RESEARCH UPDATES 2014
• BREAST CANCER
• LIVER CANCER
• LUNG CANCER
• PANCREATIC CANCER
• TUMOR DORMANCY
CELEBRATE SCIENCE:
SCIENCE UPDATE:BREAST CANCER
Wistar scientists identify protein important for metastasis in breast, bladder, melanoma and thyroid tumors.
Frank Rauscher III, Ph.D.Professor Wistar Institute Cancer Center
An international team of researchers led by scientists at SWCRF collaborator The Wistar Institute have dis-covered and defined LIMD2, a protein that can drive metastasis, the process where tumors spread through-out the body.
Their study, published in the March issue of the journal Cancer Research, defines the structure of LIMD2 and correlates the protein in metastatic bladder, melanoma, breast, and thyroid tumors. Wistar scientists have also developed and patented a monoclonal antibody that may one day be used as a prognostic test to see if tumors have LIMD2, and plans are underway to create inhibi-tors—potential drugs that may target cells that produce LIMD2.
“This is the result of a five year effort to characterize LIMD2, which is a new protein that we found to be expressed only in metastatic lesions, and not in the primary tumor or in normal tissues or organs,” said Frank Rauscher, III, Ph.D., a professor in The Wistar In-stitute Cancer Center. “LIMD2 is a great candidate for targeting with a drug, which would inhibit the ability of these cells to leave a primary tumor and to colonize other organs.”
According to Rauscher, LIMD2 is part of a family of proteins that communicate signals to the cell nucleus from the cytoskeleton of the cell—the structural scaf-folding that supports the cell. Scientists have looked to these proteins as potential drivers of metastasis since they control signals that regulate how the cell interacts
with nearby cells, including how cells may migrate and adhere to other tissues, which are traits tumors use to metastasize. LIMD2, in particular, is a key component to a chain of chemical events that control cell motil-ity, or movement, which is a defining characteristic of metastasis, Rauscher says.
LIMD2 had earlier been identified as a biomarker for papillary thyroid cancer metastasis and, as a member of the a family of proteins known to be active in both the cell’s nucleus and cytoplasm, piqued the interest of the Rauscher laboratory. Their studies demonstrated that LIMD2 appeared in abundance in samples of metastatic tumors, but were rarely expressed by pri-mary tumors or healthy cells.
To further characterize the structure and function of LIMD2, the Rauscher laboratory collaborated with scientists across The Wistar Institute Cancer Center and scientists from around the world. They developed a structural model of the LIMD2 protein and demon-strated that the protein interacted with integrin-linked kinase (ILK), an enzyme with critical importance to the process of cellular movement, proliferation, and metastasis.
Computer modeling analysis revealed that LIMD2 binds to ILK, and further studies demonstrated that LIMD2 promotes ILK activity. The “pocket” where LIMD2 binds to ILK, the researchers say, could be a promising target for a small molecule-based drug inhibitor.
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SCIENCE UPDATE:LIVER CANCER
Waxman Foundation-funded collaborators discover how mutated enzymes cause a deadly form of liver cancer.
Josep M. Llovet, M.D.Icahn School of
Medicine at Mount Sinai
The Samuel Waxman Cancer Research Foundation’s collaborating liver cancer researchers Nabeel Bard-eesy, Ph.D., Gallagher Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital and Josep Llovet, M.D., Director of the Liver Cancer Program at Icahn School of Medicine at Mount Sinai were re-cently published in the science journal Nature for their benchmark findings on Intrahepatic cholangiocarci-noma.
Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer that has increased in incidence for several decades and is among the most lethal of all human malignancies with an average survival period of less than one year. Recent work has identified mutations in the metabolic enzymes isocitrate dehydrogenase 1 or 2 (IDH1/2) as important genetic changes in this disease; however, how these mutations caused cancer remained unclear.
The study by Drs. Bardeesy and Llovet provided im-portant insights into the role of these two enzymes in liver cancer. The Mark Family support of the SWCRF Liver Cancer Research Program contributed to the funding of this collaboration, which revealed that mu-
tations in the two enzymes block the expression of a gene called hepatocyte nuclear factor 4 alpha (HNF4). Without this important gene, the liver’s own stem cells that arise during injury or with aging fail to mature into normal adult liver cells, or hepatocytes, and con-tinue to multiply.
This collaborative work has not only begun to eluci-date the origin of this challenging cancer, but it has also begun laying the groundwork for the development of therapies. By combining a mutant enzyme with a commonly mutated gene called Kras in a genetically engineered mouse model, our scientists went on to show how these cells progress in a step-wise manner from early pre-cancerous lesions to aggressive meta-static ICC tumors that mimic the human disease. This new mouse model will enable future studies aimed at identifying and testing new therapies for this currently incurable malignancy.
This project is yet another example of the productive cross-institutional collaborations borne out of the Institute Without Walls of the SWCRF and supported through our generous donors.
Nabeel Bardeesy, Ph.D.,
Massachusetts General Hospital
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SCIENCE UPDATE:LUNG CANCER
Johns Hopkins researchers identify genes that predict tumors that hide from the immune system.The Samuel Waxman Cancer Research Foundation’s team of funded researchers at Johns Hopkins Univer-sity – Stephen Baylin, M.D., Robert Casero, Ph.D., and Cynthia Zahnow, Ph.D., along with other researchers at Johns Hopkins, published a report in the journal Oncotarget detailing their discovery of genes that may predict tumors that evade detection from the immune system. The team’s research has produced a clinical trial in lung cancer that may lead to a new class of treatment.
Immune therapy for ovarian, breast and colorectal can-cer - treatments that encourage the immune system to attack cancer cells as foreign invaders - has so far had limited success, primarily because the immune system often can’t destroy the cancer cells.
In a report published in the journal Oncotarget, the Johns Hopkins team says it has identified genes that have been repressed through epigenetic changes - modifications that alter the way genes function without changing their DNA sequence - which help the cells to evade the immune system.
The researchers were able to reverse these epigenetic changes with the use of an FDA-approved drug, forc-ing the cancer cells out of hiding and potentially mak-ing them better targets for the same immune therapy that in the past may have failed.
The researchers treated 63 cancer cell lines (including breast, colorectal and ovarian) with low-dose 5-azaciti-dine (AZA), an FDA-approved drug for myelodys-plastic syndrome, that reverses epigenetic changes by
stripping off the methyl group that silences the gene. They identified a panel of 80 biological pathways com-monly increased in expression by AZA in all three cancers, finding that 20 percent of them are related to the immune system. These pathways appeared to be dialed down in the cancer cells, allowing for evasion. After treatment with AZA, the epigenetic changes were reversed, rendering the cancer cells unable to evade the immune system any longer.
The researchers found that these immune system path-ways were suppressed in a large number of primary tumors . After looking in cell lines, the Johns Hopkins team extended their work to human tumor samples. They again found evidence that these immune system pathways are turned down in some patients and, that these immune genes can be turned back up in a small number of patients with breast and colorectal cancer who had been treated with epigenetic therapies.
The hope is that clinicians could eventually pinpoint which patients with these common cancers would benefit from a dose of AZA followed by an immune therapy that stimulates the immune system to attack cancer cells.
The Johns Hopkins team has put the panel into use in a lung cancer trial. Six patients were treated first with epigenetic therapy followed by immune therapy. Though the sample is small and time has been short, four of the patients have had their cancer suppressed for many months.
From left: Robert Casero, Ph.D., Cynthia Zahnow, Ph.D. and Stephen Baylin, M.D.
Sydney Kimmel Comprehensive Cancer CenterJohns Hopkins University
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SCIENCE UPDATE:LUNG CANCER
Salk Institute scientists identify gene that fights metastasis of a common lung cancer.A team of scientists at the Salk Institute led by SWCRF-funded researcher Reuben J. Shaw, professor in Salk’s Molecular and Cell Biology Laboratory and a Howard Hughes Medical Institute early career scien-tist, have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world’s deadliest cancers.
By identifying the cause of this metastasis—which often happens quickly in lung cancer and results in a bleak survival rate—Salk scientists are able to ex-plain why some tumors are more prone to spreading than others. The newly discovered pathway, recently detailed in the journal Molecular Cell, may also help researchers understand and treat the spread of mela-noma and cervical cancers.
To become mobile, cancer cells override cellular ma-chinery that typically keeps cells rooted within their respective locations. Deviously, cancer can switch on and off molecular anchors protruding from the cell membrane (called focal adhesion complexes), prepar-ing the cell for migration. This allows cancer cells to begin the processes to traverse the body through the bloodstream and take up residence in new organs.In addition to different cancers being able to manipu-late these anchors, it was also known that about a fifth of lung cancer cases are missing an anti-cancer gene called LKB1 (also known as STK11). Cancers missing LKB1 are often aggressive, rapidly spreading through the body. However, no one knew how LKB1 and focal adhesions were connected.
Now, the Salk team has found the connection and a new target for therapy: a little-known gene called DIXDC1. The researchers discovered that DIXDC1 re-ceives instructions from LKB1 to go to focal adhesions and change their size and number.
When DIXDC1 is “turned on,” half a dozen or so focal adhesions grow large and sticky, anchoring cells to their spot. When DIXDC1 is blocked or inactivated, focal adhesions become small and numerous, resulting in hundreds of small “hands” that pull the cell for-ward in response to extracellular cues. That increased tendency to be mobile aids in the escape from, for example, the lungs and allows tumor cells to survive travel through the bloodstream and dock at organs throughout the body. Shaw and collaborators found in the new research that tumors have two ways to turn off this “stay-put” signal. One is by inhibiting DIXDC1 directly. The other way is by deleting LKB1, which then never sends the signal to DIXDC1 to move to the focal adhesions to anchor the cell. Given this, the scientists wondered if reactivat-ing DIXDC1 could halt a cancer’s metastasis. The team took metastatic cells, which had low levels of DIXDC1, and overexpressed the gene. The addition of DIXDC1 did indeed blunt the ability of these cells to be meta-static in vitro and in vivo.
Reuben J. Shaw, Ph.D.Professor, Molecular and Cell Biology Laboratory Howard Hughes Medical Institute Early Career Scientist
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SCIENCE UPDATE:PANCREATIC CANCER
Salk Institute scientists discover that a vitamin D derivative makes tumors vulnerable to chemotherapy.
Ronald Evans, Ph.D.,Salk Institute Professor Director, Gene Expression Laboratory
Salk Institute scientists, led by SWCRF-funded re-searcher Ronald Evans, Ph.D., have found that a syn-thetic derivative of vitamin D collapses the barrier of cells shielding pancreatic tumors, making them much more susceptible to therapeutic drugs. The discovery, published recently in the journal Cell, has led to hu-man trials for pancreatic cancer. By attacking a wound repair mechanism called fibrosis, the findings may also have implications for lung, kidney and liver cancer.
Dr. Evans and his colleagues knew that the ability of the pancreatic tumor to communicate with nearby cells—called the tumor microenvironment—is key to its growth. Tumor cells send out signals that make the microenvironment inflamed and dense; this “living shield” around a tumor not only helps the cancer grow, but blocks the access of immune cells and chemothera-peutic drugs, making the cancer particularly hard to treat.
Dr. Evans and collaborators around the country wanted to figure out how to restore this inflamed microenvironment to its normal state and weaken the wall around the tumor. The researchers focused on the wall’s pancreatic stellate cells, which usually respond to small injuries by briefly switching to an activated state, spurring new cell growth. In cancer, however, the stel-late cells near a tumor—in response to signals from the tumor—are constantly turned on. This chronic activa-tion of the stellate cells provides the tumor cells with extra growth factors, helping them proliferate, but also forms a wall-like barrier around the tumor that pro-tects it from chemotherapeutics and other drugs.
In 2013, Dr. Evans’ group discovered that stellate cells in the liver could be inactivated by a chemically modi-fied form of vitamin D. They wondered whether the same could hold true in the pancreas, despite the fact the vitamin D receptor was not thought to be present in pancreatic tissue. When the researchers examined the differences between activated and inactivated stel-late cells in the pancreas, they found that activated stel-late cells near a tumor had high levels of the vitamin D receptor. And when they added modified vitamin D to activated stellate cells the cells quickly reverted back to a healthy, inactivated state, stopping production of signals that spur growth and inflammation.
It turns out that activated stellate cells rapidly break down normal vitamin D, preventing the vitamin from binding to the receptor. But systematic analysis of vita-min D analogues allowed the team to discover a modi-fied form of vitamin D that is more stable, resilient and effective in vitro.
To see whether this new vitamin D-like compound could halt the growth of a tumor, the team next studied its effectiveness in mice and found that combining the drug with existing chemotherapeutics gave a 50 per-cent increase in lifespan compared to chemotherapy alone. Dr. Evans’ group has already teamed up with clinicians at the University of Pennsylvania to launch a clinical trial testing the effectiveness of using their vitamin D-like drug in cancer patients before pancreatic surgery.
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SCIENCE UPDATETUMOR DORMANCY
Nature Cell Biology publishes research by Mount Sinai tumor dormancy team led by Julio A. Aguirre-Ghiso, Ph.D.
Julio Aguirre-Ghiso, Ph.D. Icahn School of Medicine at Mount Sinai
The Samuel Waxman Cancer Research Foundation’s funded tumor dormancy investigator Julio A. Aguirre-Ghiso, Ph.D., and his team of scientists at the Icahn School of Medicine at Mount Sinai produced a research study that was published in the leading scientific jour-nal Nature Cell Biology.
In this elegant and high profile study, Dr. Aguirre-Ghiso has identified the reason why disseminated cancer cells from head and neck squamous cell carcinoma (HNSCC) appear to multiply and form metastases in some tissues like the lung but not in others like the bone marrow.
According to Dr. Aguirre-Ghiso’s research, the molec-ular “decision maker” for the selective development of metastases is TGF beta 2, a signaling protein secreted by the body’s own cells, also called a cytokine.
The bone marrow secretes high levels of TGF beta 2, which maintains the disseminated cancer cells dor-mant and in check, preventing growth of metastases. Meanwhile, in the lung where TGF beta 2 is in short supply, the cancer cells go unchecked and rapidly form aggressive tumors.
This research provides an important look at the body’s own mechanism to subdue cancer cells, and by iden-tifying where and how the body’s molecular defense system fails, it opens opportunities for the develop-ment of therapeutics.
Dr. Aguirre-Ghiso’s findings may have important impli-cations in a number of squamous cell cancers, including HNSCC, as well as breast cancer.
This exciting development is further evidence of the leading-edge science in which the SWCRF invests our supporters’ generous donations as part of our never-ending quest for a cancer cure.
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