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Q&A: Boyd Discusses How Fox Chase Plans to 'Operationalize' Personalized Medicine

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Boyd.NEW_.jpgFox Chase Cancer Center recently launched the Institute for Personalized Medicine, aiming to advance the development of genetically targeted cancer treatments.

The IPM seeks to "match emerging targeted drug therapies to the unique genetic profiles of individual patient tumors on a much larger scale than previously possible," Fox Chase Cancer Center said in a statement announcing the launch of this effort earlier this month.

With access to a large biosample repository and tumor bank, the IPM will help pharmaceutical companies generate Phase I clinical trial data that a particular drug is effective and non-toxic in genetic subpopulations of cancer patients.

"The IPM will more accurately determine which patients should be enrolled into the clinical trial, and this could significantly impact on the overall success of the trial," Fox Chase said in the statement.

Outside of the IPM, personalized cancer treatments appear to be a research focus at Fox Chase. At the American Society of Clinical Oncology's annual meeting earlier this month, Fox Chase announced that its researchers had uncovered a gene signature that predicts how patients with gastrointestinal stromal tumors may response to the drug Gleevec and had identified a genetic marker associated with earlier onset of prostate cancer in Caucasian men with a family history of the disease.

The focus at IPM will be on partnering with pharmas to advance personalized drug discoveries in the clinic. As the institute gets up and running in the next few months, Fox Chase researchers will be working on a proof-of-concept project to show industry partners that it can conduct a pharmacogenetic clinical trial for an investigational drug efficiently and cost-effectively.

Earlier this month, Jeff Boyd, Fox Chase's chief scientific officer, discussed with Pharmacogenomics Reporter how Fox Chase plans to "operationalize" personalized medicine with this new institute.

Below is an edited transcript of the interview.


Why start the institute at this time?

I think it's fair to say that decades of experience in both cancer research and cancer medicine tell us that no two cancers are alike … Let's pick colon cancer. Some colon cancers respond well to therapy, while others, seemingly identical at the clinical and pathologic level, don't respond at all. You can see that across the spectrum of human tumors. One reason for this discrepancy, especially in solid tumor cancers, is the accumulation of particular sets of mutations in many genes, and these aberrant pathways within in a cell differ in the tumors from individual patients …

We have now two areas of inquiry and scientific endeavor that have converged, that give us a lot more power than we had 10 years ago. One is information. We have the entire human genome at our fingertips … and every day that passes we're learning more and more about that genome and how that genome is impacted in a human cancer type. The other tool we have at our disposal is technology. We have the ability to mine that genome, to sequence it, to explore it, and to manipulate it with an extraordinarily powerful technology that didn't exist a few years ago, in the non-profit sector at an increasingly reduced price … We're to the point where it's entirely reasonable to say that in five years we can sequence your or my genome for $1,000 in a few days.

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We have this convergence of information and technology that makes it possible to explore the genome of a tumor in all its complexity … That is sort of the underlying rationale for why this is the perfect time to be launching an Institute for Personalized Medicine. Ten years from now this type of thing will become common in most high-end academic medical centers and freestanding cancer centers. Fifteen years to 20 years from now this will be common in the community.

Now is the time for the leading academic cancer centers to not be posturing about personalized medicine but actually be rolling it out. People think and talk about personalized medicine in different ways. What we mean here, is that we intend to leverage academic and biopharmaceutical partnerships to operationalize personalized medicine. So, basically, quit talking about it in theory and operationalize it.

How are you going to do that?

Let's take big bio-pharmaceutical Company X and [pretend] they have a lead compound that looks very promising, either a small molecule or an antibody. They tell us they think that it recognizes abnormalities in a handful of genes in a particular pathway. They have discovered this and they don’t need any help from us in doing that because they have very smart PhDs and lots of money to get to that point, to bring lead compounds to market.

What we at Fox Chase, as a medium sized and very nimble institution, have to offer is an extraordinarily large and well-annotated biorepository with tumor samples along with corresponding normal tissue from tens of thousands of cancer patients frozen away. So, the idea would be in the Institute for Personalized Medicine — which will have a director and a staff — to use this next-generation sequencing technology that would allow us to mine the genomes of these tissue specimens for relatively small amounts of money and relatively short periods of time. We will explore, for example, 1,000 tumors for the 100 most common cancers. After having sequenced the relevant genes or pathways that correspond to this hypothetical Drug X in 1,000 cancers, we'll find maybe 100 that have mutations somewhere in this pathway. Whatever [the site of the tumors], since they are very well coded and informed consent [has] already [been] obtained from patients, it will be possible to link those tumors to human beings. Some of these patients will still be alive with recurrent disease, being managed over a period of years with second- and third-line therapies.

If we identify 100 tumors out of a screen for 1,000 that have the relevant mutated genes or pathways, let's say 50 of those patients are alive with recurrent disease, we can bring those patients in. The other thing we have to leverage at Fox Chase … is our Phase I clinical trial program … We would take these 50 individuals, who would be expected to respond to this drug … That will give us a very good sense right off the bat, rather than the 0 percent to 15 percent response rate that you typically see with a drug, we might see a 90 percent response rate if the patients were pre-selected …

At this point, we have shown in a proof-of-concept study that this drug is effective in this subclass of patients regardless of the tumor type, but we're looking at the molecular genetics now as the defining characteristic of the tumor rather than the site of origin. … So then the Drug X is ideally suited for [cancer] patients with aberrations in pathway Y. That's the essence of personalized medicine. And that's how we're going to reach the next level in treating advanced cancers.

There were these incremental advances that you heard about in the ASCO [annual meeting], for example, where we saw different combinations of drugs changing survival from six months to seven-and-a-half months. These aren't the advances we're looking for. We're looking for making progress at a rate that is more rapid and more substantial than the public is used to seeing and the medical field is used to seeing.

You presented several abstracts on personalized cancer treatments at ASCO this year. Are these the first projects under IPM?

The first thing we have to do is convince these bio-pharmaceutical companies with these potentially fantastic new drugs that we are a good partner. The way to do that is to do some sort of proof-of-principle project where you essentially target a particular pathway and a particular tumor type and provide direct evidence that, yes, we can rifle through 100 ovarian cancers and look at 10 genes involved in a particular pathway that is relevant to ovarian cancer and can identify the mutations efficiently. That's going to be our first task as we get up and running in the next few months.

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We have had a number of potential pharmaceutical partners come through the center and [express] interest in partnering with us, but they've asked to see that this Institute for Personalized Medicine is real, actually works, and its more than just interviews in the press. Although our peers, the Sloan-Ketterings the MD Andersons are all moving in this direction, we have to show we're already there. That's one advantage we have as a freestanding cancer center — not existing in a large matrix medical center — is that we do have a fairly small leadership team and we are quite nimble with respect to being able to imagine and operationalize an Institute for Personalized Medicine over a period of months.

In making the case to pharma that Drug X works in a subpopulation in a Phase I trial, there are still regulatory hurdles to bringing that drug to market, pharma might need to do larger, prospective, randomized studies that are more expensive. Won't the existing regulatory infrastructure still pose a barrier to developing these industry partnerships?

There is no getting around Phase I trials. The primary point of a Phase I trial is to look at toxicity, not response. If you have 40 patients in a Phase I trial to assess toxicity with a particular drug, and 38 patients just happen to have a complete response to it and it's also non-toxic, then you're going to be moving very quickly to a Phase II trial.

There is no getting around the current regulatory framework for going from laboratory to patient. What we can do with an Institute for Personalized Medicine is to make that process a more rapid one. If the [US Food and Drug Administration] sees that not only is a drug non-toxic, but you're seeing a very high response rate in a selected patient population, one can certainly hope that we can speed this process up some.

Will you be generating IP at the institute and seeking pharma partners, or do you expect pharmas will bring the projects to you?

Certainly we are willing to engage any academic partners. But let's face it, new blockbuster drugs are rare but this is what pharmaceutical companies put millions of dollars into. Most of the drug candidates will be coming from industry. But we're certainly willing to partner with any second party, whether it be academic or for-profit. The end is important more than the means. The reality is that this is what drug companies do, create new drugs. And I'm certain that's where most of our partnerships will be.

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You mentioned you'd be using sequencing technology at the institute. Have you decided on a particular technology?

That would probably end up as an advertisement and I'd prefer not to go there. There are several companies that make very powerful and adequate instruments for doing deep-sequencing into the human genome rapidly and cheaply. The decision will be based on what other things we want to do with this $800,000 instrument. But there are several companies that make instruments … that can get the job done in this context.

Have you done an estimate of how much it might cost per patient that you plan to sequence for specific tumor genes?

We will not be sequencing the entire genome for patients at the IPM. That's an important point … We'll be sequencing a very small fraction of the human genome in these particular cases. So, we're talking about a few thousand dollars per patient at this point.

How is the IPM being funded?

It's being funded by our own operating budget. It's a $2 million line item in our FY 2010 budget, which begins July 1.

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