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The Top Ten of 10

The Top Ten of 10

As we look ahead to a 2011 filled with new cancer discoveries, let’s take a moment to revisit the Johns Hopkins Kimmel Cancer Center’s top advances of 2010:

#1:  Personalized Cancer Medicine Becomes a Reality

World renowned investigator Bert Vogelstein, M.D., and team pioneered the science that has led to personalized therapies for cancer patients. Within the next few years all cancer patients at the Kimmel Cancer Center will have their tumors analyzed to reveal a unique genetic “fingerprint” that represents the combination of genetic and epigenetic alterations specific to their cancer.  Targeting these alterations, say the scientists, will improve treatments outcomes, thwart cancers before they develop, and speed new cancer drug discoveries.

#2:  A Universal Test for Cancer

In the Kimmel Cancer Center Ludwig Center for Cancer Genetics Victor Velculescu, M.D., Ph.D., and team applied the current generation of gene sequencing technology to develop a test that not only detects cancer, but can also tell if a therapy is working by measuring, in real time, the amount of cancer DNA in the bloodstream.  Universal, precise, and specific, the test is able to pluck one abnormal cell from within a sea of 400,000 normal ones. It sees cancers invisible to CT scans, X-rays, and other existing methods of cancer detection.

# 3:  Code Cracked for Common Pediatric Brain Cancer

Bert Vogelstein, M.D., Kenneth Kinzler, Ph.D., Victor Velculescu, Ph.D., and team deciphered the genetic code for medulloblastoma, the most common pediatric brain cancer and a leading killer of children with cancer. One of their most notable findings was that children with medulloblastoma had five to ten-fold fewer cancer-linked alterations in their genomes compared with their adult counterparts.  The researchers are hopeful that with fewer alterations, it may be easier to use the information to develop new therapies.

#4:  Epigenetic Targeted Therapies

Epigenetics, or the way genes are packaged in cells, influence how genes behave and can turn them on and off. Building upon the pioneering research of Stephen Baylin, M.D., Virginia and D.K. Ludwig Professor for Cancer Research, and earlier epigenetic-targeted clinical trials in leukemia, new patient studies directed by Charles Rudin, M.D., Ph.D., combined the DNA demethylating agent 5-azacytidine with histone-specific HDAC inhibitors to target epigenetic alterations that help give cancer cells their edge. Rather than attacking and destroying replicating cells as standard chemotherapy drugs do, this therapy reprograms cells to behave more like normal cells. Clinical responses in lung cancer patients have been impressive, with responses in patients with advanced disease whose cancers did not respond to other treatment approaches. As a result, additional studies have begun in breast and colon cancers.

#5:  A Major Discovery in Ovarian Cancer

Investigators have linked mutations in two genes to ovarian clear cell carcinoma, one of the most aggressive and treatment-resistant forms of ovarian cancer.  Ludwig Center investigators Victor Velculescu, M.D., Ph.D., Nickolas Papadopoulos, Ph.D., and Siân Jones, Ph.D., reported an average of 20 mutated genes per each ovarian clear cell cancer studied, including two genes not previously linked to ovarian cancer. Their work also revealed an important new link between genetics and epigenetics. In one of the genes discovered, chromatin, an epigenetic process that compresses DNA to fit inside cells, was altered, allowing genes to be incorrectly switched on and off.

#6:  Clues From Live Prostate Tissue

Kimmel Cancer Center researchers and an international team of collaborators led by Marriki Laiho, Ph.D., Willard and Lillian Hackerman Professor of Radiation Oncology, developed a technique to keep normal and cancerous tissue surgically removed from the prostate alive and functioning for up to a week. Their discovery will help investigators better understand the biology of prostate cancer and speed the development of personalized therapies for prostate cancer, by allowing them to test anticancer drugs on live tissue. They believe it also will reveal new clues about why certain therapies work and others fail.

#7:  Advances Against a Lethal Childhood Cancer

Donald Small, M.D., Ph.D., Kyle Haydock Professor of Oncology, was the first to identify and clone the human FLT3 gene and discover drugs that could molecularly target the mutations which cause a poor prognosis in acute myeloid leukemia (AML). Now, pediatric cancer expert Patrick Brown, M.D., has moved these laboratory findings to the clinic to help speed progress in infant acute lymphocytic leukemia.  With survival rates of just 20 to 40 percent, it is one of the deadliest forms of childhood cancer. FLT3 is believed to be what allows the cancer to evade treatment, and by using drugs to block the gene, Brown and team are hopeful that the cancer will respond to chemotherapy.  A national trial of 300 patients was started.

#8:   More Time to Intervene in Pancreatic Cancer

 Research by Christine Iacobuzio-Donahue, M.D., Ph.D., indicated that pancreatic cancer spreads much more slowly than scientists had thought, providing opportunities to develop new, early diagnostic tools and to intervene with surgery. The findings contradicted earlier contentions that pancreatic cancers metastasize very early in their development and instead indicated that many cases have a long lag time before they are detected through conventional tests. Using mathematical models to study the timing of pancreatic cancer progression, the scientists conservatively estimated an average of 11.7 years before the first cancer cell develops within a high-grade pancreatic lesion. Their goal is to develop a pancreatic cancer screening method similar to the protocol used for breast and colon cancer.

#9:   The Frankenstein Approach Improves Radiation Therapy

Radiation oncology physicist Todd McNutt, Ph.D., developed a system, called “Oncospace,” to more quickly improve the clinical care of cancer patients.  The complex computerized system uses anatomy, radiation dose distributions, toxicity, and outcome data of prior patients to improve the therapy for those about to be treated.   Oncospace enables the analysis of the best outcomes, and conversely, those with less than favorable outcomes, to create the optimal treatment plan. McNutt’s work is considered one of the first demonstrations of how large data warehouses of information collected from previously treated patients can be used to make individualized treatment decisions for new patients.


Vaccine Clears Out Leukemia Cells
A newly-developed leukemia vaccine appeared to get rid of cancer cells left behind after treatment with the drug Gleevec. While the findings are preliminary, the investigators are cautiously optimistic that the vaccine could improve treatment outcomes and reduce toxic side effects for patients with chronic myeloid leukemia (CML). Researcher Hyam Levitsky, M.D., says most patients with CML will need to remain on Gleevec therapy for the rest of their lives to remain cancer free, but about 10 to 15 percent of patients cannot tolerate the drug long term. He and collaborator B. Douglas Smith, M.D., believe the vaccine could get patients off lifelong Gleevec therapy.

A few more discoveries from 2010:

-          Targeting Brain Cancer Stem Cells:  In a mouse model, Charles Eberhart, M.D., Ph.D.,  and team used drugs to target and block a chemical pathway, called Notch, known to be important for cancer stem cell growth. Cancer stem cells are a small population of cells thought to drive the growth and spread of certain cancers. The team used cells from glioblastomas, the most common brain cancer, to form neurospheres, clumps of cells that can only develop from stem cells. After treating the spheres with a drug that blocks the Notch pathway, more than 70 percent went away.

-          Half-Identical Bone Marrow Transplants for Pediatric Cancer Patients:  Pediatric oncologist Heather Symons, M.D., worked with bone marrow transplant researchers Ephraim Fuchs, M.D., and Leo Luznik, M.D., to make haplioidentical or half-identical transplants available to pediatric patients who need a bone marrow transplant but do not have a perfectly matching donor. Results in clinical trials have been so favorable, with safety and toxicity comparable to matched transplants, that Symons and team are beginning to use it earlier in the treatment of leukemias and lymphomas and exploring its use in pediatric solid tumors, such as sarcomas and neuroblastoma.

-          A New “TWIST” in Breast Cancer:  Working with mice, scientists showed that a protein made by a gene called TWIST may be the proverbial red flag that can accurately distinguish cells that drive aggressive, metastatic breast cancer from other breast cancer cells. Research led by Venu Raman, Ph.D., showed that TWIST is a driving force among a lot of other players in causing some forms of breast cancer. This finding has fundamental implications for early detection, treatment and prevention.

-          A Personalized Genetic Profile for Brain Cancer:  Cancer biology and epigenetics expert Stephen Baylin, M.D., Virginia and D. K. Ludwig Professor for Cancer Research and a national network of cancer researchers used personalized genetic profiling to predict an improved prognosis in brain cancer patients. Baylin and team identified a set of molecular changes in the brain cancer glioblastoma that correlates with better treatment outcomes.  The ability to differentiate brain tumors based on their altered genetic code lays the groundwork for more effective treatment strategies, such as targeted drug treatments

-          How Organs Grow and Stop Growing May Provide New Clues About Cancer:  A protein discovered in fruit fly eyes brought a Johns Hopkins team, led by Duojia Pan, Ph.D., closer to understanding how the human heart and other organs automatically determine when they are the correct size, a piece of information that may hold clues to controlling cancer. The protein, and the pathway it works through, appears to be a global regulator of organ size control. As cancer is a disease of uncontrolled growth, Pan and team believe it may also be involved in this process as well.  This discovery builds upon Pan’s 2007 research in which he showed that by manipulating the pathway in a mouse liver, the organ grew to five times its normal size and became cancerous.

-          Biodegradable Particles Can Transport Cancer Drugs:  Researchers have created biodegradable, ultra tiny, nanosized particles that can easily slip through the body’s sticky and viscous mucus secretions to deliver a sustained-release medication cargo. The interdisciplinary team of researchers led by Justin Hanes, Ph.D., developed the nanoparticles, which degrade over time into harmless components. The team believes they could one day carry life-saving drugs to patients suffering from dozens of health conditions, including cancer. 

-          Predicting Pancreatic Cancer:  Johns Hopkins researchers designed a computer program that can predict which changes in the DNA code may cause pancreatic cells to become cancerous and deadly. The investigators say the findings could lead to more focused studies on better ways to treat the disease. The program uses 70 different predictive features for each DNA change to identify any of the distinguishing characteristics of driver mutations — those DNA changes that contribute to cancer — compared with other genetic changes.  The results can help cancer biologists set up experiments to see how important these DNA changes really are in pancreatic cancer and whether or not they are good drug targets for potential treatments.

-          Mini Transplant Reverses Sickle Cell Disease: Scientists at the Kimmel Cancer Center and National Institutes of Health showed that "mini" stem cell transplantation may safely reverse severe sickle cell disease in adults. Using this procedure, 9 of 10 patients treated returned to normal red blood cells, rather than the painful crescent-shaped red blood cells typical of sickle cell disease, and organ damage caused by the disease was reversed. Jonathan Powell, M.D., Ph.D., explained that the intravenous transplant approach for sickle cell disease, transplants blood stem cells that carry normal copies of the defective hemoglobin gene that causes sickle cell disease.

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