A one-stop shop for myeloma research

June 9, 2010
By Kaspar Mossman, QB3

This is the first of a series of reports on how QB3 researchers produce results by crossing traditional boundaries within science and between science, medicine, and industry. Download a pdf here. Read the related article on laboratory science here.

A donation from Steve and Nancy Grand made the MMTI a reality.

Steve Grand and his wife Nancy donated to cancer research at UCSF for many years. “We always thought this was something to benefit others,” he says, “and that cancer was certainly nothing we would have to deal with personally.”

But in mid-2005, Grand, a philanthropist with a background in real estate and manufacturing, felt an odd pain in his muscles. He went to a chiropractor, who sensed a problem and ordered an MRI. Very quickly doctors determined that Grand had an advanced case of multiple myeloma. “It’s pretty scary,” Grand says. “It sneaks up on you. Everything’s fine and then a couple weeks later you find out you have what was considered, at that time, a fatal disease.”

UCSF doctors told Grand his case was very serious and they didn’t think it was treatable. But, at their suggestion, he pursued treatment at the University of Arkansas Medical Center in Little Rock, which specializes in myeloma and treats more cases of it than anywhere else in the U.S. After two months, Grand’s cancer went into remission, where it remains today. Back in San Francisco, Grand continued to see his oncologist, Tom Martin, MD, for regular checkups. He also saw Jeffrey Wolf, MD, director of the UCSF myeloma program at the Helen Diller Family Comprehensive Cancer Center.

Wolf was frustrated that UCSF could not offer the most advanced care. He had long wanted not just to diagnose and treat patients but to build a program that could apply UCSF laboratory research to discover new anticancer drugs, run patient trials, and take the drugs all the way to FDA approval. Such a program is called “translational medicine.” Wolf had a strong connection with Marc Shuman, clinical director at QB3, the California Institute for Quantitative Biosciences, which plays a prominent role in translational research at the University of California.

Wolf knew Grand was a philanthropist, and broached the topic of donation during a checkup. “You know, [the scientists’ funding] really just covers the lab stuff,” Wolf said. “We need to cover the clinical research, hire a translational scientist, put up a preclinical lab, establish a tissue bank. Can you help us out?”

No-good antibodies

Myeloma (doctors often omit the “multiple”) is a cancer of the plasma cells, the white blood cells that produce antibodies to protect us from infection. “Like any cancer, it ignores the usual rules of growth,” Wolf says. “One plasma cell forms clones, but doesn’t stop after it makes a thousand. It can make a billion, ten billion, just like itself, all making one antibody which is usually dysfunctional.” Each year 20,000 people in the U.S. are diagnosed with myeloma. Doctors attack it with chemotherapy, sometimes together with bone marrow transplants.

Myeloma cells are malignant plasma cells that secrete billions of identical, useless antibodies. Image courtesy of the MMRF.

Myeloma can be slow-moving—or fast and lethal. There is a grim spectrum of symptoms. The malignant cells crowd the bone marrow, causing anemia and poor clotting. “The proliferation suppresses other plasma cells, so you become immune-incompetent,” Wolf says. “Our patients get many different infections.” Antibody fragments can plug up the kidneys and cause them to fail. The fragments can get into nerves and cause numbness or tingling and pain. Myeloma cells also recruit other cells that erode bone, dissolving holes in vertebrae, ribs, and the skull. The multiple lesions give “multiple” myeloma its name.

The good news for a patient is that there is a national foundation dedicated to finding treatments and, ultimately, curing the disease: the Multiple Myeloma Research Foundation (MMRF), headquartered in Norwalk, CT. The MMRF is associated with the Multiple Myeloma Research Coalition (MMRC), a group of 13 major centers that share a tissue bank and focus on clinical trials. The MMRF and MMRC have enabled four new myeloma treatments to reach FDA approval, and currently support fifteen drugs at various trial stages.

From leukemia to lymphoma

Before he treated Grand’s myeloma, Wolf started out as a leukemia doctor. He was the first to carry out bone marrow transplants in northern California. At Alta Bates Medical Center in Berkeley, Wolf ran a clinical program that also included some myeloma patients. He enrolled some of them in a trial of an MMRF-supported drug, PS341, later approved by the FDA and renamed Velcade. “Up until then we didn’t have very good drugs to treat myeloma,” he says. “But we started using PS341 and saw some phenomenal results. The drug was so successful that I became a myeloma expert, because I was the only one in this part of the west coast using it.”

Jeff Wolf, MD, director of the MMTI (left) and Tom Martin, MD, associate director of the program.

Wolf moved his practice to UCSF in 2007 and began working with Tom Martin, who also carried out bone marrow transplants. Wolf and Martin were each treating about 100 patients, and saw the benefit in joining their patient pools. “We began putting together a clinical research program,” Wolf says, not only to treat patients but also to explore new therapies.

Wolf and Martin knew about the MMRC and sought membership for UCSF. “It would give us access to a lot of new drug testing for our patients,” Wolf says. The MMRC accepted UCSF in early 2008, with Wolf as director and Martin as associate director.

Besides shared talent and interest in blood cancer medicine, Wolf and Martin had something else in common: they both knew Marc Shuman, MD, and Martin had trained in Shuman’s laboratory. Shuman is a cancer researcher—his laboratory investigates prostate, breast, and brain tumors—and clinical director at QB3. Shuman is extraordinarily well-connected to doctors, laboratory scientists, and policy makers.

Wolf took Shuman for a cup of coffee in the summer of 2008. “I said to Marc, ‘Tom and I want to build this myeloma translational program,’” Wolf says. “’Do you know any basic researchers who might have an interest in myeloma?’”

Shuman said, “Of course. We have some of the world’s best researchers. Let me introduce you.”

Peter Walter, PhD, a UCSF professor of biochemistry and biophysics, Howard Hughes Medical Institute (HHMI) investigator, and member of QB3, was one of those researchers. In 2002, Shuman spent a sabbatical year in Walter’s laboratory, working with yeast models of cell death. “I got him interested in cancer,” Shuman says. Walter is an expert on a cellular process known as the “unfolded protein response.”

Marc Shuman, MD, clinical director of QB3.

In 2008, Walter, Shuman, Jim Wells, PhD, a UCSF professor of pharmaceutical chemistry, and Kevan Shokat, PhD, a UCSF professor of cellular and molecular pharmacology and HHMI investigator, with Walter’s former student Sebastian Bernales, now in Chile, won a “Collaborative Innovation Award” (CIA) from HHMI. (Wells and Shokat are members of QB3.) The award provides $4.5 million over four years for studies of the unfolded protein response’s role in disease.

“Marc had this idea that they’d be the perfect collaborators for us and maybe we could get them excited about myeloma,” Wolf says. Shuman pitched the idea to Walter, Wells, and Shokat. “They jumped on it,” Wolf says. Walter contacted HHMI and arranged to focus the work of the CIA on myeloma.

A business blueprint

Steve Grand was receptive to Wolf and Martin’s idea of establishing a world class translational myeloma program at UCSF. As a successful businessman he wanted to make sure his donation was used wisely, and he saw that the UCSF effort could benefit from the experience of successful translational centers. “There were just two doctors [Wolf and Martin] that concentrated on myeloma,” he says. “They were fully occupied with clinical practice and neither had run a translational initiative. We were starting from scratch. My thought was, ‘let’s see if we can enlist the MMRC.’ Fortunately, the MMRC was more than willing to work with us and provide expertise.”

Less than a month after Walter and colleagues had won the award from HHMI, “Jeff sent me an email,” Shuman says. “’We have a potential donor for myeloma. He’s met the dean and the CEO of the hospital. They insisted the money could not be accepted unless there was first-class research being conducted on multiple myeloma.’”

Louise Perkins, chief scientific officer of the MMRF.

“You have to be kidding!” was Shuman’s reaction. He could not believe how lucky they had been with the timing. Shuman, Wolf, and Martin formed a steering committee with Stephanie Robertson, PhD, program director at UCSF’s QB3-affiliated  Sandler Center and formerly of the cancer drug discovery company Exelixis, and Louise Perkins, PhD, the chief scientific officer of the MMRF. The MMRF would administer Grand’s donation: $1 million for the first year, with the chance of renewal each year up to a total of $5 million.

Shuman thought Grand was a savvy investor. “What was really unusual was that the donor tied the funding to having milestones,” he says. “Just like a company. Not pie-in-the-sky, but concrete accomplishments by each of the projects in year one, two, and three. NIH doesn’t operate that way.”

“That UCSF was a member of the MMRC was fantastic,” Perkins says. “That, plus the experience that the preclinical researchers brought in pathways that were of proven utility in multiple myeloma, was a real win-win. Peter Walter’s award from Howard Hughes made the project go.”

The committee hired a business writer to prepare a five-year operating blueprint for the new venture, the Multiple Myeloma Translational Initiative (MMTI). Perkins says the committee considered running the MMTI on a single, linear track, from identifying molecular targets for myeloma drugs, through drug screening and production scale-up, to clinical trials. But it didn’t seem the best idea.  There were patients eager for treatment and clinicians ready to do trials, while the biochemists were in their laboratories designing compounds and testing them on cells and mice. At the time there was no continuous pipeline.

So the committee planned several tracks to operate in parallel. “We wanted to integrate them all coherently,” Perkins says. The clinical researchers could begin trials using drugs from outside companies, while the basic scientists could test compounds on myeloma cell lines. The clinicians could provide the scientists with fresh cell samples that behave more like real tumors than the archived cell lines do. And later, once the drugs developed in-house matured into potential therapeutics, the two main tracks could merge and UCSF clinicians could run trials of UCSF compounds.

Working together

Tumors glow in a fluorescent image of a mouse implanted with myeloma cells. The experiment showed that myeloma cells home to the bone marrow, where they cause lesions in the bone. Image copyright 2010 Diego Acosta-Alvear.

Regular meetings and group presentations glue the MMTI together, coordinate work with the CIA, and create a tight feedback loop between the lab and the clinic. Walter finds the monthly meetings invaluable. “We learn what stage are we at, what’s realistic to hope to get to in the foreseeable future…how do we meet each others’ needs,” he says. “[Wolf and Martin] would like us to provide them with tools that get into the clinic as soon as possible—it’s a terrible disease that’s currently not curable.”

“It’s our job to provide them with material, so they can do research on patient plasma cells.” says Wolf. “It’s also our job to give guidance, so they know what direction to go. Which drugs are working, which aren’t. They use the cells and information we give them. In return, when they develop a molecule that works in test tubes and mice, we can ultimately test it in patients.”

Perforations in bone, including the skull, are just one in a spectrum of myeloma symptoms. Left: normal mouse skull. Right: skull of animal implanted with myeloma cells. Image copyright 2010 Diego Acosta-Alvear.

The patients are ready to donate cells for the cause. “They love it,” says Wolf. “They all want to donate their bone marrow. Even when they understand the cause is general—that they and 100 others are donating cells that are going to enable us to pick out molecules that some day may come back to help them—it could be 10 years—they’re still willing. And usually it’s not an extra bone marrow we’re doing on them. If it’s for clinical reasons, it’s 10 cc. If research—40 cc. It’s slightly more uncomfortable, but they don’t get an extra stick.”

Shokat says that samples donated by patients are crucial to the research. “We’re about to exhaust our work on the [commercial] cell lines,” he says. He only needs a small number of cells—50,000—for an experiment and, since drugs act quickly, he should be able to see whether a candidate is working within a few hours. He’s aiming to finish experiments before cells have been out of a patient’s body for 12 hours.

Tom Martin and cancer biologist Davide Ruggero, PhD, a UCSF professor of urology and member of QB3, will manage a local MMTI tissue bank. “To push forward new therapeutics and find new targets for myeloma, [a tissue bank] is essential,” Martin says. “As patients receive treatment, their myeloma cells may evolve. We’re trying to look at the changes in the cells to identify targets that may help us make the treatment more powerful.” Wolf and Martin will alert Ruggero about upcoming donations. Ruggero will purify the myeloma cells from marrow samples and freeze them as soon as possible in liquid nitrogen for long-term storage.

Real cells from a patient are more useful in many ways than long-lived lines that have been cultured for months, Shokat says. “We’ve analyzed cells straight from a tumor and seen that they’re undergoing a lot of apoptosis [cell death],” he says. “You wouldn’t see [the dying cells] if you put it in cell culture—that’s how you lose them.”

We can do it all here

Wolf relishes the idea of a mature translational program. “Eventually,” he says, “we’re going to be a one-stop shop, from test tube to people. There are a lot of steps in between, but we can do it all here.”

“Here,” in the larger scheme of things, means the Bay Area and the larger hinterland of California industry. Any drugs discovered at UCSF will take a detour out of the university before returning for clinical trials.

“We’re developing ‘proof of principle’ compounds with Jim Wells and Kevan Shokat’s labs,” Walter says. “There’s a huge experience base out there: how to take a compound and turn it into something that will actually work as a drug. Increasing its affinity, its bioavailability; decreasing its toxicity. Once we’ve proved our compounds are useful, we will hand them over to biotech.”

Steve Grand sees the California biotech and pharma industry as a big asset. “It’s a reason UCSF is a great place for translational research,” he says. “There are so many of these biotech companies in Northern California and the Bay Area. There’s the potential for research to go back and forth. To develop it in the lab is one thing—turning it into a drug is the other part. These biotech companies—that’s what they do. In addition, UCSF is known for its abundance of brilliant researchers. The combination could be unbeatable.”

One of these companies is Intellikine, headquartered in La Jolla and founded by Kevan Shokat and four others. Intellikine has several drugs in the pipeline, including one named INK128, which inhibits the enzyme mTOR. mTOR is a key control point for protein production in cells. “When I was working with Peter, Jeff, and Tom, and started to talk to clinicians,” Shokat says, “I said, ‘hey, myeloma is a cancer that cranks out a lot of protein. Why not use INK128? If you cut out the ability of plasma cells to make a lot of protein, maybe you can kill them.’”

Intellikine contacted Wolf about phase 1 clinical trials of INK128. Solid tumor studies were initiated in December, 2009 and trials should start in myeloma patients at UCSF and the Dana Farber Cancer Institute in Boston in the next few months, Wolf says.

Wolf and the MMRC influenced Intellikine’s decision to set myeloma as a priority, Shokat says. “There were many cancers we could have thrown the drug at,” he says. “[Intellikine] were doing several solid tumor trials, but myeloma is a liquid tumor, so it’s easy to get samples [without surgery].” Another factor was that myeloma cells secrete antibodies, and antibody titer in the blood is a good measure of disease progression. “Those are good things for early clinical trials.”

One year in

In May 2010 the MMTI is a little over a year into its five-year plan. From the roughly 100 patients that Wolf joined to Martin’s pool of about the same size, the program can now support and draw on more than 600 patients.  According to Martin, the MMTI has hit all of Grand’s first-year milestones, some of which are confidential. The program has more than 100 samples in the tissue bank; it is taking part in at least five new patient trials for new drugs (sourced from several Bay Area companies and obtained through the MMRC); and it has identified at least two drug lead compounds in-house.

“Not only did they meet the goals that they set for this past year, but they’ve met many of the goals they anticipated happening in future years,” says Stephanie Robertson of the MMTI steering committee. “They’re ahead of the game.”

Perkins appreciates the progress the MMTI has made, but thinks there’s room to improve. “Developing assays, cell lines, and animal models is very hard to do from scratch in an area of biology that you’re not intimately familiar with,” she says, based on her 16 years of industry experience. “What I think the MMTI could use to just blow it out of the water is have someone on board who in a prior career worked on preclinical models for multiple myeloma drug validation.”

She thinks it is wise to attack myeloma from several directions at once, as the MMTI is doing. “Cancer cells are devious in identifying ways to overcome drugs that have been thrown at them. You need multiple approaches to effectively quell active disease.”

Wolf would like potential donors to know that their money will be leveraged many times over. Grand’s funding, he says, although cut into smaller slices and distributed to several laboratories, has had an effect larger than one might think. “Seed money becomes bigger in a lab,” he says. “All these guys have very active programs. A donation gets them thinking about myeloma,” and enables them to hire an assistant or two to implement new assays.

Grand is happy that momentum is growing. “There’s a large team of researchers jumping into the myeloma challenge due to Jeff Wolf’s organizational skills,” he says. But he is content to remain hands-off. “If you have a technical discussion with the scientists,” he says, “you can follow their thoughts for about three sentences. After that it’s another world that us mortals cannot comprehend.”

For Martin, INK128 is the most satisfying result to date. “The fact that there’s a lead compound that Kevan’s lab has identified and are developing through Intellikine,” he says, “and now it’s back at UCSF for clinical trials—I think that’s pretty neat.”