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Promise and Progress - Headline Makers

Engineering Cures: Physicians and Engineers Working Together to Fight Cancer
Issue No. 2012

Headline Makers

By: Valerie Matthews-Mehl
Date: December 20, 2011

The Latest Research from the Johns Hokpins Kimmel Cancer Center

Vogelstein, Papadopolous, Kinzler
1 2 3 4
In discoveries of Kenneth Kinzler (left), Bert Vogelstein (center), and Nickolas Papadopoulous (right).

Genetic Discoveries in Head and Neck and Brain Cancers


Genetic sequencing offers powerful clues to understanding the function of various genes and their roles in cancer, and Kimmel Cancer Center investigators have produced some of the most seminal findings in cancer genetics.

Cancers are not “one size fits all” as the discoveries of Nickolas Papadopoulos, Ph.D., Kenneth Kinzler, Ph.D., and Bert Vogelstein, M.D., and their research team have revealed.   As a result, therapies cannot be one size fits all either. Their work in mapping the diverse genetic landscape of dozens of cancers is leading to prevention, early detection, and treatment strategies personalized to target the unique cellular characteristics of each individual patient’s cancer.  In the coming years, this approach is expected to revolutionize cancer therapy, improving outcomes by giving clinicians the information they need to deliver the right therapies to the right patients and to monitor, in real time, whether or not new target-specific drugs are blocking the cellular malfunctions now known to be caused by genetic alterations.

These researchers have recently sequenced the cancer genomes of two more malignancies—head and neck cancer and a brain cancer known as oligodendroglioma.

Head and Neck Cancer Genome

Little was known about the genetic causes of head and neck cancers, and this new research revealed mutations in two genes, NOTCH 1 and FBXW7, never before associated with the cancer.  In a surprising twist, the researchers found that NOTCH 1, 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.   “The mutational analysis of NOTCH clearly indicated the power of genetic changes determining the function of these genes,” says Papadopoulos.   This key finding demonstrates that genes are not preset to be either oncogene or suppressor gene, as previously thought, but instead their roles can vary among tumor types depending upon mutations. The same gene can act as a cancer growth promoter in some cases and as a growth suppressor in others, say the experts. 

Their mutational analysis also confirmed previous findings by Kimmel Cancer investigators who in 2000 linked the Human papillomavirus (HPV) to head and neck cancers and classified it as a unique subset of head and neck cancer with its own biology and associated with an improved prognosis.  The researchers uncovered the reason for the improved outcomes, finding four times fewer mutations in HPV-related cancers than non-HPV-related cancers and no mutations to the common cancer-related p53 gene. 
Another environmental risk factor, cigarette smoking, was associated with markedly increased numbers of mutations.  Tumors from head and neck cancer patients with a history of smoking had twice as many mutations as tumors from non-smokers.
Researchers will now work to decipher the function of the genes discovered and potential ways to target them therapeutically.

Oligodendroglioma Brain Cancer

Researchers have long known that up to 70 percent of oligodendrogliomas are characterized by a fusion of two chromosomes that results in the loss of many genes.  What had eluded scientists, until now, were the specific mutated genes that allowed the cancer to develop.   After sequencing this cancer, one that typically strikes younger people in their thirties and forties, the Kimmel Cancer Center team solved the mystery by uncovering mutations to two genes, CIC and FUBP 1.  Two-thirds of the tumor samples studied contained mutations in these genes.  “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,” says Kinzler.

The research team also found mutations in the PIK3CA gene, which has been well studied in cancer and is already the focus of several clinical trials of targeted therapies. As a result of these findings, scientists suspect that oligodendroglioma patients with PIK3CA mutations could potentially benefit from these experimental therapies and may be included in these clinical trials.

“Knowing the genetic roadmap of a cancer is the key to attacking it,” says Kinzler.  Having identified these key gene mutations, investigators can now focus on determining at what point in the cancer process they occur, whether they guide prognosis, and if they might be good targets for treatment.

The oligodendroglioma research was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, The James S. McDonnell Foundation, state funding from Sao Paulo (FAPESP), the National Cancer Institute, and the National Institutes of Health.

Editor’s Note:  Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, Qiagen, Invitrogen, and Personal Genome Diagnostics, Papodopoulos, Vogelstein, and Kinzler are entitled to a share of royalties received by the University on sales of products related to genes and technologies described in this article.   These researchers are co-founders of Inostics and Personal Genome Diagnostics, are members of their Scientific Advisory Board, and own Inostics and Personal Genome Diagnostics stock, which is subject to restrictions under Johns Hopkins University policy.


In Brain Cancers, Two or More Targets is Better Than One

Clinical Cancer Research, December 15, 2010

Brain cancers represent one of the most difficult types of cancer to manage.  Tumors that respond initially to treatment eventually become resistant.  Now, research by Charles Eberhart, M.D., Ph.D., reveals new clues about how cancer gene pathways conspire to circumvent therapy.

Similar to a computer network that increases its computing capabilities by linking several computers together, groups of genes work together through pathways to enhance cell function. Cancer cells manipulate these pathways to drive tumor growth and spread.
Research by Eberhart and team reveals that inhibiting a single cancer cell development pathway with drug therapy can disrupt, and may actually increase, activity in other pathways and raise the risk of tumors becoming resistant to therapy. The team found that genes involved in one pathway interacted directly with genes in another pathway.  “Our research indicates that it may be necessary to simultaneously target multiple development signaling pathways to prevent cancer from becoming resistant to therapy,” says Eberhart.  “A single agent is not likely to work for prolonged periods.”

Eberhart and team studied an agent that targets and blocks a known cancer gene pathway called Notch in glioblastoma brain cancer cell lines.  They found that when they inhibited Notch, activity increased in two other common cancer development pathways known as Hedgehog and Wnt became.  Eberhart speculates that tumors compensate for therapy directed at one pathway by turning on a different one.  Combining the Notch inhibitor with a second drug to also block Hedgehog dramatically decreased cell growth, by as much as 90 percent, in the cell line studies.  The combined approach had an antitumor effect, increasing natural cell death and hindering cells’ ability to form clusters or colonies. They achieved similar results in laboratory studies using human glioblastoma samples removed during surgery. 

Glioblastoma is one of the most aggressive types of brain cancer. Even when tumors initially respond to treatment, they almost always eventually become resistant.  As a result, most patients die within two years of diagnosis.  This research may help experts better understand the cellular mechanisms that make the cancer so deadly.

Clinical trials evaluating Notch and Hedgehog inhibitors in several types of cancer are now under way at the Kimmel Cancer Center and other cancers centers across the U.S. 

The research was funded by the National Institutes of Health, the Brain Tumor Funders Collaborative, the American Cancer Society, and a National Cancer Institute Brain Tumor SPORE grant.

Pancreas Cancer Timeline Reveals Ample Time for Early Intervention 

Nature, October 28, 2011

Kimmel Cancer Center and Sol Goldman Pancreatic Cancer Research Center investigators have developed a mathematical model that allows clinicians, for the first time, to quantify the development of pancreas cancer and how best to treat it. Their work disproved common scientific thought that this type of cancer progresses 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.  Still, another seven years may pass as that cancer grows to form a tumor, giving at least one cell the potential to break away and spread the cancer outside of the pancreas in a process known as metastasis.  This spread represents a lethal turning point in the progression of the cancer, and once it occurs, the research team reports that these patients die, on average, two and half years later. 

While the research reveals a large window of time before a pancreas cancer turns deadly, currently, “pretty much everybody is diagnosed after that window has closed,” says pancreas cancer expert Christine Iacobuzio-Donahue, M.D., Ph.D.  New, early diagnostic tests to detect these cancers during this 11 to 18 year window would provide an opportunity to intervene and potentially cure these cancers with surgery, investigators say.  Their goal is to create a screening method, similar to those used to screen for breast and colon cancers, to detect very early pancreas cancers, long before they cause symptoms.  Iacobuzio-Donahue suggests that just as colonoscopies are used to look inside the colon for precancerous lesions called polyps, physicians could use a similar technique called endoscopy, which uses an endoscope inserted through the mouth, to examine the pancreas for precancerous lesions.

To make their calculations, the team studied tissue collected at autopsy from seven patients who died of metastatic pancreas cancer. A team led by Bert Vogelstein, M.D., the world’s foremost expert in deciphering the genetic blueprints of cancer, identified and classified the genetic alterations in each patient’s pancreas tumor and the sites to which it spread.  In all of the patients, the investigators found similar mutations in both the originating tumor and the body sites where it spread, genetically linking the metastatic lesions to the original pancreas tumor from which it arose.  They classified mutations that occurred prior to metastasis and those that happened after the cancer began to spread and applied their findings to mathematical models to create a timeline of progression from precancerous lesion to deadly, metastatic disease. 

The research was funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Uehara Memorial Foundation, The AACR-Barletta Foundation, the John Templeton Foundation, the Sol Goldman Pancreatic Cancer Research Center, the Michael Rolfe Pancreatic Cancer Foundation, the George Rubis Endowment for Pancreatic Cancer Research, the Joseph C. Monastra Foundation for Pancreatic Cancer Research, the Alfredo Scatena Memorial Fund, Sigma Beta Sorority, the Skip Viragh Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Joint Program in Mathematical Biology, and J. Epstein.

Cell Cycle Clock Linked to Childhood Cancers

Immunity, February 24, 2011

Researchers linked a molecular cell cycle “clock” which regulates the timing of how DNA is broken up and copied to form new immune genes to chromosomal abnormalities found in children with leukemia and lymphoma, cancers that originate in immune system cells.
This regulatory function manages how DNA segments are split off and then reshuffled inside dividing immune cells in a process known as recombination.  It is an exceedingly complex biological process that occurs repeatedly as cells divide.  In the time it takes to read this sentence, about 10 million recombination events will occur inside the human body. Although most of the time they occur seamlessly, the sheer numbers mean that potential mismatches of genetic bits could lead to genetic rearrangements that may wreak havoc in the immune system and sometimes lead to cancer.  

“We are exposed to the possibility of cancer every time we make a new immune cell,” says Stephen Desiderio, M.D., Ph.D., director of the Institute for Basic Biomedical Sciences, the Institute for Cell Engineering Immunology Program, and a Kimmel Cancer Center investigator.  “One of the many safeguards in place to ensure that this doesn’t happen appears to be a cellular clock that times these potentially dangerous events and regulates them. 

Desiderio and team’s work focused on a molecular knife—a gene called Rag2—that chops up DNA inside of immune system cells. Rag2 is normally available during a precise window of time during the cell cycle and then cleared away to ensure proper DNA assembly.  Desiderio and team showed that if Rag2 is mutated and does not become disabled before DNA replication, it could chop the wrong genetic material at the wrong places and wrong times.  The result is strange bits joined together in odd ways causing abnormal chromosomes, like those seen in children with leukemia and lymphoma, to occur.

“Knowing the underlying mutations that make it more likely for a child to get these chromosomal abnormalities could mean, at the very least, we might be able to identify children at risk and watch them more closely,” says Desiderio.  “Perhaps in the future, the knowledge could lead to new therapies.”

The research was funded by the National Cancer Institute and a gift to the Institute for Cell Engineering.


Cells Manipulated to Repair Diseased Liver

Science Translational Medicine, May 11, 2011

In work that could one day help people with liver cancer, researchers returned a variety of adult human cells, including liver, bone marrow, and skin cells, to an embryonic state.  In animal models, these cells took root in the liver and regenerated damaged tissue. 
This early science may provide a foundation for producing functional liver cells for patients who have liver diseases and need transplants, says Yoon-Young Jang, M.D., Ph.D., the Kimmel Cancer Center scientist who led the study. The liver is one of the few organs that naturally regenerates damaged tissue, but Jang says that certain diseases, including cancer, eventually destroy this natural ability. 

Currently, the only option for many patients is to receive a new liver or liver cell transplant.  Transplantation relies on the availability of donor liver tissue, and mature liver cells, she says, are difficult to isolate or grow in the laboratory.  “Our findings could be applied clinically as an alternative to liver transplant, overcoming the problem of long waiting lists for organs and concerns about immune system rejection of donated tissue,” says Jang.  The cells Jang used in her research can be made from a tiny amount of many kinds of tissue and can be grown indefinitely in the laboratory.

The research uses induced-pluripotent stem cells (iPSCs), cells that are made from adult cells and genetically reprogrammed to revert to an embryonic stem cell-like state, with the ability to transform into different cell types.  Jang and team generated iPSCs from a variety of adult human cells, including liver cells, bone marrow stem cells, and skin cells.  While all of the cells were molecularly similar to each other, they retained a distinctive signature inherited from the cell from which they originated.  Still, Jang and team were able to induce the cells, regardless of their origin, to differentiate into liver cells.

Jang says additional studies are needed before clinical trials can begin. By nature of their  role to form new cells, the iPSCs intrinsically have the potential to cause tumors, and though no tumors developed in the animal studies, Jang and team are conducting ongoing research to ensure they are stable.

The research was funded by the National Institutes of Health and the Maryland Stem Cell Research Fund.

Dual Approach Better for Liver Cancer

The Journal of Clinical Oncology

A combined treatment for liver cancer that uses one oral drug and another delivered directly to tumors via tiny drug-filled microbeads could potentially improve outcomes for patients with these fast-growing and often deadly tumors.

Both the oral drug, sorafenib, and the one used in the microbeads, doxorubicin, have been approved individually for liver cancer treatment.  Investigators are hopeful that combining them through this novel delivery method could make treatment more effective against liver cancer, which is seeing increased incidence in the United States. 

"Both therapies have increased survival rates in advanced liver cancer, and combining them may push those survival rates further," says interventional radiologist and study leader Jean-Francois Geschwind, M.D.  He and his team treated 35 patients, using the oral drug to block the formation of blood vessels that nourish tumors and the microbeads to provide prolonged delivery of an anticancer drug directly to the tumor.

Geschwind used a method known as chemoembolization, using a tiny catheter, the size of a single hair, inserted into the tumor to deliver approximately 200,000 cancer-drug filled microbeads.  For three or more weeks, the drug seeps out of the microbeads to attack cancer cells.  Geschwind, surgeon Timothy Pawlick, M.D., medical oncologist David Cosgrove, M.D., and collaborators believe this dual approach could prolong the antitumor effects of chemoembolization. 

Liver cancer tends to grow rapidly without causing noticeable symptoms.  As a result, Geschwind says it is inoperable by the time most patients are diagnosed, offering a dismal survival outlook of less than a year.  In these patients, he says, chemoembolization can often increase survival by as much as 10 to 15 months. 

Clinical studies of chemoembolization, with and without the oral drug, are ongoing. "We're on the path to improving the standard of care for liver cancer," says Geschwind.

This study was funded by Bayer HealthCare and Onyx Pharmaceuticals, which manufactures sorafenib, and Biocompatibles, makers of the microbeads.  Geschwind and Pawlick are consultants to Bayer HealthCare Pharmaceuticals, and Geschwind is a consultant to Biocompatibles. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

Genetic Causes of a Type of Pancreas Cancer Uncovered

Science Express, January 20, 2011

Kimmel Cancer Center researchers in the Ludwig Center have once again pieced together the genetic puzzle of a cancer, this time deciphering the genetic causes of a type of pancreas cancer known as neuroendocrine or islet cell tumors. 

This is the latest work from the team who has led the world in uncovering the genetic causes of dozens of cancers, including colon, breast, brain, pancreas, and head and neck cancers.

In this cancer, researchers uncovered a unique genetic code specific to each patient that predicts how aggressive the disease is and how well it will respond to specific 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., director of translational genetics.
Pancreatic 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 difficult to distinguish from other types of pancreas cancers. 

To better understand how these stealth tumors develop and grow, the investigators studied 68 non-hormonal pancreatic neuroendocrine tumors.   Their work revealed several common gene mutations, including two genes that had not been previously linked to cancer.   In addition, they found that patients whose tumors contained mutations in three genes, called MEN-1, DAXX, and ATRX, 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 to a family of genes called mTOR in about 14 percent of tumors that they believe would be good targets for personalized therapy.  Patients whose tumors contain alterations to mTOR would be candidates for treatment with agents that inhibit these genes, says Papadopoulos.

The research was funded by the Caring for Carcinoid Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, the Joseph Rabinowitz Fund for Pancreatic Cancer Research, the Virginia and D. K. Ludwig Fund for Cancer Research, the Raymond and Beverly Sackler Research Foundation, the AACR Stand Up to Cancer’s Dream Team Translational Cancer Research Grant, and the National Institutes of Health. 

Editor’s Note:  Papadopoulos and other members of the research team are co-founders and members of the scientific advisory board of Inostics, a company developing technologies for the molecular diagnosis of cancer. 

Antifungal Drug Works Against Prostate Cancer

The American Society of Clinical Oncology Annual Meeting, June 2011

A drug used to treat nail fungus appears to keep prostate cancer in check.  In a study of the oral antifungal, called itraconazole, researchers found that it helped some men with advanced prostate cancer, keeping their cancer stable, delaying progression and the need for chemotherapy.

Forty-six men with prostate cancers which had spread to other organs and who were not responding to hormone therapy (the standard course of treatment for metastatic prostate cancer) were treated with either low or high doses of itraconazole. While low doses had minimal effect, the high dose treatment led to stable or declining levels of PSA (prostate specific antigen), a prostate cancer marker, in 11 of 24 men who received it.

Kimmel Cancer Center researcher Emmanuel Antonarakis, M.D., led the team that came upon the drug and its anticancer potential when reviewing a database of more than 3,000 FDA-approved drugs.  In laboratory tests by Jun Liu, Ph.D., the drug was able to shrink human prostate tumors implanted in mice. It appears to work by blocking tumor vessel blood growth and disrupting a main cancer-initiating gene pathway called Hedgehog.  Antonarakis and team are planning larger studies of the high-dose itraconazole therapy.

This research was funded by the Department of Defense Prostate Cancer Research Program, the Commonwealth Foundation for Cancer Research, the David H. Koch Charitable Foundation, a 2009 American Society of Clinical Oncology Young Investigator Award granted to Antonarakis, and the National Cancer Institute.

Effectiveness of Half-Identical Transplants Confirmed


The results of two clinical trials found that bone marrow or blood stem cell transplants using half-matched bone marrow or umbilical cord blood are comparable to fully matched marrow.  The finding means that nearly all patients in need of a transplant can find donors, says bone marrow transplant researcher Ephraim Fuchs, M.D., who helped develop half-match, or half-identical, (haploidentical) transplants.

Bone marrow transplantation is a potentially curative therapy for cancers of the blood and immune cells, such as leukemia and lymphoma.  Although patients and physicians may seek donors through national registries, frequently no match is found, and the search can take weeks to months, time that delays treatment and allows the cancer progress.  “People are dying waiting for matched donors from a registry,” says Fuchs.

He began is research of halploidentical, or half-identical, transplants as an option for these patients.  Half-identical matches are parents, children, and most siblings, so virtually every patient has a suitable donor. To make it work, however, he and his team had to circumvent a life threatening complication, known as graft versus host disease (GVHD), that occurs when the donor immune system sees its new host as a foreign invader and launches an attack against the patient’s tissue and organs.   Fuchs and team pioneered a post-transplant therapy, using the drug cyclophosphamide, that reprograms the immune system and prevents severe GVHD. 

With the ability to safely perform half-identical transplansts and evidence that they are as clinically effective as full matches, the treatment will likely be expanded to autoimmune diseases, including aplastic anemia, lupus, sickle cell anemia, and lupus.

Funding for the clinical trials was provided by the National Heart, Lung and Blood Institute and the National Cancer Institute.

Gene Test IDs Bad Pancreatic Cysts

Science Translational Medicine

Kimmel Cancer Center scientists have developed a gene-based test to distinguish precancerous pancreatic cysts from harmless cysts.  The investigators estimate that these fluid-filled cysts are identified in more than a million patients each year, and their test may eventually help some of these patients avoid needless surgery.

"Most cysts are benign," says pathologist Ralph Hruban, M.D., director of the Johns Hopkins Sol Goldman Pancreatic Cancer Research Center, "but distinguishing between the harmless and dangerous ones is challenging for doctors and patients alike."
Helping to make the distinction is leading cancer genetics expert Bert Vogelstein, M.D. Vogelstein and team analyzed 132 precancerous cysts for mutations in 169 known ca

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