Stemming the Tide

Michigan’s universities are developing innovative new methods to detect and treat disease with inventions that are migrating from the laboratory to the marketplace
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Illustration by James Yang

Drugs that target the root cause of cancer. Minimally invasive biopsies that tell surgeons in real time whether tissue is diseased or healthy. A faster, less-expensive, and greener process for making drugs.

These made-in-Michigan innovations are more than futuristic projects in academic labs. The potentially game-changing technologies are migrating from the University of Michigan, Wayne State University, and Michigan State University into the marketplace through the creation of companies and ties to industry. The projects of an oncologist, an engineer, and a chemist, respectively, each remains at the early stages of commercial development, though, and each faces challenges before becoming a mainstay in the clinic, operating room, or pharmacy. But success leads to better patient care, profits for the universities that own the patents, and new jobs for the region and state. It’s also part of the $36.7 billion the health-care industry contributes to Michigan’s economy in annual wages, salaries, and benefits.

“The universities are absolutely critical for ensuring that innovation and innovative technologies have the opportunity to be commercialized successfully,” says Stephen Rapundalo, executive director of the state trade association MichBio. “They’re the pivotal first step.”

Killing cancer at its source

Chemotherapy and radiation, the standard treatments for cancer, can be brutal on patients and sometimes offer a hit-or-miss approach for eliminating the disease. The outcome is especially dire for patients with advanced metastatic cancers — cancers that spread to other organs — as well as cancers that appeared to have gone away during treatment, only to reappear hardier than ever. This year, the University of Michigan Comprehensive Cancer Center expects to conduct clinical trials on two types of drugs that, theoretically, will be less debilitating to the patient and more devastating to the cancer.

The goal is to crush cancer at its root source — the stem cells. U-M oncologist and cancer center director Max Wicha and his colleague Michael Clarke first identified cancer stem cells in solid tumors about five years ago and, in 2004, launched a biotech company called OncoMed Pharmaceuticals to develop drugs that target the cells.

“Hopefully, we thought, it would be a better way to treat cancer,” says Wicha, a practicing clinician and researcher. “The dream is to come up with a new idea and see patients benefit from it.”

The conventional view of cancer is that cells either mutate or are genetically predisposed to become malignant, meaning they replicate beyond their normal confines to produce tumors. Malignant cells can also spread through the blood or lymph systems and colonize in distant organs. Chemotherapy treatment offers a scattershot approach for destroying rogue cells, while radiation is directed at specific tumors. It’s generally believed that any cancerous cells that fail to swallow chemo’s poison pill or wither under a radiation beam have the potential to repopulate.

Wicha and Clarke offer an alternative view. They argue that only a few cells in a tumor, meaning cancer stem cells, have the capacity to proliferate and form new tumors. Like normal stem cells, cancer stem cells make exact copies of themselves, as well as offspring like daughter cells that perform specific functions. All tissues have stem cells, and all stem cells have the potential to repeatedly self-replicate, whereas daughter cells that specialize will sputter out after a set number of cell divisions. (Neither cancer nor normal stem cells are embryonic stem cells, which are more of a cellular blank slate.)

Chemo might succeed in wiping out so-called daughter cells, which divide more frequently and are less robust than stem cells, but it can miss the cancer stem cells that drive malignancy, Wicha says. That’s why tumors may shrink or become undetectable, and then reappear. “They’re actually starting with a [stem] cell that has already evolved a tremendous amount of protective mechanisms,” he says. “That’s why it’s been so hard to cure cancer. It’s a tremendously hard job, and it still will be a tremendously hard job. If we begin to see why it’s so hard to kill cancers, then we can develop the right targets.” Wicha, a breast-cancer specialist, and Clarke, who is now an associate
director at Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine in California, first identified cancer stem cells in 2003 embedded in breast tissue samples. In order to do so, they had to develop a method for separating cancer stem cells by finding markers or proteins on the outside of cells specific to cancer stem cells. U-M patented its invention, which is licensed exclusively to OncoMed. Since then, cancer stem cells have been found in myriad other cancers, including the brain, colon, pancreas, head, and neck.

 

In April, Wicha’s team began Phase 1 clinical trials, which typically determine the safe dosage of a treatment, using a small molecule pharmaceutical by drug giant Merck & Co. Inc. A second trial scheduled to begin by the end of 2008 will test a monoclonal antibody developed by OncoMed. Each approach has benefits and disadvantages. Small molecule drugs can be given as pills, but they tend to be more diffuse and may become more toxic once they’re metabolized, leading to unwanted side effects. Antibodies are more targeted, but are harder to manufacture and must be given through infusions. The first trial involves about 30 patients with advanced metastatic cancer. To avoid any conflict of interest, Wicha, a co-founder of OncoMed, will not be involved in the OncoMed trial.

“It’s a different model in which we’re trying to hit a particular pathway in a particular cell type — [or] interfere with a particular pathway that the cell needs in order to survive,” he says. “The endpoint isn’t necessarily toxicity or the patients getting sick. As a matter of fact, if we do this right, what we’re looking for is what we call the biological effective dose, rather than a toxicity dose.”

Baylor College of Medicine in Houston and Dana-Farber Cancer Institute in Boston are also participating in the studies. Paul Hastings, president and CEO of OncoMed, says the company identified traits specific to cancer stem cells and developed antibodies that target those traits, essentially stunning cancer stem cells while leaving normal stem cells unscathed. Two markers identified by Wicha and Clarke consistently appear in all solid tumors, as well as in blood cancers such as leukemia, offering a potentially lucrative bull’s-eye for OncoMed.

“We want to be as broad as possible and be as effective as possible,” developing antibodies that target numerous cancers, as well as one-offs that treat a specific cancer, Hastings says. “A home run would be broad, or one that works in one cancer. Obviously, we’ll shoot for the broad.” Of course, he’ll be pleased with any successful outcome.
OncoMed raised $100 million in venture capital and, in December, received cash and an equity investment from GlaxoSmithKline to develop and market drugs that target cancer stem cells. The deep reserve will help OncoMed survive the costly and time-consuming process of getting a drug to market. OncoMed is also eligible for $1.4 billion in payments from GlaxoSmithKline if it meets specified milestones. But, Wicha says, “that’s a big if.” And the jury is still out on whether cancer stem cells exist or whether they play the lead role in cancer.

“Until it’s actually [proved] in the clinic, there’s a lot of skepticism — healthy skepticism, I would say, because the clinicians have seen plenty of so-called breakthroughs that really haven’t panned out,” Wicha says. “I think what’s going to really change this field is just to have one or two clinical trials where you can show you can knock out the cancer stem cell and the patients live longer.”

Biopsies with real-time results

The microscope is a mainstay in medicine, but it has its limitations. It can’t go where the disease is, and that’s frustrating for doctors such as Michael Klein, surgeon-in-chief at the Detroit Medical Center’s Children’s Hospital of Michigan, especially when operating on cancer patients. During an operation, they must wait 20 minutes for a pathologist to spot-check cells at the edges of excised tissue to see if doctors removed the entire tumor — and even that’s no guarantee. Doctors must then wait another 12 to 24 hours for the pathologist to finish a more thorough analysis that may show some cancer remained, necessitating a second operation. But nothing is ever 100 percent certain; cells that look normal under a microscope may be undergoing biochemical changes that presage disease.

“The pathologist can only tell you what’s in front of him,” Klein says. “He can’t tell you what’s in the patient.”

 

A team of engineers and scientists at Wayne State has paired up with doctors at Children’s Hospital to develop a biopsy device that allows surgeons to test patients’ tissue during operations and get results in real time. The probe uses Raman spectroscopy, which is usually the domain of chemists and physicists, to distinguish between healthy and cancerous cells. They also hope to create a fiber-sized version of the probe to perform minimally invasive biopsies as diagnostic follow-ups to surgery.

Klein credits Gregory Auner, an engineer at Wayne State and director of the university’s Smart Sensors and Integrated Microsystems program, with the idea of integrating Raman technology with cancer detection. Raman relies on the distinctive signals that molecules scatter back when they’re exposed to light. Auner reasoned that cancerous tissue would send different signals from healthy tissue. Starting around 2000, they began testing Raman technology to see if they could distinguish between, say, a pig liver and a human liver. Once they were sure it worked, Klein and Auner began building a data bank of various cancerous versus healthy tissues. They refined the process to distinguish between benign and malignant tumor cells, as well.

“[Cancer] cells need energy in order to replicate, and they generate more of certain proteins, and those protein interactions between each other are physically and mechanically different,” Auner says. “With Raman, we can determine not only that range of protein to lipids, which is one of the key indicators [of cancer], but we can also look at how the membrane changes with the interaction of proteins. It physically gets harder, and that shows in shifts in the Raman signals.”

For the last three years, they’ve conducted validation trials in the operating room, testing the probe on biopsied tumors. Doctors used the probe to determine whether the tissue was cancerous or not. The sample was then sent for analysis to a pathologist, who was not told the initial results. The probe proved to be highly accurate.

“Raman does a wonderful job,” Klein says. It takes only two minutes to get results, he says, and the findings may include subtleties that are undetectable by a microscope.

“There’s the impression that it sees differences in tissues that you don’t see under the microscope,” such as the biochemical machinations of a normal cell shifting toward a cancerous state.

The probe has yet to begin clinical trials, but Auner anticipates that, because the device uses materials that have already been approved by the Food and Drug Administration, they’ll be able to skip Phase 1 safety tests. A medical-device manufacturer is interested in the technology, but Auner wouldn’t specify whom. Auner and Klein expect the probe will augment rather than replace pathologists.

“What we want to do is make that cutting-edge new technology and bring it into the surgical field — and medicine in general,” Auner says. “It’s another tool to use.”

A better way to make drugs

The drug discovery process puts major dents in the pocketbook. The pharmaceutical industry spends $21 billion a year on research and development in an effort to get new drugs in the marketplace, and then often passes the tab on to “Joe and Jill” Consumer. In 2007, pharmaceutical drug sales reached $286.5 billion in the United States, according to industry tracker IMS Health, and they’re on track to set the bar even higher this year. One reason drug prices are so high, manufacturers argue, is industry’s need to recoup the cost of research and development.

Chemists at Michigan State and the startup they co-founded may ease the pain with a patented method of making drugs that could save time, money, and, yes, even the environment. Their Novi-based company, BoroPharm, holds exclusive licensing rights to a catalytic process invented by Milton Smith III and Robert Maleczka that reduces the number of steps needed to make the core structures in drugs. The researchers received a $1.4 million 21st Century Jobs Fund Award in 2006 to refine the technology and market their chemical compounds. BoroPharm is positioning itself to cash in not only on the research side of drug development, but also on the production side of drug manufacturing.

 

Creating a new drug is often a painstaking process akin to building an intricate 3-D sculpture, with chemical core structures as the foundation. Smith likens the cores to spools in a Tinker Toy set. The ideal core structure offers numerous reactive sites — think of the holes on the Tinker Toy spool — where other chemical compounds bind. Those compounds may serve as a peg on which another chemical group can attach or be substituted. The final product may be a complex construction that meets the varied needs of drugmakers — needs that sometimes include biological challenges such as timed release in the body, as well as commercial requirements such as a long shelf life.
The MSU researchers found a more efficient way to produce cores that are also more versatile; in other words, they use less material and less energy to make more spools that have more holes. Instead of working in wood or plastic, though, they focus on boron compounds. In 1999, Smith discovered a catalytic method that eliminated some steps needed to create boron-carbon bonds, drug designers’ building block of choice. The catalyst was “initially terrible,” Smith says, unsuitable for any practical application, but after years of tweaking it, his group improved its efficiency by more than a thousand-fold. In 2003, Smith and Maleczka invented a “one-pot” approach that made more cores with many binding sites, and that required less energy and produced less waste than traditional methods. MSU licensed the technology to BoroPharm in 2006, and the researchers received a $100,000 “green chemistry” award from the American Chemical Society in 2007 for their invention.

“Every time you make a reaction,” Smith says, “it takes energy and creates waste, [and] some byproducts can be environmentally bad. We didn’t get rid of all the waste, but [we eliminated] what generally is more problematic.”

Todd Zahn, acting CEO of Boro-Pharm, says the company serves pharmaceutical, agro-technology, and chemical supply companies across the world. While BoroPharm is working with drug-discovery and drug-development scientists, it also sees opportunity in drug manufacturing as a less expensive and more environmentally friendly substitute for existing boron-based compounds.

“Our competitors use traditional methods to make them,” Zahn says. “Ours is more efficient. We can compete on cost and produce compounds that other people can’t produce. … It’s green chemistry. We’re not creating the magnitude of waste as others.”

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