Genomic Research Fuels Innovation at Johns Hopkins

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It is often said that to be successful, it is important to stick to your knitting. In other words, focus on doing what you do best. At the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, physician researchers do just that.

Since its inception in 1973, the Cancer Center has been dedicated to improving our understanding of human cancers and finding more effective treatments. One of only 40 cancer centers in the country designated by the National Cancer Institute as a Comprehensive Center, researchers at the institution have been characterizing the acquired genome defects in cancers for the better part of the past few decades. And according to William Nelson, MD, director of the Kimmel Cancer Center, they have gotten very good at it.

“I think the real challenge is going to be how we harness this incredible body of information,” Nelson said. “What is [the body of information] going to mean for how you can best be treated with what everyone anticipates will be this evolving portfolio of targeted agents that are somewhat different than drugs we’ve used in the past? I think that’s a challenge that we are very well positioned to meet.”

Eradicating dandelions

Richard Jones, MD, professor of oncology and director of Bone Marrow Transplant, explained that there are cancer drugs available that are very effective at placing patients in remission; the problem is that patients do not stay in remission. The hypothesis behind those relapses is the existence of cancer heterogeneity. In other words, there are cancer cells that are sensitive to treatments and other cancer cells that are highly resistant. The latter—referred to as cancer stem cells—are what lead to relapse. Jones uses a metaphor that works scientifically and in explanations to patients: Cancer is a dandelion.

“Cancer is heterogeneous, with the bulk of the cancer being the part of the dandelion you can see, and the cells responsible for the growth of the cancer are the root, or the cancer stem cells,” Jones explained. “We’ve developed a lot of lawnmowers with our treatments, but we all know what happens if you just mow the dandelion [down]. It’s eventually going to grow back.”

Jones and his colleagues are actively studying how cancer stem cells operate in a variety of malignancies, including leukemia, ovarian cancer, and breast cancer. The Cancer Center has several clinical trials underway, Jones said. He explained that they are looking for treatments they can bring in to “get rid of the root once the weed [has been] mowed.” The challenge, according to Jones, is that just like the roots of the dandelion, these cancer stem cells are biologically quite different from the rest of the tumor being treated. However, they might not be that different from one another.

“What allows us to characterize a plant is the plant itself,” he explained. “It’s the same thing in cancer. Breast cancer cells look like breast cancer; leukemia looks like leukemia. But the cancer stem cells in these disorders look a lot more like each other, just like the roots of a tulip and the roots of another plant. It’s very possible that these treatments that we’re using to target one type of cancer stem cell are going to be active against other cancer stem cells.” If that happens, he said, “We may be looking at truly a cure for cancer, not just a cure for breast cancer or leukemia.”

Next generation sequencing

Researchers at the Kimmel Cancer Center are poised to use a new technology called next generation sequencing to dramatically improve the battle against cancer. According to researcher Bert Vogelstein, MD, Clayton Professor of Oncology and Director of the Ludwig Institute at the Johns Hopkins Kimmel Cancer Center and Investigator, Howard Hughes Medical Institute, next generation sequencing harnesses the most advanced technologies in imaging, optics, molecular biology, chemistry, computer science and engineering to make analyzing genetic alterations in tumors more feasible, faster, and for less money.

Vogelstein said that at the start of 2010, there were 73 tumors throughout the world in which all of the genes had been sequenced. When the process of sequencing first began several years ago, it cost an estimated $150,000 to $200,000 to do so for each patient. Using today’s next generation sequencing technology, that cost has been reduced tenfold, to roughly $20,000. And what used to take about a month now takes a matter of days.

“The real breakthrough is the ability to [gene sequence] at a cost that will eventually be affordable in a clinically applicable way,” said Vogelstein, noting that the next generation sequencing instrument costs roughly $500,000, and the computers that collect the data add another $200,000. “In a couple of years, today’s cost will undoubtedly come down to something like $1,000 or $2,000, and then it will be in the range of other sophisticated patient tests like MRIs.”

Vogelstein looks at next generation sequencing and sees both promise and obstacles. He explained that, based on genetic studies and clinical information, it has been documented that tumors generally take 2 or 3 decades to develop to a malignant state, and the metastatic process only occupies the last 2 or 3 years of that time span. Learning to detect tumors early in that large window, when they are still curable by surgery and have not yet metastasized to other organs is what Vogelstein believes will lead to a decline in tumor deaths.

One major obstacle, however, is the time it takes to develop new cancer-fighting drugs. “The speed at which we’re able to understand genomes is infinitely faster than the speed at which new drugs are being developed,” Vogelstein said “Optimally, the two would go hand in hand, but the practical reality is it takes an average of 15 years to develop each drug.” He said the information obtained from using sophisticated genetic technologies will only be fully realized when more drugs are available that target the specific abnormalities identified. “That’s going to be a slow process,” said Vogelstein.

Radiation sciences heats up

Theodore DeWeese, MD, is chairman of the department of Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins School of Medicine. He said that the department’s goal is to achieve excellence in research that is primarily laboratory-based, then moves to the clinic, and uses molecular techniques to modify the way radiation is used to treat patients.

One of the hottest topics is heat sensitivity research. DeWeese explained that it has been well known for decades that increasing the temperature of cancer cells renders them more susceptible to the effects of radiation or chemotherapy. The challenge is heating the cancer cells without harming the patient in the process, particularly if the tumor is deep within the body or if the patient has tumors at multiple sites within the body.

Researchers at Hopkins have begun putting magnetic nanoparticles, such as iron or oxide, into the tumor either directly through injection or through indirect accumulation after intravenous injection. The particles are then heated using an alternating magnetic field. “The heat is localized to the site where you’d like it to be,” DeWeese said. “Moreover, because we’ve now shown that we can target these nanoparticles by both R&A molecules and antibodies, they are not just going to the tumor, but specifically to whichever tumor type we’ve targeted. So, we believe that we’re taking something that previously had been a local treatment and making it a systemic treatment to treat the patient.”

DeWeese said that, on the flip side, nanoparticles administered intravenously tend to accumulate not only in the tumor, but also in the liver. “There’s always a risk of toxicity from any of our treatments of any cancer therapy,” DeWeese explained and said his team’s goal is to gain a better understanding of toxicities associated with giving iron oxide nanoparticles to people. DeWeese said the next steps are determining the best targeting molecule, finishing the toxicologic work, and then getting a clinical trial investigating nanoparticles in prostate cancer up and running in late 2011.

Getting personal

Nelson believes that with research heading down the road toward personalized cancer treatment, significant efficiencies in cost and time can be gained when developing new cancer drugs. He explained that in 2009, only a handful of the approximately 900 new anticancer agents placed in clinical trials were approved.

“What that means for cancer drug development is that we push a lot of things into clinical trials…spending a lot of money in that discovery and development process…that [do not] prove to be helpful ultimately,” Nelson said. He believes the work being done in next generation sequencing and cancer stem cells is the key to finding a better, more efficient and cost-effect way to proceed. “I think the idea that we might pick winners from losers earlier, before we invest a lot of money, and then have our clinical trials be quite efficient, that’s where the savings are,” he said. In addition to saving money, it will save many patients from wasting time on therapies unlikely to prove beneficial and speed the process toward developing new, more effective therapies, which is what Johns Hopkins is all about.

Ed Rabinowitz is a veteran healthcare journalist based in Bangor, Pennsylvania