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Promise and Progress - Headline Makers
Special Commemorative Issue of Promise & Progress: The Ludwig Center at Johns Hopkins
Date: January 2, 2014
The Ludwig Center at Johns Hopkins
Ludwig Center at Johns Hopkins Established
A research team at the Sidney Kimmel Comprehensive Cancer Center was one of six in the nation to share in a $120 million gift from the Ludwig Fund, named for the late shipping tycoon Daniel K. Ludwig. Some $20 million went to the newly formed Ludwig Center at Johns Hopkins in 2006 as well as a lifetime annual commitment of $2 million.
"We recognize that it takes more than a good idea to drive future discoveries in cancer research," says Bert Vogelstein, M.D., co-director of the Hopkins center. "It takes resources, and we're grateful to the Ludwig Fund for its support." Vogelstein and co-director Kenneth Kinzler, Ph.D., were among the pioneers in uncovering genetic mutations responsible for the onset and development of cancer. "The Ludwig Fund has given us the tools to explore comprehensive genetic studies so that we can make a collective impact against this disease," said Dr. Kinzler.
With Ludwig Fund support, their team completed the first map of mutations found in colon and breast cancers. "Johns Hopkins is revered as one of the outstanding institutions for cancer research in the world, and Drs. Vogelstein and Kinzler have been mighty contributors to this renown," says Lloyd J. Old, M.D., Chairman of the Ludwig Fund's Trustees. "Their work on the genetics of human cancer forms much of the basis for our current understanding and has identified a plethora of potential new therapeutic targets for cancer. The trustees are delighted that Drs. Vogelstein and Kinzler and their outstanding colleagues at Johns Hopkins will become an integral part of the collaborative Ludwig Cancer network of Ludwig Centers and the Ludwig Institute for Cancer Research. " The six Ludwig Centers will collaborate with the Fund's Institute with branches and affiliate sites in more than 15 countries worldwide.
Tough cases require innovative medicine, and for colon cancer patients whose cancers have not relented to other treatments, a new therapy called COBALT (combined bacteriolytic therapy), has shown promise. At the center of the therapy is the bacteria Clostridium novyi-NT, a germ that causes gas gangrene when it gets into wounds.
A research team led by Shibin Zhou, M.D., Ph.D., and Bert Vogelstein, M.D., genetically modified the bacteria creating a strain without a lethal toxin.
Delivered via a single intravenous injection, the bacteria work within the oxygen-starved core of tumors. Researchers use the bacteriolytic therapy in combination with chemotherapy with the goal of selectively attacking tumors from the inside with bacteria and from the outside with chemotherapy. Anticancer drugs cannot reach places where blood does not circulate, so this is where Clostridium novyi-NT goes to work. The investi- gators use mitomycin C, a well-known chemotherapy agent, to attack dividing cells by entangling their DNA strands with chemical cross-links. With mitomycin eroding the surface of tumors and the bacteria chewing away inside, a final blow comes from another drug, dolastatin-10, which closes down the tumor's blood vessels.
In animal studies, this combined germ/chemo approach temporarily wiped out both large and small tumors in almost 100 percent of mice and permanently cured more than two-thirds of them. The reined-in bacteria selectively targeted colon cancer cells and showed no interest in normal cells. Clinical trials in a limited number of patients are ongoing. However, in human studies, the use of live bacteria calls for extreme caution, and so our clinicians and investigators are moving ahead slowly. Patients who develop fevers following treatment must be given antibiotics, which, of course, eliminate the bacteria and prevent it from doing its job. As the team demonstrates control over the bacteria, they look forward to less stringent FDA controls, including scaled-back use of antibiotics, to allow the bacteria to finish its job against the cancer.
Rampant Oncogene Is Treatment Target for Colon Cancer
American Association for Cancer Research
The oncogene PIK3CA gene is not only mutated in 32 percent of colon cancers, but now Ludwig Center researchers say it plays an active role in the progression and spread of this and other cancers.
PIK3CA is part of a family of genes encoding lipid kinases, enzymes that modify fatty molecules and direct cells to grow, change shape, and move. PIK3CA alterations selectively alter other genes in its pathway hampering cell death and aiding tumor spread.
"It is now clear that PIK3CA is one of the two most highly mutated oncogenes discovered in human tumors," says Bert Vogelstein, M.D. "Cancer cells appear to be addicted to this pathway. If we can inhibit the gene, we can potentially kill the cancer." Treating cells with a PIK3CA inhibitor blocked the gene's ability to signal other genes and shut down the growth of cells containing mutant PIK3CA, opening the door to potential new therapies.
The Blueprints for Cancer
Investigators Reveal Cancer Genome for Colon and Breast Cancers
It's hard to fix something if you don't know what's broken. This has been the problem tormenting cancer researchers and clinicians for decades. What exactly is it that goes wrong in the normal cell to transform it into a cancer cell? Now, the Johns Hopkins Ludwig Center group that helped define cancer as a genetic disease has uncovered and mapped the bulk of the culprit genes for colon and breast cancer. It is the first comprehensive examination of gene mutations in cancers.
This is a different approach from past discoveries that revealed mutations in individual genes, mostly in colon cancer and linked primarily to inherited forms of cancers and cancer progression. Though important in terms of screening and early detection in high-risk populations, they were only a part of the picture. What the investigators have now revealed is the actual blueprint-a schematic of what is wrong in the colon and breast cancers' control centers. "Cancer is the enemy, and now we know its game plan," says Kenneth Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and a lead investigator of the study.
The research reveals about 100 broken genes overall for each type of cancer. It includes the genes they previously discovered, but the majority are new genes that, until now, were not known to play a role in tumors. As intriguing as the number of new mutations found is the realization that the mutations vary from tumor to tumor, with a combination of at least 20 alterations driving each individual colon or breast cancer. The wide range of genetic profiles of tumors came as a surprise to the investigators who said they were expecting to see fewer changes and more similarities. However, it helps explain why cancers of the same organ often respond so differently to therapies, they say. "Each cancer has a different blueprint," says Bert Vogelstein, M.D., co-director of the Ludwig Center. "No two patients are identical."
Tumors that appear to be the same under the microscope are often genetically very different, say the researchers. "It's like a city. From far away, all of the buildings look the same, but as you get closer and closer, you see how many differences there really are," says Dr. Vogelstein. He expects investigators from the Kimmel Cancer Center and other Centers around the country to begin taking a closer look at the newly identified genes. He also expects that the approaches pioneered in this study will be used to create blueprints for other types of cancer.
The method was built upon computerized and other technologies developed by the researchers over the last two decades. The team started with 11 samples from each tumor type and examined the well-characterized human genes-13,023 to be exact. This represents about two-thirds of all the genes that are thought to be present in the human genome. The researchers sifted through more than 500 million letters (ATCG) that make up the coding sequences of these genes to identify those rare transposed letters that translate into alterations in the genetic code. After validating their findings in two dozen more breast and colon tumors, the team whittled down the field to 189 genes.
Despite the genetic differences among the tumors, the researchers suspect that further research will reveal similarities among the pathways through which these genes operate. This new information should enable novel strategies for detection or treatment.
The researchers say the promising effects of new gene-specific drugs like Gleevec and Herceptin prove that targeting genetic alterations is a viable treatment option. Dr. Vogelstein says researchers can now begin to search for how these mutations occur, looking for both environmental and cellular processes that drive these changes.
Mountains and Molehills: Mapping the Genetic Landscape of Cancer
Colon Cancer Mountain Range: In the landscape of a typical colorectal cancer, large peaks indicate the gene mountains, or genes frequently mutated in all colon cancers, while small peaks are gene hills or less frequent mutations that vary from person to person. The dots correspond to genes that were mutated in the particular cancer, called Mx38, illustrated here.
In cancer, it may be wise to make mountains out of molehills. In their latest research, the Ludwig Center team that just over one year ago began mapping the colon and breast cancer genome, has completed the job and found the gene landscape to contain a variety of different, less frequently occurring mutations that vary from patient to patient. This explains why seemingly similar cancers often respond very differently to standard therapies. On the molecular level, they are genetically different. While there are a few mountains, like APC and p53 gene mutations, that still remain the most commonly mutated genes in colon cancer, there are far more "hills"-less frequently occurring mutations but just as culpable as the mountains in the incredibly complex process that leads to colon and breast cancer development and progression.
Everest-like genes such as APC and p53 have stood out among other mutations because they were so commonly mutated. These genes, and others like them, have been the focus of cancer research for years because they were the only genes known to contribute to cancer, says Bert Vogelstein, M.D. "Now that we can see the whole picture, it is clear that lower peaks or 'gene hills,' though mutated less frequently, are the predominant feature."
In their research of the cancer genome, the investigators found that an average of 77 genes are mutated in an individual colon cancer and 81 in breast cancer. About 15 mutations likely contribute to a cancer's key characteristics, and most of the mutated genes may be different for each patient.
Blueprints for Pancreas and Brain Cancers Revealed
The complete genetic blueprint for lethal pancreatic cancer and brain cancer was deciphered by the same Ludwig Center team who completed maps of the breast cancer and colorectal cancer genomes in 2007.
Believed to be the most comprehensive result to date for any tumor type, the new map evaluated mutations in virtually all known human protein-encoding genes, composed of more than 20,000 genes, in 24 pancreatic cancers and 22 brain cancers. A core set of regulatory gene processes and pathways, about a dozen for each tumor type, were found to be altered in the majority of tumors studied by the researchers.
The Ludwig Brain Tumor Initiative represents the first formal collaboration of Ludwig Centers since the six Ludwig Centers were established by the Ludwig Fund in 2006.
In pancreatic cancer, these 12 pathways, including those linked to DNA damage control, cell maturation, and tumor invasion, were altered in 67 percent to 100 percent of tumors. "This perspective changes the way we think about solid tumors and their management because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies, " says Bert Vogelstein, M.D., co-director of the Ludwig Center.
In addition to the pathway discoveries, a number of individual mutated genes were identified, including 83 cancer genes in pancreatic cancer and 42 in the most lethal form of brain cancer, glioblastoma multiforme (GBM). In addition, 70 genes that were dramatically overexpressed in either cancer encode proteins that are on the surface of cells or secreted, making them potential diagnostic and screening targets.
The researchers found one gene, isocitrate dehydrogenase 1 (IDH1), was frequently mutated in a subset of GBM brain cancers. The mutations were significantly more common in young GBM patients and were associated with improved survival. IDH1 mutations were also found in nearly all cases of secondary GBMs (cancers that progress from preexisting lower grade tumors), raising the possibility that this mutation may be a useful marker for identifying which low-grade brain tumors are most likely to develop into the lethal GBMs. Patients with IDH1 mutations may ultimately benefit from different treatments, potentially by targeting IDH1.
"The landscape of human cancers is clearly more complex than has been previously appreciated. Fighting it is going to be more of a guerilla war than a conventional one because there are dozens of mutated genes in each tumor, " says Kenneth W. Kinzler, Ph.D., Ludwig Center co-director. "Individually, these mutations don't seem formidable. But working together, they form an enemy that will require us to develop novel strategies to combat them, and the best long-term strategy may be early detection of tumors, when the number of guerilla warriors is still small and more easily handled. "
Test Finds, Measures, and Monitors Cancer
Virtually all cancers arise through mutation of genes that control cell growth. As the cancers grow, they shed fragments of DNA, biological evidence of these mutant genes, into the blood stream. Ludwig Center researchers developed a novel test to measure this biological DNA evidence in the bloodstream. The blood test is based on the unique genetic signature of every cancer. It detects the presence of cancer and also tracks its progress. "Just as DNA has been used to detect, measure, and manage chronic viral infections, like HIV, measuring circulating tumor DNA could similarly enhance the management of cancer," says Ludwig Center clinician-scientist Luis Diaz, M.D.
Every cancer has a set of mutated genes that are present in cancer cells but not in normal cells. Using tumor tissue from 18 patients with colorectal cancer, Dr. Diaz and team identified the mutations in each patient's cancer and used a technology developed in the Ludwig Center laboratory to search for corresponding mutant tumor DNA in plasma from these patients. Their test not only detected the mutant genes in all 18 cases but also measured the level of circulating tumor DNA. Higher levels of circulating tumor DNA translated to more disease. The new approach monitors tumor burden in real time based on the mutations that actually cause the disease. Moreover, it has the sensitivity to measure minimal residual tumor cells undetectable in X-rays and CT scans.
Patients in the study underwent potentially curative surgery for colorectal cancer and were followed for up to two years. After surgery, the test detected circulating tumor DNA in all patients whose disease later recurred, often as soon as one day after surgery and months before it was visible in X-rays and CT scans. Patients whose mutant DNA levels fell to undetectable levels after surgery remained disease-free.
"We know that not all patients need intensive adjuvant chemotherapy, and this test could help us decide who would benefit," said Dr. Diaz. He says the test could be applied to any cancer that is linked to a known gene mutation.
Colon Cancer's Sugar Fix
Starving colon cancer cells of sugar may make them die. It is not the kind of sugar bought in the grocery store, but the nutrient glucose, a critical component, or fuel, of normal cellular function. (The scientists caution that limiting the consumption of dietary sugar will not impact cancer development and growth.) Ludwig Center researchers found that colon cancer cells hijack a gene called GLUT1, to improve their ability to soak up glucose, allowing them to grow and thrive in sugar-depleted environments that would otherwise be inhospitable to cell growth.
"We think increased GLUT1 is a survival adaptation that makes cancer cells very efficient at gathering what little circulating sugar exists in the nutrient-scarce inner environment of tumor cells," says Nicholas Papadopoulos, Ph.D.
In laboratory studies, cancer cells with the common cancer-associated KRAS and BRAF gene mutations were most commonly found to survive in sugar-depleted environments while cells without these mutations died. As a result, mutant cells become the predominant cells. "These gene mutations clearly give colon cancer cells the ability to grow," says Dr. Papadopoulos.
In mice, the researchers used an experimental drug that blocks glucose metabolism to stop cancer growth without any toxic side effects. They are working to further develop this therapy.
Personalized Genome-Based Therapy Heals Patient with Advanced Pancreas Cancer
Culling together the results of several genetic research projects, Ludwig Center researchers and clinicians were able to develop a personalized treatment for one pancreas cancer patient.
This dramatic outcome stemmed from new research that used personalized genome sequencing on an individual with a hereditary form of pancreatic cancer to locate the gene mutation responsible fore initiating the disease. The discovery marked the first use of a genome scanning system to uncover suspect mutations in normal inherited genes.
It revealed the culprit as a gene called PALB2, which stands for "partner and co-localizer of BRCA2." PALB2 seems to disrupt BRCA2 interactions that are critical to DNA repair. Alterations to the BRCA2 gene were linked in research done years earlier to 10 percent or more of pancreas cancers and found to make these cancers more responsive to treatment with the FDA-approved drugs mitomycin C and cisplatin.
Investigators observed that a personalized xenograft (a mouse implanted with a human tumor sample) was having a remarkable response to the drugs mitomycin C and cisplatin. The tumor sample used in the xenograft came from a patient who had advanced pancreas cancer that was virtually unstoppable with standard therapies. Genetic analysis of the patient's tumor revealed an inactive PALB2 gene. Based on these findings, the patient was treated with several cycles of the two drugs and went from having just three months to live to symptom-free.
Although there is much left to do, this work illustrates the potential of personalized cancer medicine to improve cancer therapy.
Two Mutant Genes Linked to Brain Cancer
The New England Journal of Medicine
In a collaborative study, scientists at the Ludwig Center at Johns Hopkins and the Duke University Medical School linked mutations in two genes, IDH1 and IDH2, to nearly three-quarters of gliomas, one of the most common types of brain cancer. The researchers founds that certain patients that carry these mutations survive at least twice as long as those who do not have the mutations. Additional research on the genes could lead to more precise diagnosis and treatment of the deadly cancer.
Major Discovery in Ovarian Cancer
Investigators linked mutations in two genes to ovarian clear cell carcinoma, one of the most aggressive and treatment-resistant forms of ovarian cancer. Ludwig Center Researchers, including Nickolas Papadopoulos, Ph.D., and Siân Jones, Ph.D., reported that they found an average of 20 mutated genes per each ovarian clear cell cancer studied. Two genes not previously linked to ovarian cancer--ARID1A, which normally suppresses tumors, and PPP2R1A, an oncogene that, when altered, helps turn normal cells into tumor cells--were more commonly mutated among the samples. ARID1A mutations were identified in more than half of the tumors studied. In addition, the mutations in ARID1A provide an important new link between genetic and epigenetic (alterations to the environment of genes) mechanisms in human cancer. An epigenetic component, known as chromatin, compresses DNA to make it fit inside cells and provides a means for controlling how and when the DNA is read. In ARID1A, the chromatin remodeling complex is altered, allowing genes to be incorrectly switched on or off. The researchers believe alterations to these genes and their cellular environment may play a significant role in ovarian clear cell cancer and provide opportunities for developing new biomarkers and targeted therapies.
First Pediatric Cancer Genome Mapped?
Ludwig Center scientists were the first to decipher the genetic code of a pediatric cancer. Using sophisticated new gene sequencing technologies, the researchers mapped the genetic sequence of medulloblastoma, the most common type of pediatric brain cancer. As suspected, this analysis showed that genetic changes in pediatric cancers are remarkably different from adult tumors. The work revealed fewer genetic alterations than are typically found in adult tumors, and the researchers believe this may make it easier to use the findings to develop new therapies. The research also uncovered epigenetic alterations, biochemical variations that occur to the environment of genes and have the ability to turn genes on and off without mutating them, as a more significant culprit in pediatric cancer than commonly thought. Using drugs to block the abnormal biochemical activity can return normal gene function and stop the development of cancer cells. "Information like this, gained from gene sequencing technology, could potentially help our team change the course of some relentless childhood cancers. As a result, we hope to continue this work in other pediatric cancers," said Ludwig Center co-director Bert Vogelstein, M.D.
Cancer Gene Discoveries in Head and Neck Cancer
Ludwig Center researchers sequenced the cancer genome of head and neck cancer. Little was known about the cause of head and neck cancers, and this research revealed mutations in two genes, NOTCH1 and FBXW7, never before associated with the cancer. In a surprising twist, the researchers found that NOTCH1, identified as a cancer cell growth-promoting oncogene in blood and bone marrow cancers, is a malfunctioning tumor suppressor gene in head and neck cancers. This key finding demonstrated that genes are not preset to be either oncogene or suppressor gene, but, instead, their roles can vary among tumor types, depending upon mutations. "The mutational analysis of NOTCH clearly indicated the power of genetic changes determining the function of these genes," said Nickolas Papadopoulos, Ph.D.
The team's mutational analysis also confirmed earlier findings from Kimmel Cancer Center investigators that linked the human papillomavirus (HPV) to a biologically unique subset of head and neck cancers associated with improved prognosis. The Ludwig team revealed that the reason for the improved outcomes was that HPV-related head and neck cancers had four times fewer mutations than the non-HPV cancers and no mutations of the common cancer-related p53 gene. On the other hand, cigarette smoking, was associated with markedly increased numbers of mutations. Head and neck tumors from smokers had twice as many mutations as tumors from nonsmokers.
The researchers next step is to decipher the function of the mutated genes they discovered and their potential as targets for treatment.
Brain Cancer Genome Sequenced
Researchers have long known that up 70 percent of a type of brain cancer known as oligodendroglioma are characterized by a fusion of two chromosomes that result in the loss of many genes. Ludwig team researchers revealed what had eluded scientists for years-the specific mutated genes that allowed the cancer to develop. In their analysis, they found that two-thirds of the tumor samples they studied contained mutations in two genes, CIC and FUBP1. "Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for cancer development and the biology of the tumor," said Ludwig Center co-director Kenneth Kinzler, Ph.D. The researchers also found mutations in the PIK3CA gene, which has been well studied in cancer and the focus of several clinical trials of targeted therapies. Oligodendroglioma brain cancer patients are typically younger, often in their thirties or forties, and those with PIK3CA mutation in their tumors may benefit from these clinical trials.
Pancreas Cancer Timeline Reveals Ample Time for Intervention
For the first time, investigators quantified the development of pancreas cancer and disproved popular scientific thought that the disease progressed to a deadly stage very early in its development. To the contrary, the research team calculated that it takes an average of 11 years before a cancer cell arises from a precancerous pancreas lesion, and another seven years may pass as that cancer grows to form a tumor and gives at least one cell the potential to break away and spread the cancer outside of pancreas. The spread, or metastasis, represents a lethal turning point in the progression of the cancer.
To make their calculations, the team studied tissue collected at autopsy from seven patients who died of metastatic pancreas cancer. Ludwig Center investigator Bert Vogelstein, M.D., and team, identified and classified the genetic alterations in each patient's pancreas cancer and the sites to which the cancer spread. In all patients studied, the investigators found similar mutations in both the original tumor and the body sites to which it spread, genetically linking the metastatic lesions to the original pancreas tumor. They classified mutations that occurred prior to metastasis and those that happened after the cancer spread. They applied this information to mathematical models to create a timeline of progression.
Although their findings reveal a large window of time before a pancreas cancer turns deadly, most patients are diagnosed after that window has closed. The researchers plan to develop a screening method, like those used to screen for breast and colon cancers, to detect very early pancreas cancers before they cause symptoms.
Genetic Cause of a Pancreas Cancer Uncovered
Ludwig Center investigators pieced together the genetic puzzle and deciphered the genetic causes of a type of pancreas cancer known as neuroendocrine or islet cell tumors. The researchers uncovered a unique genetic code, specific to each patient, which predicted how aggressive the disease was and how well it would respond to treatments. "This tells us that it may be more useful to classify cancers by gene type rather than organ or cell type," says Nickolas Papadopoulos, Ph.D.
Pancreas neuroendocrine tumors make up about five percent of all pancreas cancers. Some of these tumors produce hormones that leave telltale biological signs of their existence, including changes in blood sugar levels, weight gain, and rashes. Hormone-free tumors do not produce these signs, making them difficult to detect and to distinguish from other types of pancreas cancers.
The research team studied 63 nonhormonal pancreas neuroendocrine tumors and revealed several common gene mutations, including two in genes that had not previously been linked to cancer. Mutations in three genes, MEN-1, DAXX, and ATRX, seemed to translate to a survival advantage. Patients whose tumors had these mutations, survived at least 10 years after diagnosis, while more than 60 percent of people whose tumors did not have the mutations, died within five years of diagnosis. The team also found mutations in a family of genes called mTOR in about 14 percent of patients. These patients would be candidates for treatment with agents that inhibit these genes.
Gene Test IDs Bad Pancreas Cysts
Science Translational Medicine
Ludwig Center scientists developed a gene-based test to distinguish precancerous pancreas cysts from harmless cysts. The r