From Bench to Bedside

Translational medicine is all about connecting basic research to patient care – linking discoveries made in the laboratory more directly to the patient. The key to achieving this, says Dom Spinella, Senior Director of Translational Medicine at Pfizer, is communication. “We need to ensure that discovery teams understand what’s necessary in the clinic and that clinical teams communicate that to discovery,” he says. “It’s about unifying the discovery and clinical segments, and one way to improve that is to have representatives from both lines on the project teams from the earliest phases of the preclinical discovery process. That’s what we try to do at Pfizer.

“My translational medicine group provides guidance to the discovery teams on what is needed in the clinic, which is not just the drug in question but also a means to quickly ascertain whether the drug is hitting its intended target and displaying its intended pharmacology at a safe and tolerated dose. If we don’t have both the drug and the means of evaluating it – in other words, a biomarker – it’s not going to go forward smoothly. The teams are beginning to understand that and deliver those biomarkers along with the drug.”

Spinella also feels that in discovery, oncology needs to get away from the standard subcutaneous xenograft models that employ tumor cell lines, such as the NCI 60 panel. “We are moving towards using primary patient tumor xenografts in orthotopic sites and transgenic models that we think are likely to be more predictive of efficacy in real patients.

“However, I would not disparage the standard models as much as they have been. They’re not so predictive in a positive sense, but in a negative sense I think they’re quite predictive – if a drug doesn’t work in these models, it is very unlikely to work in a patient. So they are at least useful as preliminary screening tools.

Opportunities and challenges

Spinella points out that there have been many exciting recent developments in translational medicine. Technology is continually evolving, and there are novel methodologies emerging for doing mutational analysis and proteomics, and methodologies that allow scientists to carry out the kind of research they need more quickly. Spinella believes this can make a real difference. “If you can get an answer quickly, you’re more likely to go after it; whereas if it’s a slow, tedious process, you’re more likely to rely on empirical clinical data: ‘Let’s just try it and see what happens.’ But if you can get a quick answer based on new technology, you’ll employ it.”

On the other hand, there are also challenges, particularly on the regulatory side: “I don’t think the regulatory authorities are really following their own critical path initiative. We keep talking about drug development based on biomarkers and on surrogate endpoints, but it practically takes an act of God to get even a conditional approval for a drug based on those kinds of endpoints.”

Spinella believes that part of the problem is that regulatory authorities are reflecting public concern about drug toxicity. The unintended downside of this is that more patients may be suffering and even dying for lack of access to drugs that might help them than would have suffered from unexpected toxicities. He says that when it comes to drugs, risk and benefit are two sides of the same coin and the pendulum may have swung too far toward avoiding toxicities at all costs, even in the face of substantial benefits.

“We don’t always know or can’t always predict, biomarkers not withstanding, which patients are going to experience drug adverse events. It’s the same way with vaccines, if you think about it. The occasional patient is going to have an adverse event from vaccines, even to the point of lethality, but it doesn’t mean vaccinations should be eliminated. The risk/benefit equation is still positive in favor of vaccination and more people are going to be suffering life-threatening diseases without vaccines than would ever suffer untoward events.

“We’ve wiped out smallpox, of course, but there are many other diseases for which vaccines have proved to be a major benefit, even though there are occasional patients who suffer serious side effects. The same is true of many therapeutics: the net public health benefit exceeds the risk, but in our zeal to eliminate risk, the public doesn’t always understand that.”

Another important issue in Oncology is effective use ofdrug combinations and sequencing. “Everyone initially develops these new targeted agents as individual therapies, but in the clinic they’re never used that way,” Spinella underlines. “So, for example, one can envision cytostatic agents inducing tumor growth arrest, followed by a ‘drug holiday’ that synchronizes the tumor into a burst of proliferation. Perhaps that’s the time to hit them with a cytotoxic agent that knocks out the vast majority of tumor cells that have been pushed into the cell cycle by withdrawal of the cytostatic therapy. Much more work could be done in the preclinical space to explore the best way to combine and sequence cancer drugs.

Can many of the cytotoxic effects that limit the utility of these agents be circumvented by drug holidays or intermittent exposures: expose for a week, then a week off? Do we need continuous dosing? We always think we do, but then again, we often don’t test various regimens and sequences to see whether or not we could produce the same disease-altering effects and take some of the toxicities out of the equation. That needs to be explored more.”

Exciting developments

In Spinella’s opinion, we are coming to a point in oncology where the drugs that are currently in big pharma and biotech pipelines, as well as currently marketed agents, may have the answer for cancer. “There are so many exciting new drugs and targets in various stages of R&D across the industry. It’s now becoming a question of how we use these drugs in combination, how we sequence them, and how we dose them effectively. The existing anti-cancer pharmacoepia may be very close to being able to contain most cancers in the same way we have contained HIV.

“However, there needs to be a bit of a paradigm shift on the part of pharma and biotech to say, ‘All right, let’s stop worrying about the next target all the time and focus a bit more on understanding our existing drugs and how we utilize them in combination with other drugs – chemotherapeutics and targeted agents – and try to hit multiple oncogenic pathways at the same time.’

“A big problem in oncology is that eventually tumors acquire resistance to whatever agents they’re being exposed to. It’s just natural selection on a small scale. Tumors are already genetically unstable and all it takes is a few cells to acquire a mutation that confers resistance to an initially effective drug. Those will grow out to form a resistant tumor.

“However, if we can beat up the tumor early, simultaneously attacking different pathways that tumors use as drug resistance mechanisms, perhaps we can eliminate those mutants and wipe out the whole tumor so that resistance isn’t an issue. If we can do that while keeping the toxicities manageable, we may be able to control this disease. But these targets and pathways also play their roles in normal cells and tissues, so toxicity will never be completely eliminated. It all comes down to that risk/benefit equation. Still, we may be getting close to this, and I find that very exciting.”

About Dominic Spinella

Dominic is Senior Director, and Head of Oncology Translational Medicine, at Pfizer. He leads the clinical biomarker work for the company’s oncology portfolio and serves on several national and international cancer biomarker development bodies.