From a Trailer to a Multimillion-Dollar Research Clinic

How one U-M doctor is charting a course for bringing breakthrough cancer research out of the lab and delivering it directly to patients.

Do a Google search for “top cancer centers in the U.S.” and the usual suspects pop up: New York’s Memorial Sloan-Kettering, the Cleveland Clinic, and MD Anderson in Texas.

However, Dr. Max Wicha, director of the University of Michigan’s Comprehensive Cancer Center in Ann Arbor, has a different list in his head. It puts Michigan at No. 1.

Wicha wants to make the University of Michigan the center for the most promising — and potentially lucrative — cancer therapies in the country, notably in the rapidly developing area of stem cell research, which targets cancers at the molecular level.

To make it to the top, Wicha and his team of what he calls “physician researchers” are putting into place plans to transform how basic research moves out of their university labs, into the marketplace and, most importantly, to patients.

Traditionally, university research has been passed to private companies —  which then invest millions of dollars in clinical trials and development, so they can bring cancer-fighting products to market. Soon, however, U-M’s cancer center will take a far more active role in that early stage by testing drugs, therapies, and diagnostic tools. In addition, the university will assist researchers in creating spinoff businesses.

The linchpin of the ambitious plan is the cancer center’s new translational oncology unit, which is slated to open within the year at the university’s North Campus Research Complex (NCRC), the former site of Pfizer’s  global drug development headquarters on Ann Arbor’s north side (see page 61). The university bought the 2.2-million-square-foot facility for $108 million last year after Pfizer shut down the campus as part of a corporate consolidation effort. Left behind were state-of-the-art drug development labs filled with millions of dollars worth of equipment.

“We needed a unit that would allow us to be very entrepreneurial,” Wicha says. “This will let us take our discoveries and develop practical drugs and devices, and then test them in patients in early-phase clinical trials.” Those important Phase 1 clinical trials will be headed by Dr. Moshe Talpaz, a leading clinical researcher Wicha hired away from MD Anderson four years ago.

The new facility will fill a major gap in the cancer center’s core strengths, Wicha says. The center currently has a small clinical trial unit tucked away in a corner, but without a place to conduct major clinical trials, the operation has lacked the ability to take research from its lab and carry it all the way to cancer patients. The center has been strong in both basic research and in patient care; it ranks 13th in the 2010 U.S. News and World Report rankings of cancer centers, and is third in the nation for long-term basic research funding from the National Cancer Institute. But what is lacking is the clinical research expertise that would tie research and patients together.

Linking those two could be a big boost for Michigan’s economy if the center becomes a major player in this promising new area of cancer research and therapy. “We’ve already seen eight biotech companies spun off of research from the center, and one of them is my own,” says Wicha, who was one of the first researchers to find stem cells in breast cancer and investigate their importance to the growth and spread of the disease. “If these therapies just sit in the lab, they don’t do anyone any good. We have to see them applied.”

While concrete numbers on cancer spending in the U.S. are hard to come by, one estimate, reported in the Journal of Clinical Oncology in 2007, pegged it at around $100 billion. That number doesn’t include research funds, etc., which reach into the tens of billions of dollars. The National Cancer Institute’s budget alone is close to $5 billion; the private sector, such as large pharmaceutical companies, adds in billions more.

It will take more than great science, however, for the cancer center to become a primary player in the multibillion-dollar business. It will require major shifts in the way the university, investors, and the pharmaceutical industry think about how to fund new therapies for cancer by betting on many treatments versus one blockbuster drug.

In short, it will necessitate a vastly different way of thinking — then again, Wicha has been thinking differently about how to attack cancer for more than 30 years.

For decades, cancer was seen as a single disease that most often was bluntly attacked with chemotherapy, radiation, and surgery. “We believed that any cell could become cancerous, and that virtually all cells were malignant,” Wicha says. “It seemed the logical model because it was the natural-selection model. A mutation in a cell causes cancer, so any cell could cause a mutation.”

Fighting cancer under the single-disease model was straightforward: Kill off all cells (even healthy ones) with harsh remedies such as chemotherapy and radiation. Surgery, meanwhile, was indiscriminate — removing healthy tissue along with cancerous tissue.

Even as a young doctor, 30 years ago, Wicha was considering different methods of treating patients. In his specialty — breast cancer — he pioneered efforts to combine radiation with selective surgery, instead of the traditional path of a full mastectomy. The new approach came out of Wicha’s belief that his breast cancer patients needed to be treated by multidisciplinary teams of physicians and researchers, instead of being passed from expert to expert.

“In the 1980s, it could take weeks from the time a woman had a biopsy to seeing a surgeon, who would tell her one thing. Then, a week later, a radiation oncologist would tell her another,” he says. “It was so confusing. She was getting all these different and competing ideas of how to treat her cancer.”

Wicha believed there was a better way to work with patients, and he suspected it may also lead to better therapies to treat their cancers. “It was clear to me that the care of patients was fragmented and the research was fragmented, as well,” he says. He proposed and instituted a new model of care: a multidisciplinary clinic, where patients’ cases were seen by a “tumor board” made up of all the doctors who would be treating that individual. Today, such tumor boards are increasingly common in cancer treatment.

Wicha had even bigger ideas about how to rally researchers and physicians around specific cancers, to gain better understanding of the diseases. He wanted more than teams of doctors getting together a few times a month. He envisioned an entire building devoted to this teamwork approach.

By the late 1980s, the university had applied for and received its designation as a comprehensive cancer center, making it one of just a few dozen hospitals with that role. “Getting the designation as a national cancer center was a tour de force,” says Marcy Waldinger, who joined Wicha’s team in 1992 as chief administrator.

However, prestige didn’t come with the building that Wicha needed. In the early 1990s, he was still operating the center out of a trailer behind the university’s hospital. His lab was a refurbished women’s bathroom that still had the silhouette drawing of a woman on the door. It was fitting, given that Wicha focused on breast cancer, but it wasn’t the kind of symbol he needed to make U-M a nationally ranked cancer center.

In 1997, almost 10 years after the university was named a comprehensive cancer center, Wicha and his growing team of physician-researchers settled into a $100-million building. There he proved his theory that cancer needed to be fought by teams of scientific and medical disciplines working in tandem. The type of environment he had created for breast cancer patients grew to include those suffering from other cancers, such as melanoma, prostate, and lung. Today, says Waldinger, Michigan has more multidisciplinary teams working on specific cancers than any other center.

The research labs, which take up four floors of the center, are designed around specific cancers, as opposed to departments such as chemistry or biology. Waldinger says it was the first center to put labs and clinics together under one roof. “It’s not rocket science to see that if you have doctors seeing patients and then going to the labs upstairs, you’re likely to hasten the discovery process of cancer,” she says.

This concept of team science also paid off financially, most notably in terms of the amount of research dollars the center has been awarded. Last year, the university garnered $87 million in research grants from the National Cancer Institute, just behind MD Anderson and Harvard University’s Dana-Farber Cancer Center.  In December, the center received a five-year, $10.7-million grant from the National Cancer Institute to study colorectal and pancreatic cancer. The Specialized Program in Research Excellence, or SPORE, grant in gastrointestinal cancers brings together basic and clinical researchers to test new approaches for cancer prevention, early detection, diagnosis, and treatment.

“The standard has always been that you did your own research and got your own funding,” Wicha says. “But if you put together teams of scientists to work together, you can bring in much larger grants.”

Wicha also searched for and hired people he believed would work well in this multidisciplinary approach. “I’ve felt that you need ‘physician-scientists,’ people who had a foot in both camps. We needed really good clinicians who could also do research.”

Wicha is one of those physician researchers. He continues to see 20 patients a week in the breast cancer clinic, and then takes the elevators to his research labs on the sixth floor to work on new ways to attack the cancer. It was there, in the early years of the last decade, that he began contemplating what is still considered a controversial theory in cancer research. He believes it will put Michigan at the front of cancer research and treatment in the coming years.

His theory is this: What if only some cancer cells were responsible for the disease? Instead of the traditional theory, in which any healthy cell can become cancerous, Wicha suspected that cancer’s stem cells were the culprits in the growth and spread of the disease. Working with Michael Clark, of Stanford University, Wicha tested his theory on mice in 2003.

He says they found that only 1 to 5 percent of human breast cancer cells could transfer to the mice. As a result, Wicha and his team were the first to find stem cells in breast cancers. The findings revealed that only a certain type of cell — the cancer’s stem cell — was actually responsible for the growth of cancer. Their first paper, published in 2003, was the only paper on stem cells presented at a major cancer conference that year. At the 2009 conference, more than 200 papers were presented.

Wicha’s research not only changed the way he and others thought about cancers and how to treat them; it gave him firsthand knowledge in what it will take to move cancer stem cell research out of the lab. That experience is driving what he envisions for the labs at the NCRC.

With their first paper published, Wicha and his team quickly moved into early clinical trials testing existing drugs that block the pathways stem cells use. The so-called Phase 1 clinical trial, meant only to test toxicity, showed that the drug was safe to use — but it also showed that it reduced the number of stem cells in the tumor.

This was a huge discovery, since such findings generally are reserved for later-stage trials. Excited by the breakthrough, Wicha and his partners decided to found their own company to discover and test drugs that would attack cancer stem cells, rather than turning their research over to a pharmaceutical company.

They founded OncoMed in 2004, and hoped to headquarter the company in Michigan. But after two years of attempting to raise venture capital funds in the state, Wicha and his partners went to California. Wicha says Michigan investors wanted a faster return on their investments, while California investors seem to understand that turning research into a business takes longer. “It should have been here,” Wicha says. To date, OncoMed has raised $350 million and has 75 employees.

Wicha hopes Michigan’s venture capital community has grown up enough in the past several years to be more open to funding ventures from the new unit he hopes will be spun off in the coming years. To aid in that process, the university is moving its technology transfer and business engagement offices to the new research center. “That way we can work with (investors) directly,” Wicha says. “We can be developing a new business plan from the very beginning.”

Philanthropy is another source of funding for developing innovative treatments for diseases such as cancer. The A. Alfred Taubman Institute helps to support “high-risk, high- reward” research by Wicha and other University of Michigan physician-scientists in their efforts to move discoveries out of the laboratory and into clinical trial. The National Institutes of Health and other traditional sources of funding are reluctant to support translational research, leaving that gap to be filled by private philanthropy or private industry.

Wicha’s research, which has taken less than a decade to move from lab to clinical trial, is a clear demonstration of the need for tighter connections between research and business.

“Fifteen years ago, basic research and clinical research really operated in two parallel lines that had little reason to meet. Basic research was too far ahead of clinical research for them to come together,” says Talpaz, who will head up the Phase 1 clinical trials for the center. “Oncology was an empirical profession where we took the drugs from a company and tested them to see what worked and what didn’t.”

Wicha explains it more dramatically: “You took patients who were at the end stage and had no other option. You would start with a low dose and keep increasing it until they got sick. It may not benefit them, but it would benefit future patients.”

That began to change in the late 1990s. Talpaz’s research into chronic myelogenous leukemia was one of the first studies to target cancer at a molecular level with the drug Gleevec, instead of attacking both healthy cells and cancerous cells with chemotherapy, radiation, or surgery. “We identified the enemy, we identified its vulnerabilities, and we attacked it with specific drugs,” he says.

While it was a breakthrough for cancer patients, such personalization flies in the face of how pharmaceutical companies historically have made a profit from treating cancer patients. In the past, large numbers of patients received the same drugs, no matter what type of cancer they had. This new way of thinking about cancer is far more personalized and requires a different way of bringing treatments to market.

Talpaz says that, in the future, patients will have their cancer genome sequenced to see where the mutations are at the cellular level. Indeed, this could change the way we think about cancer — the notion that it’s something that happens in a specific part of the body. “It may be that we talk about the underlying defect, as opposed to whether the cancer occurred in the breast or the colon,” he says.

This will require everyone working on cancer — especially large pharmaceutical companies — to see it as a boutique business,  Talpaz says. “The drug companies are often looking for the next billion-dollar drug, but they are changing,” he says. “Now, instead of going after cancer with one drug where only 5 percent of people respond well, we will go after very specific targets with different drugs, where far more people respond to the treatment.”

Talpaz sees the University of Michigan as being at the forefront of understanding the variety and complexity of the disease. The new translational oncology center will give him the patients he needs to delve deeply into new ways of thinking about cancer. He estimates that the center will have up to 500 patients in clinical trials, up from the estimated 100 the center has now. “This new center is in the spirit of Max,” Talpaz says. “He’s a visionary who wants to push the envelope of what’s possible.”

For Wicha, it’s just the next step in the vision he’s had for more than 30 years.