Her team has identified a new class of antibodies – anti-LG3 – which when activated lead to severe rejection episodes associated with a high rate of organ loss. This discovery, which holds promise for organ recipients, was published in the online version of the American Journal of Transplantation.
Rejection is one of the major obstacles to organ transplantation. For the most part, it occurs when the recipient’s immune system recognizes the transplanted organ as a foreign body that must be eliminated. However, even when there is a good donor-recipient immunologic match, the recipient’s immune system can attack the transplanted organ’s blood vessels. Called acute vascular rejection, this phenomenon often leads to a high rate of graft loss.
Hébert’s team has characterized anti-LG3, an antibody that some patients produce to attack LG3, a protein that plays an important role in vascular repair and regeneration. “In these patients, the secretion of LG3 by the new kidney stimulates the activity of these antibodies which attack and injure the blood vessels of the transplanted organ. The net effect is that the normal healing process of the transplanted organ is hindered, if not interrupted, leading to impaired kidney function and even loss,” explains Dr. Hébert.
By identifying the heightened presence of anti-LG3 antibodies in patients prior to transplantation, researchers will be able to predict the development of severe rejection episodes. “These results are quite exciting,” notes Hébert, “and suggest that new therapies aimed at eliminating LG3 antibodies prior to transplantation could reduce organ rejection or limit its severity.”
Given that LG3 is present in all blood vessels and thus in all transplanted organs, Hébert’s results could also explain rejection of other types of transplanted organ, such as the heart, lung and pancreas.
About Dr. Hébert
Dr. Marie-Josée Hébert is a transplant nephrologist at CHUM and a bert: researcher with the CRCHUM’s Infection, Immunity and Inflammation research axis. She is also the Shire Chair in Nephrology Transplantation and Renal Regeneration, a professor in the Faculty of Medicine and Director of the Organ Transplant Program at the University of Montreal*. Her research is funded by the Kidney Foundation of Canada, Canada Foundation for Innovation, the Fonds de recherche du Québec – Santé, and the Canadian Institutes for Health Research.
About the CRCHUM
The University of Montreal Hospital* Research Centre (CRCHUM) improves the health of adults through a high-quality academic research continuum which, by improving our understanding of etiological and pathogenic mechanisms, fosters the development, implementation and assessment of new preventive, diagnostic and therapeutic strategies. The CRCHUM provides a training environment to ensure the development of new generations of researchers committed to research excellence.
*The University of Montreal Hospital and the University of Montreal and are known officially as Centre hospitalier de l’Université de Montréal and Université de Montréal, respectively.
For information :
Centre hospitalier de l’Université de Montréal (CHUM)
Telephone : 514 890-8000, extension 15380
Pager : 514 860-7110
BY KRISTA CONGER
Anthony Oro (right) and Scott Atwood found a second method of blocking a biological pathway, which may lead to more effective treatments for skin cancer.
Hailed as a major step forward in the effort to develop targeted cancer therapies, a recently approved drug for the most common type of skin cancer has been a mixed blessing for patients. Although the initial response is usually dramatic, the tumors often recur as the cancer becomes resistant to treatment.
Now researchers at the Stanford University School of Medicine have identified a second way to block the activity of the signaling cascade, called the Hedgehog pathway, that is abnormally active in these cancers. The researchers hope the new approach may not only one day help patients with tumors that have become resistant to the first drug, vismodegib (marketed as Erivedge), but may also provide a novel combination therapy for newly diagnosed tumors that may be more effective than either treatment alone.
“These new, highly targeted therapies work really well,” said dermatology professor Anthony Oro, MD, PhD, who was one of several Stanford researchers involved in the multiyear effort that brought vismodegib to market in 2012. “But this type of treatment is a race against evolution. Within a year, many of the tumors recur when the cancers become resistant to the inhibitor.”
The effect on patients, particularly those with a severe condition called Gorlin syndrome, is a heartbreaking yo-yo as the tumors that cover most of their bodies disappear within weeks, but often recur in force.
But Oro and his colleagues’ discovery of another, previously unknown component of the Hedgehog pathway — a component vital to its cancer-causing ability — could address this problem. Blocking the activity of this protein, called aPKC, can stop the growth in mice of transplanted skin tumors and tumor cells resistant to vismodegib. The finding, published Feb. 28 in Nature, may pave the way to a future in which cancers are treated with more than one specifically targeted drug.
“Although these tumors evolve in response to targeted drug treatment, we believe there’s a limited number of ways they can escape these therapies,” said Oro. “If we were able to hit them at the time of diagnosis with drugs that target more than one step in the pathway, they may be less able to evade treatment. We’ve identified a new target in the Hedgehog pathway and we’ve developed an inhibitor of this target that we hope will work in human cancers.”
Oro, who is the senior author of the study, was also one of several authors on a series of three papers in the New England Journal of Medicine last June describing the effectiveness of vismodegib in treating the most common type of skin cancer, basal cell carcinoma. Postdoctoral scholar Scott Atwood, PhD, is the lead author of the current study.
Taken together, the recent studies illustrate the nature of the constant battle among physicians and the rapidly growing and changing cancer cells they strive to eradicate. Targeted treatments that focus on unique vulnerabilities exhibited by specific types of cancers can be highly effective. They can also minimize the unpleasant side effects of less-specific treatments that kill many other non-cancerous cells. But their very specificity encourages and drives the tumor cells to evolve resistance in a way that might not be possible against a more broad-based therapeutic approach. Many researchers believe that a multipronged attack targeted at more than one point in critical cancer-causing pathways could be an effective way to combat resistance.
“Our goal is to provide precision cancer care at the time of diagnosis,” said Atwood. “We’re working toward developing better, more specific single and combination therapies to reduce the chance of resistance through tumor evolution.”
The Hedgehog pathway is critical to many aspects of embryo development in animals as diverse as fruit flies and humans. When abnormally activated, it can cause uncontrolled cell growth. The pathway was first linked to human cancer about 16 years ago by researchers, including Stanford professor of developmental biology Matthew Scott, PhD. Since that time, researchers around the world, including a large group at Stanford, have worked to learn more about the pathway and how to inhibit it.
That work led to the development of vismodegib, which blocks a protein called Smoothened, or Smo, that acts near the beginning of the Hedgehog pathway. Smo sits in the cell membrane and sends signals into the interior of the cell. When activated, it initiates a biological cascade of signaling molecules that culminates in the cell’s nucleus at a protein called Gli, which governs gene expression.
Oro and Atwood discovered another, previously unknown protein player in the Hedgehog pathway called aPKC. This protein perpetuates Gli’s ability to transcribe, or activate, certain genes by giving it a specific molecular tag (a process called phosphorylation). The phosphorylated Gli in turn goads aPKC to higher levels of activity in what’s known as a positive feedback loop.
The researchers studied human skin cancer cells removed from patients and grown in a laboratory dish. They also used a model in which basal cell carcinomas were transplanted onto mice. They looked at levels of aPKC activity and gene expression profiles in the tumors.
“We’ve found that aPKC is highly active in human basal cell carcinomas that have become resistant to vismodegib,” said Atwood. “This positive feedback with aPKC allows tumors to grow really well even in the presence of vismodegib.”
When the researchers used an aPKC inhibitor to treat mice bearing transplanted tumors or tumor cells resistant to Smo inhibitors, the growth of the cancer cells was suppressed and the tumors shrank.
The researchers are now working to optimize the selection and design of the aPKC inhibitor. They are also interested in exploring its effect in other cancers in which the Hedgehog pathway is implicated.
“There are a host of Hedgehog-dependent cancers,” said Oro, “and we have many researchers and clinicians here at Stanford poised to conduct clinical trials of these types of therapies. It’s very exciting.”
Other Stanford researchers involved in the work include former undergraduate student Mischa Li, technician Alex Lee and assistant professor of dermatology Jean Tang, MD, PhD.
The research was funded by the National Institutes of Health (grants 1F32CA14208701, AR052785 and AR046786). Information about Stanford’s Department of Dermatology, which also supported the work, is available at http://dermatology.stanford.edu/.
– See more at: http://med.stanford.edu/ism/2013/february/oro.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+NewsFromStanfordsSchoolOfMedicine+%28News+from+Stanford%27s+School+of+Medicine%29#sthash.zWkdtfLM.dpuf