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Sanford-Burnham Science Blog

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Nanoparticles seek and destroy glioblastoma in mice

by Heather Buschman, Ph.D. on October 3, 2011 at 12:00 pm | 0 Comments
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Erkki Ruoslahti, M.D., Ph.D., distinguished professor in both Sanford-Burnham’s NCI-designated Cancer Center in La Jolla and the Center for Nanomedicine, a Sanford-Burnham collaboration with the University of California, Santa Barbara

Erkki Ruoslahti, M.D., Ph.D., distinguished professor in both Sanford-Burnham’s NCI-designated Cancer Center in La Jolla and the Center for Nanomedicine, a Sanford-Burnham collaboration with the University of California, Santa Barbara

Glioblastoma is one of the most aggressive forms of brain cancer. Rather than presenting as a well-defined tumor, glioblastoma will often infiltrate the surrounding brain tissue, making it extremely difficult to treat surgically or with chemotherapy or radiation. Likewise, several mouse models of glioblastoma have proven completely resistant to all treatment attempts.

To overcome this hurdle, Sanford-Burnham scientists and their collaborators at the Salk Institute developed a method to combine a tumor-homing peptide, a cell-killing peptide, and a nanoparticle that both enhances tumor cell death and allows the researchers to image the tumors. When used to treat mice with glioblastoma, this new nanosystem eradicates most tumors in one model and significantly delays tumor development in another. These findings were published the week of October 3 in the Proceedings of the National Academy of Sciences of the USA.

“This is a unique nanosystem for two reasons. First, linking the cell-killing peptide to nanoparticles made it possible for us to deliver it specifically to tumors, virtually eliminating the killer peptide’s toxicity to normal tissues. Second, ordinarily researchers and clinicians are happy if they are able to deliver more drugs to a tumor than to normal tissues. We not only accomplished that, but were able to design our nanoparticles to deliver the killer peptide right where it acts—the mitochondria, the cell’s energy-generating center,” says Dr. Erkki Ruoslahti, senior author of the study and distinguished professor in both Sanford-Burnham’s NCI-designated Cancer Center in La Jolla and the Center for Nanomedicine, a Sanford-Burnham collaboration with the University of California, Santa Barbara.

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10 years of science & counterterrorism

by Communications Staff on September 11, 2011 at 6:41 am | 0 Comments
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Crystal Structure of Anthrax Lethal Factor complexed with a small molecule inhibitor

Crystal Structure of Anthrax Lethal Factor complexed with a small molecule inhibitor

As the United States pauses to observe the 10th anniversary of the September 11th terrorist attacks, we reflect on the research advances that contribute to new counterterrorism measures—understanding anthrax, for example—and the health of our soldiers in Iraq and Afghanistan, including under-studied conditions such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Here are a few examples, and these only cover discoveries made at Sanford-Burnham since September 11, 2001. Can you think of more? Please share your thoughts in the comments below.

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Normal in development, abnormal in cancer

by Bruce Lieberman on August 19, 2011 at 5:16 am | 0 Comments
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Dr. Danielle Murphy (right)

Dr. Danielle Murphy (right)

It’s an amazing and frightening thought: some of the same genetic signaling that shapes the development of an embryo also drives the spread of cancer. But that’s what a new study by Dr. Sara Courtneidge’s lab suggests.

Dr. Courtneidge’s lab primarily studies cancer metastasis—the spread of cancer from a tumor to another part of the body. Cancer cells do this by moving from the tumor through the vasculature and into the extracellular matrix, which provides structural support for tissues and organs. A few years ago, Dr. Courtneidge’s lab showed that cancer cells rely on a protein called Tks5 to form invadopodia, structures on the surface of cells that enable cancer cells to “walk” from one place in the body to another.

Cell migration, of course, is not a process unique to cancer and occurs during other normal and disease states. For example, cells move to the site of a wound during healing, during angiogenesis when new blood vessels form in response to injury, and during an immune response to infection. Cell migration is also crucial during embryonic development. So the Courtneidge lab decided to unravel Tks5’s role in development using the tiny zebrafish as an experimental model.

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Searching for new cancer drugs: Part 2

by Heather Buschman, Ph.D. on July 27, 2011 at 9:26 am | 0 Comments
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Scientists in Sanford-Burnham's Conrad Prebys Center for Chemical Genomics use robotic arms like this one to search for compounds that alter cellular behavior—precursors to new medicines.

Scientists in Sanford-Burnham's Conrad Prebys Center for Chemical Genomics use robotic arms like this one to search for compounds that alter cellular behavior—precursors to new medicines.

Yesterday, we introduced a study in which scientists in Sanford-Burnham’s NCI-Designated Cancer Center and Conrad Prebys Center for Chemical Genomics were looking for compounds that regulate invadopodia, cellular projections that allow cancer cells to invade and metastasize. They used robotic technology and automated microscopy to screen a library of pharmacologically active compounds—compounds already known to influence cellular function. In the course of the study, the researchers found some compounds that inhibit invadopodia and some that promote their formation. One of the latter was paclitaxel. Paclitaxel, also known by the brand name Taxol, is an FDA-approved drug currently used to treat several different kinds of cancer. The drug’s anti-tumor activity is based on its ability to bind and stabilize microtubules, one component of the cellular cytoskeleton, thereby halting cell division and inducing cellular suicide (a good thing, for cancer).

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Searching for new cancer drugs: part 1

by Heather Buschman, Ph.D. on July 26, 2011 at 3:10 pm | 1 comment
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Metastatic cancer cells form invadopodia (shown here as bright red spots).

Metastatic cancer cells form invadopodia, shown here as bright red spots. (Image by Begoña Díaz)

Metastasis—the spread of cancer from the place where it first started to another place in the body—is the most common reason that cancer treatments fail. To metastasize, some types of cancer cells rely on invadopodia, cellular membrane projections that act like feet, helping them “walk” away from the primary tumor and invade surrounding tissues. To determine how cells control invadopodia formation, Sanford-Burnham scientists screened a collection of pharmacologically active compounds to identify those that either promote or inhibit the process. They turned up several invadopodia inhibitors that target a family of enzymes called cyclin-dependent kinases (Cdks), revealing a previously unrecognized role for Cdks in invadopodia formation. These findings appeared online July 26 in Science Signaling.

“Previous studies by our group and others have demonstrated that we might be able to target invadopodia to prevent cancer cell invasiveness,” says Dr. Sara Courtneidge, professor and director of the Tumor Microenvironment Program in Sanford-Burnham’s NCI-Designated Cancer Center and senior author of the study. “In this study, we established a cell-based screening assay to help us identify regulators of invadopodia formation.”

Dr. Courtneidge’s group has been studying invadopodia for a number of years with the goal of unraveling how they regulate tumor cell invasion. Here, her team, led by postdoctoral researcher Dr. Manuela Quintavalle, joined forces with scientists in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (Prebys Center). This collaboration provided the Courtneidge lab with extra expertise in chemical genomics, the robotic technology necessary to rapidly and reproducibly screen more than 1,000 compounds with known pharmacological activity in cell-based assays, and automated microscopy capable of detecting and measuring invadopodia formation.

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CARing for pulmonary arterial hypertension

by Heather Buschman, Ph.D. on July 22, 2011 at 9:57 am | 0 Comments
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Dr. Masanobu Komatsu

Dr. Masanobu Komatsu

Pulmonary arteries carry blood from the heart to the lungs, where they pick up fresh oxygen for distribution to the rest of the body. Since almost every cell in the human body needs oxygen in order to convert nutrients into energy, pulmonary artery function is crucial. Pulmonary arterial hypertension (PAH) occurs when pressure builds up in these blood vessels, impairing this function. People with PAH experience shortness of breath, fatigue and chest pain. As the condition worsens, the heart has to work harder and harder to pump blood, sometimes leading to heart failure.

Despite eight approved clinical therapies for PAH and additional therapies currently in trials, there is no cure. What’s more, current treatments don’t specifically target pulmonary arteries, which can lead to severe side effects.

Sanford-Burnham scientists, led by Drs. Masanobu Komatsu and Dr. Takeo Urakami, in collaboration with VBS Pharmaceuticals, recently discovered a peptide (a short protein) that selectively targets and penetrates lung blood vessels affected by PAH. When the team tested this peptide, called CARSKNKDC (or CAR for short) in a rodent model of PAH, it homed in on hypertensive lungs, but spared healthy lungs and other organs. CAR also accumulated in other regions of the respiratory system that play crucial roles in PAH development and progression.

Published in the June 2011 issue of the American Journal of Pathology, these findings indicate that CAR could be used to deliver therapeutic compounds and imaging probes directly to PAH lungs.

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The San Diego Foundation supports science

by Faculty Contributor on July 20, 2011 at 1:45 pm | 1 comment
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iRGD peptides can specifically target cancer drugs (red) to the blood vessels that feed tumors (green). (Image courtesy of Dr. Kazuki Sugahara)iRGD peptides can specifically target cancer drugs (red) to the blood vessels that feed tumors (green). (Image courtesy of Dr. Kazuki Sugahara)

iRGD peptides can specifically target cancer drugs (red) to the blood vessels that feed tumors (green). (Image courtesy of Kazuki

At a time when scientists are having increasing difficulty acquiring financial support from federal sources, alternative sources of funding are becoming more important for maintaining the momentum of critical research at universities, research institutes and even industrial laboratories. At Sanford-Burnham, research assistant professor Dr. Kazuki N. Sugahara was recently awarded a one-year, $75,000 grant from The San Diego Foundation, via the The Blasker-Rose-Miah Fund. This marks one of the few times that a Sanford-Burnham investigator has received funding from this source, underscoring the novelty and importance of the project. This key piece of local funding will allow Dr. Sugahara to continue his research on the use of tissue-penetrating peptides that can detect developing tumors and enhance the delivery of cancer therapeutic drugs.

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Flash mob against cancer

by Josh Baxt on June 29, 2011 at 9:51 am | 0 Comments
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Signaling nanoparticles (blue) can locate a tumor, then set off a chemical reaction that attracts a mob of drug-delivering nanoparticles (pink) to the site. (Image by Gary Carlson)

Signaling nanoparticles (blue) draw in a mob of receiving nanoparticles (pink) to target tumors. (Image by Peter Allen, UCSB)

Researchers have been working for decades to develop nanoparticles that deliver cancer drugs directly to tumors, minimizing the toxic side effects of chemotherapy. However, even with the best nanoparticles, only small amounts of the treatment actually reach the tumor. Scientists at MIT, Sanford-Burnham’s Center for Nanomedicine at the University of California, Santa Barbara and the University of California, San Diego (UCSD) may have found a way to attract treatment-laden nanoparticles to tumors. Think of it as a therapeutic flash mob.

The team designed a delivery system in which nanoparticles home in on a tumor and then call in a much larger second wave of nanoparticles to dispense an anti-cancer drug. This communication between nanoparticles, enabled by the body’s own biochemistry, boosts drug delivery to tumors more than 40-fold in mouse models. The study, which was led by MIT’s Dr. Sangeeta Bhatia and received significant contributions from Sanford-Burnham’s Dr. Erkki Ruoslahti and UCSD’s Dr. Michael Sailor, was recently published online in the journal Nature Materials.

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Two-Faced Nanoparticles and Cancer

by Josh Baxt on June 20, 2011 at 9:42 am | 1 comment
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Janus particles

Janus particles, image courtesy of the Smith laboratory.

Nanoparticles hold great promise for improving cancer treatment. For example, they can guide drugs directly to tumors, increasing effectiveness and reducing side effects. However, significant challenges need to be overcome before these engineering marvels make it to the clinic.

On the engineering side, it’s difficult to make anything that small, around 100 nanometers (a nanometer is one billionth of a meter). Researchers also must generate particles that are uniform in size and shape and, once they’ve done their job, these particles must break down safely in the body.

On the treatment side, nanoparticles share the same obstacles as all potential treatments—cancer is wily. Because the disease evolves so rapidly, it finds ways to escape treatments, leading to drug resistance. So even the perfect nanoparticle, containing a single treatment, might not be effective in the long run.

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Happy Birthday ELISA

by Communications Staff on June 17, 2011 at 1:09 pm | 0 Comments
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Dr. Eva Engvall

Dr. Eva Engvall a few years after her work on ELISA.

You may never have heard of ELISA, but you have almost certainly been touched by it. Since its creation by Dr. Peter Perlmann and Dr. Eva Engvall at Stockholm University in 1971, ELISA (an acronym for enzyme-linked immunosorbent assay) has been one of the most widely used research and diagnostic tools ever. The purpose of an ELISA is to determine if a particular protein, chemical or pathogen is present in a sample (such as blood or urine) and if so, how much. ELISA was created to help bench scientists with their research, but overachieved in a big way. Consider the sheer variety of conditions ELISA can detect: allergies, HIV, West Nile virus, malaria, blood glucose concentrations, pregnancy, food-borne pathogens, the list goes on and on. Then think about all the technological changes the biological sciences have experienced over the past 40 years—and yet, ELISA remains a laboratory staple.

ELISA sandwich assay

Image by Jeffrey M. Vinocur

One of ELISA’s appeals is its simplicity. One version of the technique, called the sandwich ELISA, works something like the diagram to the right. 1) First, a plate is coated with “capture” antibodies that will specifically bind the protein of interest. 2) Then, a mixed sample containing the protein is applied. When the excess fluid is rinsed off, just the target proteins bound to antibodies remain. 3) To determine how much protein is there, “detection” antibodies are applied. These also bind the proteins, leaving them sandwiched between two antibodies (hence the name of the technique). 4) Next, a secondary antibody is added. This one is linked to an enzyme (represented by a black dot in this diagram). 5) In the last step, a chemical substrate is applied and the enzyme converts it to a product that can be measured. Often, the enzymatic conversion will result in a color, shown here in red. The more protein present in the sample, the redder solution becomes. By comparing the results to control reactions with known amounts of protein, scientists can determine the exact concentration of the protein in their starting sample.

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Fueling cancer cell growth

by Josh Baxt on May 17, 2011 at 8:00 am | 2 Comments
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Dr. Jorge Moscat and Dr. Maria Diaz-Meco

Dr. Jorge Moscat and Dr. Maria Diaz-Meco

May is National Cancer Research Month, created by Congress in 2007 to recognize the American Association of Cancer Research (AACR) for its contributions to the field. To honor AACR and highlight some of the important cancer research being done at Sanford-Burnham, we will be posting a series of articles on the ongoing work in our National Cancer Institute-designated Cancer Center. The vast majority of this research is made possible by funding from the National Institutes of Health (NIH), which includes the National Cancer Institute (NCI).

Fifty years ago, cancer biologists were convinced that understanding cancer metabolism would lead to a cure, until discoveries about cancer genetics shifted the research focus in other directions. But now the pendulum is swinging back, renewing interest in metabolism’s role in cancer.

Dr. Jorge Moscat and Dr. Maria Diaz-Meco, who both recently arrived at Sanford-Burnham from the University of Cincinnati, have been working together for more than twenty years to understand the mechanisms that allow cancer cells to grow at such a breakneck pace. Their investigations have led them to a network of proteins characterized by having PB1 domains. This network of proteins controls inflammation, how cells communicate with each other, and how they sense nutrients—all key drivers of cancer growth.

For example, the PB1-containing scaffold protein p62 regulates an enzyme called protein kinase C zeta (PKCZ), which is often missing in human cancers. PKCZ is a tumor suppressor that prevents inflammation and ensures that cells remain sensitive to nutrient levels. Cells without PKCZ get reprogrammed to endure food scarcity.

“If they lack this gene, they don’t care if glucose is unavailable,” says Dr. Moscat, “they just use other nutrients.”

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Leaders among peers

by Heather Buschman, Ph.D. on April 29, 2011 at 9:32 am | 0 Comments
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Wordle archive

Sanford-Burnham scientists are leading several exciting symposia over the next few months. Please follow the links below for more event and registration information.

2011 Signaling, Metabolism and Hypoxia Symposium
Chaired by Dr. Ze’ev Ronai

May 6, 2011, 2:00 – 5:30 p.m. (PDT)
Sanford-Burnham Medical Research Institute
10901 North Torrey Pines Road
La Jolla, California

2011 Glycobiology Gordon Research Conference
Chaired by Dr. Hudson Freeze

May 8 – 13, 2011
Il Ciocco Hotel
Lucca (Barga), Italy

Sanford-Burnham’s 33rd Annual Symposium: Structural Systems Biology
Chaired by members of the Bioinformatics and Systems Biology Program
Drs. Adam Godzik, Dorit Hanein, Andrei Osterman, Niels Volkmann

June 7, 2011, 9:00 a.m. – 5:15 p.m. (PDT)
Hilton La Jolla Torrey Pines
La Jolla, California

Cardiomyocyte Regeneration and Protection
Chaired by Dr. Mark Mercola

Sponsored by Abcam
June 20 – 21, 2011
Hilton La Jolla Torrey Pines
La Jolla, California

2011 Molecular Therapeutics of Cancer Research Conference
Chaired by Dr. Sara Courtneidge

Sponsored by the Cancer Molecular Therapeutics Research Association
July 10 – 14, 2011
Asilomar Conference Center
Pacific Grove, California

Seventh General Meeting of the International Proteolysis Society
Chaired by Dr. Guy Salvesen and Dr. Matthew Bogyo

October 16 – 20, 2011
Hilton San Diego Resort and Spa
San Diego, California

Targeting Arterial Plaque

by Josh Baxt on April 19, 2011 at 4:00 am | 1 comment
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Dr. Erkki Ruoslahti

Dr. Erkki Ruoslahti

Atherosclerotic plaque is the fatty material that builds up on arterial walls, where it can lead to heart disease and stroke. Atherosclerosis is currently treated with dietary changes, angioplasty (which uses a balloon to move the plaque aside) or more invasive procedures. Using drugs to break up these fatty plaques would be an enticing alternative, but delivery poses a problem. How do we precisely target the therapeutic agent to the diseased areas, leaving healthy tissues unaffected?

Dr. Erkki Ruoslahti and colleagues at Sanford-Burnham and UC Santa Barbara may have found a solution. For many years, Dr. Ruoslahti has been using specially designed peptides (pieces of proteins) to target cancer and other diseases. In a paper published online on April 11 by the Proceedings of the National Academy of Sciences, the Ruoslahti lab reports the discovery of a new peptide that can guide drugs or imaging agents specifically to atherosclerotic plaques.

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Seeing is believing

by Heather Buschman, Ph.D. on April 6, 2011 at 10:01 am | 1 comment
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Left: traditional electron microscopy view of actin filaments. Right: Dr. Dorit Hanein's 3-D view of actin.

Left: electron microscopy view of actin. Right: Dr. Dorit Hanein's 3-D view.

Life is complicated. Even one tiny cell has a lot going on at any given time, even when things are running smoothly. Normal cellular functions and their emergency responses (like to injury or infection) are mostly carried out by proteins. Proteins tell other proteins what to do by carrying signals, tagging one another with chemical groups, chewing up other proteins or helping assemble new ones, and so on. They also help orchestrate which genes are turned on or off and when.

The cell itself is constantly sensing and reacting to constant environmental fluctuations, as are the individual proteins and other molecules. So how do you connect these two things?

“You can see a cell by eye, using a standard microscope. But you can’t see individual molecules that way,” explains Sanford-Burnham’s Dr. Dorit Hanein. “A cell is on the micrometer scale (one-thousandth of a millimeter), while an individual molecule is on the nanometer scale (one-millionth of a millimeter). That’s like the difference between walking the 500 miles from here [San Diego] to San Francisco, versus walking from here to the moon.”

What Dr. Hanein and other scientists need are techniques that allow them to look not just at the moon, but at the earth, the moon and everything in between.

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Measuring Nanoparticles

by Josh Baxt on March 14, 2011 at 1:11 pm | 2 Comments
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One of the problems with nanoparticles is that, well, they’re just so small, making them difficult to study. Researchers may have solved that problem by building an instrument that can detect nanoparticles as small as tens of nanometers (billionths of a meter). The research team was led by Dr. Andrew Cleland, professor of physics at the University of California, Santa Barbara, and included Sanford-Burnham’s Dr. Erkki Ruoslahti. The study was published on March 7 in the journal Nature Nanotechnology.

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