Conventional treatments for diseases such as cancer can carry harmful side effects—and the primary reason is that such treatments are not targeted specifically to the cells of the body where they’re needed. What if drugs for cancer, cardiovascular disease, and other diseases can be targeted specifically and only to cells that need the medicine, and leave normal tissues untouched?
Sanford-Burnham's Erkki Ruoslahti, M.D., Ph.D., is a co-author of the study.
Maurizio Pellecchia, Ph.D., in his lab.
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.
These nanoparticles of porous silicon, each 100 times smaller than a human hair, contain microscopic reservoirs that can hold and protect sensitive drugs. The surface of the particles can be covered with targeting molecules. (Photo by Chia-Chen Wu, UC San Diego)
The U.S. Defense Advanced Research Projects Agency (DARPA) has awarded $6 million to a team of researchers to develop nanotechnology therapies for the treatment of traumatic brain injury and associated infections. The award brings together a multi-disciplinary team of renowned experts in laboratory research, translational investigation, and clinical medicine. The team includes Sanford-Burnham’s Erkki Ruoslahti, M.D., Ph.D., and is led by Professor Michael J. Sailor, Ph.D., from the University of California San Diego. Also on the team are Sangeeta N. Bhatia, M.D., Ph.D., of Massachusetts Institute of Technology, and Clark C. Chen, M.D., Ph.D., of UC San Diego School of Medicine.
Sanford-Burnham benefactor Malin Burnham (left) raises a toast to Dr. Kristiina Vuori and Dr. John Reed, surrounded by faculty and staff
It’s a good idea for the people within an organization to stop and look around once in a while. And there is perhaps no better time for reflection than during a time of transition.
As John C. Reed, M.D., Ph.D., put it, “All organizations benefit from fresh leadership approximately every decade, and that time is now for Sanford-Burnham.” Reed announced on January 14 that he would be stepping down after 11 years as CEO to accept a position with pharmaceutical company Roche.
This turn of events led to an opportunity to reflect on our past, present and future, when Sanford-Burnham’s leaders presented “Reflections on a Decade of Growth.” Our scientists and staff heard from Reed, as well as distinguished professor and past president (1989-2002) Erkki Ruoslahti, M.D., Ph.D., and president and interim CEO Kristiina Vuori, M.D., Ph.D.
Their inspiring presentation including four key observations:
![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:
Erkki Ruoslahti, M.D., Ph.D., distinguished professor
Thomson Reuters has selected Erkki Ruoslahti, M.D., Ph.D., cancer researcher and distinguished professor at Sanford-Burnham Medical Research Institute, as one of its 2012 Citation Laureates. Citation Laureates are scientists that Thomson Reuters has predicted to win the Nobel Prize.
Thomson Reuters Citation Laureates are chosen based on how frequently their research has been cited by other researchers. Many studies have shown a strong correlation between citations and regard by one’s peers, which is a factor often reflected in major professional awards. Using this quantitative approach, Thomson Reuters has made many correct predictions—in the past 10 years, 26 Citation Laureates received Nobel Prizes. The 2012 Nobel Prizes will be announced beginning October 8.
Ruoslahti is among the 50 most-cited researchers of the last 20 years and an influential figure in cell biology and cancer research. He was one of the early pioneers in research on cell adhesion—the study of how cells stay in place by sticking to their surrounding environments. Ruoslahti’s work has clarified many of the fundamental mechanisms responsible for clinically relevant problems, including blood clotting, immune cell homing, and tumor metastasis. His research spawned many drug-discovery programs around the world aimed at finding new treatments for arterial restenosis, thrombosis, cancer, and more—some of which have resulted in FDA-approved drugs.
In addition to his research, Ruoslahti distinguished himself through the leadership and vision he provided during his 13 years as president and chief executive officer of Sanford-Burnham Medical Research Institute (1989-2002). Under his direction, Sanford-Burnham’s National Cancer Institute (NCI)-designated Cancer Center became one of the leading basic cancer research centers in the world.
Panelists Dr. Erkki Ruoslahti, Dr. Anna Barker, Ron Andrews, and Dr. Robert Abraham with moderator Dr. Mary Walshok
“We’re at the end of the beginning,” is how Anna Barker, Ph.D., speaking during a May 20 panel discussion, described our progress in the War on Cancer. Sanford-Burnham hosted the event, What Will it Take to Cure Cancer?, at the San Diego Natural History Museum, as a benefit to its President’s Circle members, donors who contribute $1,000 or more annually. Dr. Barker, former deputy director of the National Cancer Institute (NCI), sat alongside Erkki Ruoslahti, M.D., Ph.D., distinguished professor and former president of Sanford-Burnham, Ron Andrews, president of medical sciences at Life Technologies, and Robert Abraham, Ph.D., senior vice president at Pfizer Worldwide Research. Together, they represented expertise along the continuum from basic scientific discovery to the production of drugs.
Hongbo Pang, Ph.D.
Meet Hongbo Pang, Ph.D., a postdoctoral researcher in the laboratory of Erkki Ruoslahti, M.D., Ph.D.
Meet Aman Mann, Ph.D., a postdoctoral researcher in Sanford-Burnham’s NCI-designated Cancer Center.
Atomic model of the NSP-p130Cas complex
Sanford-Burnham has a long history with proteins of the so-called Cas family, particularly one member called p130Cas. For more than a decade, some of our top researchers, including Kristiina Vuori, M.D., Ph.D., Erkki Ruoslahti, M.D., Ph.D., and Elena Pasquale, Ph.D., have studied the biology of these proteins and the role they play in cancer. And they made several groundbreaking findings.
One of these was the co-discovery of a family of novel cell-regulating proteins that interact with Cas proteins, called the NSP family. When Cas and NSP proteins get together, they help a cell migrate or invade surrounding tissues—processes that can be either beneficial, as when immune cells mature, or harmful, as when a cancer cell metastasizes. Furthermore, one particular pair of Cas and NSP proteins were found to cause breast cancer cells to become resistant to anti-estrogen drugs such as tamoxifen, one of the major challenges in fighting this devastating disease.
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.
L to R: Armi Williams (accepting on behalf of Roberto Tinoco), Gregory Aubért, Martina Pröll, Aman Mann, and Malene Hansen (accepting on behalf of Caroline Kumsta)
Sanford-Burnham’s founders, William and Lillian Fishman, appreciated the important impact that postdoctoral fellows have on medical research and created a tradition of fostering the development of young scientists. The Fishman Fund Award was established in 2001 by Mary Bradley and Reena Horowitz to honor that tradition. Each year, five individual awards of $6,000 each are given to select postdocs for career development. This year’s award was presented on September 8. Read about each of the winners, their research, and their career goals below.
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.
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.
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.