waxman foundation scientists research progress updates 2014
Post on 06-Apr-2016
Embed Size (px)
DESCRIPTIONThe Samuel Waxman Cancer Research Foundation's funded scientists from renowned research institutes have been published in leading science journals for their discoveries relating to lung, breast, liver and pancreatic cancer as well as tumor dormancy.
RESEARCH UPDATES 2014 BREAST CANCER
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-torspotential 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 cellthe 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 cells 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.
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 Foundations 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 livers 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
SCIENCE UPDATE:LUNG CANCER
Johns Hopkins researchers identify genes that predict tumors that hide from the immune system.The Samuel Waxman Cancer Research Foundations 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 teams 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 cant 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
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 Salks 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 worlds deadliest cancers.
By identifying the cause of this metastasiswhich often happens quickly in lung cancer and results in a bleak survival rateSalk 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 can