Why does cancer respond to a drug in one patient but not another? Why does cancer often return resistant to treatment that worked before? Why so little progress in the treatment of cancer?

“Why” questions have stymied physicians since Hippocrates first described cancer in about 400 B.C. While medical researchers have put the brakes on many forms, multiple myeloma is evasive. While ‘why’ questions do continue, the completion of the Human Genome Project in 2003 has led to new technologies that let researchers focus on genetics. They are seeing and identifying not only genes involved in myeloma’s development but also their mutations.

Fruits of this new molecular direction are beginning to be harvested from two on-going projects as part of the collaboration between Mayo Clinic and the Phoenix-based Translational Genomics Research Institute (TGen).

The future, notes Keith Stewart, M.B., Ch.B., of Mayo Clinic’s Multiple Myeloma Research Program in Scottsdale, Ariz., may see people carrying their genomes on a DVD. Doctors would use data on these DVDs to help them treat not only cancer, but also heart disease and even diabetes based on what each individual’s genetic profile shows.

“These are very exciting times for all of us in cancer research, because we have the opportunity to integrate science and genomics into the potential for targeted patient care,” said Rafael Fonseca, M.D., deputy director of Mayo Clinic Cancer Center in Arizona. “We have much more to learn, and I think it will take many years before all of this moves forward into extensive application.”

Multiple myeloma is an incurable malignancy of the blood. It forms when a plasma cell mutates and divides recklessly, embedding into bone marrow. It often responds favorably to initial treatment but inevitably is followed by relapse with new tumors highly resistant to drugs that previously had worked. Some 16,000 new cases emerge each year in the United States.

Drs. Stewart and Fonseca, who see 200 new myeloma-diagnosed patients a year, are among a group of Mayo Clinic doctors collaborating with TGen. Under an agreement that began in 2003 and expanded in 2008, TGen researchers and physicians in the Mayo Clinic’s Comprehensive Cancer Center are exploring the development of individualized, specifically targeted drug therapies based on molecular profiling. TGen’s Pharmaceutical Sciences Division is on Mayo’s Scottsdale campus.

Two Significant Projects

In one, the researchers, Dr. Stewart at Mayo Clinic and John Carpten, Ph.D., director of TGen’s Integrated Cancer Genomics Division, have obtained the complete genome of a woman who has suffered repeated relapses of multiple myeloma. The project still is in the data-analysis stage but genetic snapshots gathered four times in the patient’s life have unveiled an unexpected and enlightening surprise.

Initial treatment eliminated the woman’s original tumor. In each subsequent relapse, researchers detected genetic changes in the cancer itself.

“The tumor that emerged at relapse was ancestrally related but otherwise was quite unique from the one that had vanished,” Dr. Stewart said. “We had always had this notion that this was a longitudinal process — you get one genetic hit, then you get two or three genetic hits, and it becomes drug resistant, but everything else is the same. It looks like that thinking is not the case.”

Old and new versions shared six genetic mutations, “but there were also 40 to 50 things that were quite different, some of which indicated simultaneous evolution of the cancer,” Dr. Stewart said. “To me this was a surprise. That’s the kind of thing we are learning as we look at the whole genome of cancer patients.”

Drs. Stewart and Fonseca agree that what they are learning may help treat this patient, but the overall information they are gleaning from the project more likely will drive how treatment plans are drawn for future patients.

“What is missing now is the clinical relevance,” Dr. Fonseca says.

Obtaining an individual’s genome is not cheap, although new technologies are driving prices down. The multiple views of this patient cost about $10,000 each, plus additional expenses for staff time and analyses. So far the total cost is about $200,000 but is covered by funding from the National Cancer Institute.

“We’ll soon have a $1,000 genome, but additional costs will come at the back end through the development of software for analyses, supercomputer power and staff time,” says the Scottish-educated Stewart. “A genome has to be cut into its base parts and then lined up in the right order by the supercomputer. We used the Arizona State University supercomputer around the clock for a week and we still have two chromosomes to go.”

The other TGen-Mayo collaboration is a national project led by Daniel von Hoff, M.D., TGen’s physician-in-chief and an expert on pancreatic cancer. Mayo Clinic participated in this study along with eight other centers. Tom Fitch, M.D., and Donald Northfelt, M.D., in Arizona led the Mayo effort.

Preliminary results, announced by Dr. von Hoff in April at the annual meeting of the American Association for Cancer Research in Denver, show that molecular profiling of 66 patients at nine U.S. cancer centers led to specific individualized treatments that kept cancer growth at bay for longer periods than with traditional approaches. In some cases, the tumors actually shrank.

All patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy. Among the patients, 27 percent had breast cancer, 17 percent had colorectal cancer, 8 percent had ovarian cancer and 48 percent had cancers that were classified as miscellaneous.

“One of the most important things about this study was that targets can be identified through a rather complex molecular test and paired with existing drugs,” Dr. Fitch said. “The purpose was to look at patients who had failed in standard therapy and find molecular targets. In the vast majority of patients this approach led to individualized treatment, and we did see responses. These are early days, but this is a step in the right direction.”

The goal is that all patients coming into Mayo Clinic in Arizona are molecularly profiled, Dr. Fonseca said. “We have been integrating genetic information,” he says, “but how to translate this into something that is valuable to patients is our challenge.”

Dr. Fonseca moved from Mayo Clinic in Minnesota, where he had been for 10 years, to Arizona in January 2004 to focus more strongly on hematological, or blood-borne cancers. He and Dr. Stewart work closely with P. Leif Bergsagel, M.D., in Mayo Clinic’s Multiple Myeloma Research Program.

“Our first step is to understand the disease,” Dr. Fonseca says. “We’ve been looking closely at myeloma and in collaboration with others on lymphoma and other tumor types. In parallel, people have been working in drug development. There is a whole array of new compounds that target different diseases. But the clinical development for that has gone more in the way of having a drug and testing it against, say, lung cancer. Some patients respond. Some don’t.”

It turns out the “why” is tied to genetics.

“We are finding out more and more that it is the people who have specific genetic features who are going to respond to a particular drug. We now know there are drugs that can affect certain gene pathways,” Dr. Fonseca says. “We have to match a patient’s genetic features with known drug capabilities.”

Dr. Fonseca and colleagues are not strangers to tracking down such pathways. In their focus on the genetics of myeloma and lymphomas, they found that one such pathway in the immune system — NFkB, or Nuclear Factor kappa B — is involved in possibly half of all multiple myeloma cases. The myeloma team has been experimenting with drugs that can tap into the NFkB pathway.

“Working together as a team here, we have been able to find at least 5 or 6 different genetic changes, mutations and translocations that result in the activation of the pathway and accelerate the growth of myeloma cells,” Dr. Fonseca said.

“While we work with cell lines in the lab, the bulk of our work remains very much focused on our patients,” Dr. Fonseca says. “I personally like that. It keeps what we are doing very relevant.”

The treatment of cancer, he says, is moving onto a new playing field, combining science and genetics to derive target-specific treatments that even could put discarded and unrelated drugs into play.

“The direction we are going, integrating this information with what we can do in the clinic, is incredibly exciting,” says Mexico City-born Fonseca. “It’s not far-fetched to think that in just a few years we will have more and more targeted therapies that are unique to each patient’s tumor. We will be able to open options that currently are not available for patients with the use of tumor genetic profiling.”

— Jim Barlow, December 2009