As National Cancer Research Month draws to a close, we profile important work by three Sanford-Burnham researchers in this last post of our May cancer research series: Drs. Erkki Ruoslahti, Maurizio Pellecchia and Ranjan J. Perera.
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May is National Cancer Research Month
May is National Cancer Research Month, so we thought we’d highlight exciting cancer research underway at Sanford-Burnham. Today, we focus on a few of the strategies our researchers are pursuing to better understand the pathologies of cancer tumors—and stop them in their tracks.
Quebec (Photo by Martin St-Amant, Wikimedia Commons)
Calling all cytokine scientists…
What: 14th International Tumor Necrosis Factor Conference
When: July 7-10, 2013
Where: Loews Le Concorde, Quebec City, Canada
Who: Hosted by the International Cytokine Society; attended by more than 300 academic and biopharma industry scientists from around the world
Registration: Visit www.tnf2013.com
The Florida Translational Research Program provides Florida-based scientists with access to Sanford-Burnham's drug-discovery technology and expertise.
We announced today the selection of the first five research organizations that will participate in the Florida Translational Research Program (FTRP) to advance drug discovery in the state. The projects focus on cancer, diabetes, and obesity, and are led by scientists from the University of Central Florida, the University of Florida, the University of Miami, Scripps Florida, and a team of our own Lake Nona scientists. The Florida Department of Health and Sanford-Burnham established the FTRP as a competitive grant program that provides funding for collaborative drug discovery projects. The overall goal of the program is to translate research discoveries made in Florida laboratories into the medicines of tomorrow.
T. Denny Sanford
Philanthropist T. Denny Sanford has reaffirmed his commitment to Sanford-Burnham and expressed his confidence in our interim chief executive officer, Kristiina Vuori, M.D., Ph.D., by pledging a seven-figure donation to cancer research.
“At this time of transition, I want to provide both financial support and a personal endorsement of Sanford-Burnham’s excellence,” said Mr. Sanford. “I have the utmost confidence in the Institute’s future and Dr. Vuori’s leadership as interim CEO.” Mr. Sanford’s previous pledges to the Institute total in excess of $70 million, including the transformative gift that resulted in the Institute’s name change in 2010.
Vuori, president of the Institute since 2010, was named interim CEO last month when John C. Reed, M.D., Ph.D., stepped down from the position. Reed and Vuori worked closely together during a time when the Institute emerged as a world leader in research and early-stage drug discovery.
“Mr. Sanford has made an indelible mark on this institution through financial support which he has characterized as investments in medical research. He envisions a healthier future and we are honored to be part of that vision,” Vuori said. “As a cancer researcher, this latest substantial gift means a great deal to me personally, as well as to Sanford-Burnham.”
Potential cancer drug sabutoclax blocks Bcl-2 protein family members that help keep cancer cells alive. This image shows the structure of one Bcl-2 protein, known as Bcl-Xl. (Image courtesy of the Pellecchia laboratory)
Researchers find that certain types of drug-resistant leukemia stem cells are vulnerable to sabutoclax, a novel cancer stem cell-targeting drug based on Sanford-Burnham research.
New experiments show that sabutoclax, a novel cancer stem cell-targeting drug that grew out of research at Sanford-Burnham Medical Research Institute, in combination with other therapies, could effectively treat diseases like chronic myeloid leukemia (CML). Sabutoclax might also lower the chance of relapse.
“The demonstration of sabutoclax’s preclinical activity in mouse models of CML is exciting and encourages further evaluation of this promising drug candidate for aggressive leukemias. We look forward to continuing our collaborative studies of sabutoclax, as we move this drug closer to the clinic,” said John Reed, M.D., Ph.D., professor and Donald Bren Chief Executive Chair at Sanford-Burnham.
Sabutoclax was first discovered as a result of research in the laboratories of Reed and his Sanford-Burnham colleague, Maurizio Pellecchia, Ph.D. The pair is now working with biotechnology company Oncothyreon Inc to develop sabutoclax into a potential anti-cancer drug. This latest study of sabutoclax’s efficacy, published January 17 in the journal Cell Stem Cell, was led by Catriona Jamieson, M.D., Ph.D., at UC San Diego Moores Cancer Center, in collaboration with Reed, Pellecchia and others.
![3D structure of CXCR1, a G protein-coupled receptor that transmits inflammatory signals [Image courtesy of Stanley Opella, UCSD]](http://beaker.sanfordburnham.org/wp-content/uploads/2012/12/CXCR11_top10.jpg)
3D structure of CXCR1, a G protein-coupled receptor that transmits inflammatory signals [Image courtesy of Stanley Opella, UCSD]
Cellular sensor’s 3D structure reveals new clues for combating cancer
Originally published October 23, 2012
Scientists have, for the first time, determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor (GPCR) in its native environment: embedded in a lipid membrane.
The team, led by Stanley Opella, Ph.D. at the University of California, San Diego and Francesca Marassi, Ph.D. at Sanford-Burnham Medical Research Institute, used a technique called NMR spectroscopy to map the arrangement of atoms in one particular GPCR, called CXCR1. Their finding was published by Nature on October 21.
Weon-Kyoo You, Ph.D., postdoctoral researcher in the Stallcup lab
Editor’s note: We’ve previously described serendipity’s important role in the scientific discovery process. Because this phenomenon is such a strong recurrent theme in science, there are almost an unlimited number of stories about scientific progress in which serendipity was a major factor. One such story occurred recently in the lab of William Stallcup, Ph.D., here at Sanford-Burnham.
Striking out
A few years ago, a collaborator in Italy gave the Stallcup lab a mouse model genetically engineered to lack the collagen VI protein. Collagen VI is part of the support scaffold surrounding fat tissue.
“Collagen VI is also one of the important binding partners for NG2, a protein we’ve long studied in our lab for its role in cancer,” relates Stallcup. “There was a report published showing that breast cancer progression is slowed in mice lacking collagen VI, which is the same phenomenon we have seen in mice lacking NG2.”
In addition, other studies reported that collagen VI loss leads to poor mammary fat cell function. That was similar to the Stallcup lab’s observations of altered fat cell behavior in the absence of NG2.
“So we thought there was a strong chance that loss of the NG2-collagen VI interaction in fat cells might provide a unified explanation for the poor fat cell function and reduced mammary tumor progression seen in both types of mice,” Stallcup says.
Yet the group could never reproduce the mammary tumor findings that were reported for the collagen VI knockout mouse, and so their theory could not be proved. They abandoned the project.
Enter serendipity
Symposium attendees await the announcement of Best Talk and Best Poster awards (Photo by Karolina Kucharova)
Each year, the Sanford-Burnham Science Network, our organization of postdoctoral researchers and graduate students, holds a symposium for young scientists to practice presenting their work and gain valuable feedback from their peers and our faculty members. This year, the La Jolla group’s event was held at the Sanford Consortium for Regenerative Medicine.
Here are five random things we learned last week at the 11th annual symposium:
Left: Medulloblastoma tumor (green) from untreated mouse. Right: Corresponding tissue from mouse treated with bFGF lacks tumor growth.
Brain tumors arising from different cell types might require different—and more personalized—treatment approaches.
Cancers arise when a normal cell acquires a mutation in a gene that regulates cellular growth or survival. But the particular cell this mutation happens in—the cell of origin—can have an enormous impact on the behavior of the tumor, and on the strategies used to treat it.
Robert Wechsler-Reya, Ph.D., professor and director of the Tumor Development Program in Sanford-Burnham’s NCI-designated Cancer Center, and his team study medulloblastoma, the most common malignant brain cancer in children. A few years ago, they made an important discovery: medulloblastoma can originate from one of two cell types: 1) stem cells, which can make all the different cell types in the brain or 2) neuronal progenitor cells, which can only make neurons.
Stem cells and progenitor cells are regulated by different growth factors. So, Wechsler-Reya thought, maybe the tumors arising from these cells respond differently to different therapies…
![Breast tumor (blue) surrounded by blood vessels (red) [Image provided by Dr. William Stallcup]](http://beaker.sanfordburnham.org/wp-content/uploads/2012/10/breast-tumor_Stallcup1.jpg)
Breast tumor (blue) surrounded by blood vessels (red) [Image provided by Dr. William Stallcup]
What is breast cancer?
Breast cancer is the second most common type of cancer in women. In 2007 (the most recent year for which data is available), 202,964 women in the U.S. were diagnosed with breast cancer and 40,598 women died from the disease, according to the CDC. Approximately 12 percent of women in the general population will develop breast cancer sometime during their lives.
The most common types of breast cancer include ductal carcinoma, which begins in the cells that line the milk ducts of the breast, and lobular ductal carcinoma, which originates in the breast lobes.
A variety of genetic and environmental influences can increase a person’s risk of breast cancer. However, some breast cancers are associated with inherited mutations in a few specific genes. The best known are mutations in the genes BRCA1 and BRCA2 (BRCA stands for breast cancer susceptibility gene), which account for five to 10 percent of all breast cancer cases.
Depending on the type of breast cancer and its progression, treatments can include surgery, chemotherapy, radiation therapy, hormone therapy, or targeted therapy aimed specifically at disrupting the molecular underpinnings of the disease.
Breast cancer research at Sanford-Burnham
Sanford-Burnham is home to one of just seven National Cancer Institute (NCI)-designated basic cancer centers in the United States. Researchers in this center aim to preempt cancer before it develops, detect the disease at its earliest point, and eliminate its spread.
Historically, our scientists have made seminal contributions to breast cancer. Kristiina Vuori, M.D., Ph.D., now director of Sanford-Burnham’s Cancer Center, and others published early findings on cellular communication networks in breast cancer cells. John C. Reed, M.D., Ph.D., now Sanford-Burnham’s CEO, and his laboratory made seminal contributions to the understanding of how certain proteins direct programmed cell death (a process called apoptosis) in breast cancer cells and how these proteins allow breast tumors to resist chemotherapy.
While many researchers in Sanford-Burnham’s Cancer Center study cellular growth and lifespan—work that impacts almost every type of cancer—our scientists are also pursuing several strategies for finding new treatments that specifically target breast cancer.
Here are a few current breast cancer studies at Sanford-Burnham:
![3D structure of CXCR1, a G protein-coupled receptor that transmits inflammatory signals [Image courtesy of Stanley Opella, UCSD]](http://beaker.sanfordburnham.org/wp-content/uploads/2012/10/CXCR11.jpg)
3D structure of CXCR1, a G protein-coupled receptor that transmits inflammatory signals [Image courtesy of Stanley Opella, UCSD]
Scientists have, for the first time, determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor (GPCR) in its native environment: embedded in a lipid membrane.
The team, led by Stanley Opella, Ph.D. at the University of California, San Diego and Francesca Marassi, Ph.D. at Sanford-Burnham Medical Research Institute, used a technique called NMR spectroscopy to map the arrangement of atoms in one particular GPCR, called CXCR1. Their finding was published by Nature on October 21.
What are GPCRs?
Scientists have long known that cells must have some sort of sensor that allows them to detect external signals like aromas, hormones, and neurotransmitters. Adrenalin, for example, hits the outside of a cell yet manages to trigger changes inside the cell—the “flight or fight” response—without actually entering it. For decades, the link between the outside of a cell and the inside remained unknown—until GPCRs were discovered by Robert J. Lefkowitz, M.D. and Brian K. Kobilka, M.D., a finding for which they were awarded the 2012 Nobel Prize in Chemistry earlier this month.
Cancer stem cells in a low-oxygen environment (left) remain stem cells. In a normal-oxygen environment (right), the stem cells form differentiated, non-cancerous cells (red and green cells). Cancer stem cells may hide in tumor regions with poor blood supply and low oxygen.
Today is Stem Cell Awareness Day, sponsored by the California Institute for Regenerative Medicine. Read about some new research on cancer stem cells below, and learn more about stem cells and clinical trials at an event tonight at the Sanford Consortium for Regenerative Medicine in La Jolla, Calif.
Not all cells that make up a tumor are necessarily the same. Recent research suggests that a special population of cancer stem cells might be at the root of some tumors. These stem cells can self-renew, generating both tumor cells and more stem cells. Cancer stem cells may be one reason that some tumors become resistant to standard therapies. They could also be the reason some tumors reappear—in actuality, the cancer stem cells never truly disappeared.
A Sanford-Burnham research team recently isolated cancer stem cells from a mouse model of breast cancer and showed that these cells are able to generate new tumors similar to the ones from which they originated—even when starting from just a single cell.
To survive, tumors need blood supply to provide them with nutrients and oxygen. To get that supply, cancer cells stimulate new blood vessel growth—a process called tumor angiogenesis. Many attempts have been made to inhibit this process as a means to choke off tumors. But tumor angiogenesis can be sloppy, resulting in immature and malformed blood vessels. Since anti-cancer drugs are carried to tumors by the bloodstream, abnormal blood vessel development also hampers delivery. What if, rather than putting a stop to angiogenesis, we could help tumor blood vessels mature more completely, so tumor-killing therapies could more effectively reach their targets? This counterintuitive concept was proposed several years ago, but researchers lacked a way to do it. Now, in a paper published August 14 in the journal Cancer Cell, Sanford-Burnham researchers found a molecule that promotes the tumor vessel maturation process—a discovery that might provide a method for improving cancer drug delivery.
“Our finding suggests that an ability to regulate this molecule could allow us to solve various problems caused by blood vessel abnormalities, including inefficient drug delivery to tumors,” said Masanobu Komatsu, Ph.D., associate professor at Sanford-Burnham and senior author of the study.
Dr. Maurer with Sanford-Burnham co-founder Lillian Fishman
Meet Jochen Maurer, Ph.D., a postdoctoral researcher in the lab of Robert Oshima, Ph.D, professor in our NCI-designated Cancer Center.