA sequence.

• Lewis C. Cantley, Ph.D., director of the Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital, was awarded for his discovery of PI 3-Kinase and its role in cancer metabolism. His research discovered that human cancers frequently have mutations in PI3K and he has worked to identify new treatments for cancers that result from defects in this pathway.

• Titia de Lange Ph.D., head of the Laboratory of Cell Biology and Genetics, and director of the Anderson Center for Cancer Research at the Rockefeller University, was awarded for her research on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer. De Lange identified a protein complex within telomeres, called shelterin, and has shown how this complex hides the chromosome end from cellular machinery that detects and repairs broken DNA tips.

• Napoleone Ferrara, M.D., distinguished professor of pathology and senior deputy director for basic sciences at Moores Cancer Center at the University of California, San Diego, was awarded for his discoveries in the mechanisms of angiogenesis that led to therapies for cancer and eye diseases.  Ferrara’s research has helped identifying the role of the human VEGF gene in promoting angiogenesis—the formation of new blood vessels that can feed tumor growth—and subsequent development of two major drugs: bevacizumab (Avastin) which is used to treat multiple forms of cancer and ranibizumab (Lucentis), which treats age-related macular degeneration, a leading cause of blindness in the elderly.

• Eric Lander, Ph.D., founding director and core member of the Broad Institute of MIT and Harvard, was awarded for the discovery of general principles for identifying human disease genes, and enabling their application to medicine through the creation and analysis of genetic, physical and sequence maps of the human genome. Lander was one of the leaders of the Human Genome Project.

• Charles L. Sawyers, M.D., chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, was awarded for his work in cancer genes and targeted therapy.  Sawyers research focuses on cancer drug resistance, which led him to the discovery of the drug enzalutamide (Xtandi), used for advanced prostate cancer.

• Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator, was awarded for his work in cancer genomics and tumor suppressor genes. Vogelstein’s identification of p53 gene mutations in colon cancer was groundbreaking and resulted in further research linking this gene mutation to other cancers. It is now known as the most common gene mutation in all cancers.

• Robert A. Weinberg, Ph.D., professor for cancer research at MIT and director of the MIT/Ludwig Center for Molecular Oncology, was awarded for his characterization of human cancer genes. Weinberg is known for his discoveries of the first human oncogene—a gene that causes normal cells to form tumors—and the first tumor suppressor gene.

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Arnold Rabson, M.D., left, accepts the Special Recognition Award from AACI, on behalf of his father. Presenting the award at the Oct. 15 ceremony is AACI President William S. Dalton, M.D., Ph.D., chief executive officer and director of the Moffitt Cancer Center. Photo by Mike Gatty.

His son, Arnold Rabson, M.D., accepted the award on his behalf.

In addition to his tenure at NCI, the senior Rabson is also a member of the Institute of Medicine and a fellow of the American Association for the Advancement of Science. He has held clinical professorships in pathology at Georgetown University Medical Center and George Washington University, and at the Uniformed Services University of the Health Sciences.

The Association of American Cancer Institutes comprises 95 leading cancer research centers in the United States. The award was presented to during the 2012 AACI and Cancer Center Administrators Forum Annual Meeting.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues—skin, gut, lung—have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities. This study provides new insights into the protective role of skin commensals and demonstrates that skin health relies on the interaction of commensals and immune cells.

The study was led by investigators in the laboratories of Yasmine Belkaid, Ph.D., at the National Institute of Allergy and Infectious Diseases, in collaboration with Julie Segre, Ph.D., at the National Human Genome Research Institute, and Giorgio Trinchieri, M.D., and Kong at the National Cancer Institute.

Understanding the Good Bacteria in Our Skin:

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Orentas receiving research grant award at Hyundai Hope On Wheels ceremony

Hyundai Hope On Wheels handprint ceremony

Rimas Orentas, Ph.D., from NCI’s Pediatric Oncology Branch in the Center for Cancer Research, is one of the 2012 recipients of a $250,000 research grant from Hyundai Hope On Wheels. This grant, given in honor of National Childhood Cancer Awareness Month, will allow Orentas to focus on new therapeutics for immunotherapy of pediatric tumors. Dr. Orentas’ current research focuses on the engineering of T lymphocytes for the immunotherapy of cancer in both mouse and human systems.

Orentas received his award at a Hyundai Hope On Wheels handprint ceremony where young cancer patients placed their paint-coated, colorful handprints on his lab coat.

Hyundai Hope On Wheels involves more than 800 dealers across the U.S. to raise awareness for childhood cancer.  The nonprofit has committed close to $57 million to childhood cancer research since its inception in 1998.

Steven A. Rosenberg, M.D., Ph.D.

Steven A. Rosenberg, M.D., Ph.D., a pioneer in the fields of basic tumor immunology and cancer immunotherapy, can add recipient of the 17th annual Keio Medical Science Prize to his list of academic and professional honors.

The prize, awarded by Keio University in Tokyo, recognizes the outstanding and creative achievements of researchers in the fields of medicine and life sciences, in particular those contributing to scientific developments in medicine. Six recipients of the Keio Medical Science Prize have later won the Nobel Prize.

Rosenberg, chief of surgery at the National Cancer Institute and head of the Tumor Immunology Section in NCI’s Center for Cancer Research, has been at the forefront of efforts to develop an effective immunotherapy for human cancer. In his recent work, he has used genetic engineering to develop anti-tumor immune lymphocytes.

“I am deeply grateful to the selection committee for awarding me the very prestigious Keio Medical Science Prize,” Rosenberg said. “This award recognizes our efforts to develop new immunotherapies for patients with cancer. It is a great honor to be able to work to develop new treatments for patients with this devastating disease.”

Matthew Meyerson, M.D., Ph.D.

Matthew Meyerson, M.D., Ph.D., a professor of pathology from the Harvard Medical School in Cambridge, Mass., and associate professor of pathology at the Dana-Farber Cancer Institute in Boston, led the writing committee for The Cancer Genome Atlas project on lung squamous cell cancer. He recently discussed his perspective on the findings.

NCI: Were there genes identified in the TCGA study that were unexpected, or was it more a matter that nobody has really interrogated the squamous cell genome that carefully heretofore?

Meyerson: I’d say the most unexpected finding was of some loss-of-function mutations in the HLA-A gene, which encodes a major histocompatability complex that plays an important immune regulatory role on the surface of cells. HLA-A codes for a protein on the surface of most cells that presents antigens to the immune system. So there’s been a concept that cancers evade the immune system, but this is the first evidence of somatic cancer genome alterations evading the immune system by changing their surface antigens. There were some papers published on models last year that showed this same concept in mouth cancers, but this is the first evidence in lung cancer.

NCI: Were there any other genes identified in the TCGA study that you think are noteworthy?

Meyerson: The HLA finding is new. Most of the other major genes that we’re identifying have previously been found, but this is the first comprehensive study of squamous cell lung carcinoma, and because of its comprehensive nature, what we’ve found is that there’s a gain-of-function mutation in many of the previously identified genes. This is quite important. A gain-of-function mutation in a targetable gene that codes for either a protein kinase or other type of kinase was found in more than 60 percent of the cases, and this might even be an underestimate. So this means that most cases of squamous cell lung cancer are now potentially treatable with targeted therapies—at least with investigational agents. I really think that this is going to catalyze a revolution in the treatment of squamous cell lung cancer. With lung adenocarcinoma, over the past decade or so, we’ve had a number of specifically targeted treatments introduced, and they are really advanced treatments for that subset of lung cancers. I think we’re going to see the same kind of development in squamous cell lung cancer.

NCI: There is an active cancer vaccine program at NCI, particularly in prostate cancer.  Does this finding suggest that we may also want to pursue vaccines in this form of lung cancer?

Meyerson: Absolutely. In fact, there were several clinical trials recently involving molecules that are known as immune system modulators. They’re basically antibodies that down-regulate the immune system. They are being used for exceedingly difficult cancers, and they’ve shown great promise in clinical trials for squamous cell lung cancer in particular. One of the trials is headed up by Julie Brahmer, M.D., at Johns Hopkins University.  It is one of the largest trials in this area.

NCI: Since we really didn’t know about HLA, were trials targeting surface antigens potentially the best approach, or should we rethink our vaccine approach?

Meyerson: No, those trials target antibodies that basically up-regulate the whole immune system. So there is no real specific targeting, but this TCGA finding suggests that a variety of targeting approaches might be suitable for squamous cell lung cancer.

NCI: How prevalent is squamous cell as a subset of lung cancers?

Meyerson: The mortality numbers for squamous cell lung cancer and lung adenocarcinoma aren’t exactly clear, but approximately 30 percent of lung cancer deaths are due to squamous cell lung cancer. There are approximately 150,000 to 160,000 lung cancer deaths per year in the United States. If you do the math on those two numbers, it gets you somewhere in the 40,000-plus range for deaths per year for squamous cell lung cancer in the United States alone, and that’s more than breast cancer, more than prostate cancer. It’s more than colorectal cancer; it’s more than pancreatic cancer. If you actually look at squamous cell lung cancer on its own, it would be the second-leading cause of cancer death after lung adenocarcinoma.

NCI: In terms of cancers related to smoking, squamous lung cancers congregate more in the center of the lung, whereas adenocarcinomas are more peripheral. Does this finding tell us anything about the components in cigarette smoke that may cause the subtypes of lung or how they develop?

Meyerson: Not yet. We haven’t learned a lot about the smoking signature from our study. There’s a distinct pattern of mutations that are associated with cigarette smoking, and we see that pattern of mutations in squamous cell lung carcinoma. Perhaps other researchers will take the information that we’ve generated, to gain more insight into the mechanisms by which cigarette smoking affects squamous cell lung cancer.

Some of the members of TCGA lung cancer disease working group

NCI: We have done a number of Genome-wide Association Studies, or GWAS, to get at some potential mechanisms or associations by which smoking initiates or promotes lung cancer.

Meyerson: There’s one interesting result of a genome-wide association study that recently came to light. The investigators found several loci on the HLA-A gene associated with squamous lung cancer.

NCI: Does this finding tell us that we may need a multiple number of drugs to hit a multiple number of targets in squamous lung cancer?

Meyerson: Absolutely. For squamous cell lung cancer, we will need multiple drugs for multiple targets, and I think the picture is similar to lung adenocarcinoma, although the distribution of targets is very different. For example, for the epidermal growth factor receptor, or EGFR , which is mutated in about 10 or 15 percent of lung adenocarcinomas for patients in the U.S., and nearly half of lung adenocarcinomas in Asia, it’s treatable with particular drugs or drug combinations. In squamous cell lung cancer, it was actually thought that wasn’t a good target, but actually one surprise is we did actually find EGFR mutations in about 1 percent of the cases. So while it’s a lot lower frequency, it is a different spectrum of EFGR mutations, but they are there and that should actually give us a target to hit in the future.

NCI: In terms of treating this particular form of lung cancer, how many drugs do you get a sense that will have to be created de novo versus those that we could take off the shelf and find some real use for?

Meyerson: I think that a lot of the drugs that could be useful are currently in clinical trials. These include fibroblast growth factor receptors, or FGFR inhibitors, and PI3-kinase inhibitors. That means, of course, we don’t know yet how they’re going to perform. I think there are going to be other drugs that will include many of the classes of enzymes that we’ve found to be mutated in adenocarcinomas. Most cases of squamous cell lung cancer demonstrate a loss of a type of tumor suppressor gene called CDK, or cyclin dependent kinase genes.

There is a loss of this tumor suppressor, so you can imagine that if you actually used cyclin dependent kinase inhibitors that you might be able to treat tumors with this loss.  This would be an argument that we don’t know what drugs in clinical trials will be effective, but that we should certainly test these drugs in squamous cell lung cancers.

Because there are drugs now in clinical trials, I would view our results as not leading to an immediate change in the practice of squamous cell lung cancer, but rather leading to a change in what clinical trials we can do to improve the care of squamous cell lung cancer.

NCI:  This was the first TCGA study to incorporate whole genome sequencing, although I think just in 19 samples.

Meyerson: This is the first one to incorporate whole genome sequencing events in cases. I actually think full genome sequencing is a challenge right now. I’m expecting that the whole genome sequencing data that we’ve provided are going to be incredibly useful for discovery. I don’t think we’ve actually captured all of the important observations in our paper, and my expectation is that cancer genome projects around the world will be working at the whole genome sequence data generated by TCGA, and that a lot of the most important discoveries may be made by re-analyses by other scientists over the next couple of years.

I think we’re going to learn more and more. I think we can understand a lot about genome alterations in the coding sequences of genes, but we really don’t understand much at all about the genome alterations of the non-coding sequences.

I think this has been a really strong collaborative effort across many, many, many institutions, and I think that one impact of that is that the participation of many groups in many institutes are in a way stimulating lung cancer research throughout the U.S., along with our partners from Canada, throughout North America, even throughout the world. The other thing I should mention is there are several other systematic one-character genome papers coming out over the next few weeks that will add to our knowledge base.

Finally, TCGA has also started a group that’s called the pan-cancer analysis group, and I think it is now possible to start looking at what we’re learning in all the different types of cancers and putting that together.

NCI: So it’s no longer a physiological examination? It’s looking for genetic markers that may have commonalities in a lot of different cancers?

Meyerson: Right. Commonalities, differences; just being able to analyze across cancers. I think that’s mostly commonalities to give us kind of an understanding so we’re amassing the dataset that makes that possible.

NCI: The final question is really a big picture question in terms of TCGA and the pace of discovery. As this is the fourth comprehensive report from TCGA, what has this effort shown us so far about how we can work globally with other partners in terms of really accelerating genomic research?

Meyerson: What I would say is after ramping up in the pilot phase, I think TCGA is really proving to be a very effective project, and as you mentioned, this is the fourth comprehensive report with colorectal, squamous cell lung cancer, and breast all coming out over the past or next few months. Within the next year I think we can expect kidney cancer, endometrial cancer, lung adenocarcinoma, head and neck cancer, maybe melanoma, and, I think, bladder cancer. So probably another six or seven reports in the next year, and these are providing both the discovery set and a reference data set that cancer researchers will be able to use to advance cancer discovery over the next few years.