In this interview we discuss advances in whole-genome analyses, as well as novel blood-based assays in development to help diagnose and follow cancer patients through their treatment.
Today we are discussing advances in whole-genome analyses, as well as novel blood-based assays in development to help diagnose and follow cancer patients through their treatment. We are speaking with Kenneth Kinzler, PhD, professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine in Baltimore. Professor Kinzler studies the molecular genetics of cancer and has developed whole-genome approaches to analyze expression changes and a range of different types of mutations in human cancers, including colorectal, breast, pancreatic, and brain cancers.
-Interviewed by Anna Azvolinsky, PhD
Cancer Network: There have been whole-genome analyses, both transcription levels and genetic analyses, to look for mutations and changes in expression for a range of different tumor types. Broadly, what can we learn from these studies, what have we learned, and what are some of the applications of this research?
Dr. Kinzler: Sure. It’s actually quite an amazing time in terms of cancer research. We really know that at its essence, cancer is a genetic disease; it is a defect in our genetic code that instructs our cells how to behave. When that code is damaged, the cells can misbehave and become cancer. We are the first generation in the history of the human race to know the sequence of our genetic instructions. We now have the technology to assay these genetic instructions relatively quickly. We can define the damage that occurs in a cancer cell that allows it to become cancerous. This is quite useful because it provides us with insight into what went wrong and how we may be able to tackle cancer. This also gives us markers that specifically identify cancer cells.
Cancer Network: The whole-genome analyses that have been done so far have focused mostly on primary tumor tissue, but now there is much more interest in sequencing metastatic tumors. Could you talk about that and what we can learn from each type of sample?
Dr. Kinzler: Yes. There has been a variety of strategies to look at cancers. Some have focused on looking at the primary tumor. Our particular studies actually initially focused on metastatic cancers, with the rationale that cancers had acquired all of the genetic changes necessary to kill a patient. We could use that analysis to then look back and see if there are differences between the advanced tumor sample and the primary tumor that has not metastasized yet.
Cancer Network: Could you give one or two examples in which these types of analyses have led to either a clinical biomarker that is used now or the development of a targeted agent?
Dr. Kinzler: This type of genetic analysis, the identification of mutated genes in human cancers, has been going on for several decades. The poster child for what we hope will be the outcome is imatinib, a kinase inhibitor commonly known as Gleevec. It has been shown to be quite useful in treating chronic myeloid leukemia (CML) because it inhibits the mutated protein that results from the mutated gene in CML. The drug also works in GIST, which is gastrointestinal stromal tumor, where it inhibits the product of the mutated KIT gene. This is sort of the poster child for where a drug is designed specifically to inhibit a mutant pathway in a cancer. The revolution is that we have moved from looking at one gene at a time several decades ago to now, when we can look at all of the genes in the human genome. And that has only been going on for about the last 5 years. We don’t see drugs for the mutations we have identified yet, but one of the best examples of a promising lead is the gene IDH1, which is mutated in gliomas. This gene is actively being targeted to develop therapies against, and there are many more. But it will take time to see the results of this genomic revolution.
Cancer Network: Switching to some of the blood-based assays, it has become clear over the last decade or so that sampling and analyzing a cancer patient’s blood can provide insight into their disease. What are the types of molecules that researchers can now detect and to what end?
Dr. Kinzler: Previously I talked about how mutated genes can be targeted by therapies and that is the hope for therapeutic interventions. But these same genes are released by tumor cells and can be detected in plasma; for example, in a Pap smear fluid and in urine. These mutated genes that are released from the tumor cells are like the tumor’s fingerprints. They are very specific and they allow us to begin to think about using these readouts to manage patients. What we would like to do, for example, and the ultimate goal really, is to use this for screening cancer genes in plasma. We could find the cancer even before the patient had symptoms and when a surgeon could cure a patient of the cancer. That is a screening application. Another application is, after a tumor has been removed, we can assay for these mutated genes, specific to the tumor, and make sure the tumor is not coming back. After therapy, we can look at these mutated genes in the blood to see if the tumor is responding to treatment. This class of cases in which we detect the mutated genes is really a biomarker. And this type of biomarker is attractive relative to other biomarkers because it is relatively specific for the cancer and it is related to cancer development.
Cancer Network: How long do you think before this technology is really developed and translated into the clinic and used generally by the spectrum of oncologists?
Dr. Kinzler: In fact, some of these are already being actively translated. There are assays that look for the presence of colon cancer by looking for mutant genes in the stool. Pharmaceutical companies are now looking for mutations as part of clinical trials testing targeted agents, and there are some commercial companies trying to translate these assays to the clinic.
Cancer Network: What do we know about circulating tumor DNA that is released from tumor cells? At what cancer stage can they be detected and how abundant are they?
Dr. Kinzler: We have learned a lot over the last few years about how this released tumor DNA will behave and how we can use it as a biomarker. First, we know that not every tumor releases its DNA into the blood. We know that the majority of advanced tumors, ones that have metastasized, do release their DNA into the blood. For many of the common human cancers, one half of the early-stage cancers, the types that have not yet metastasized, release DNA and we can detect this. Benign disease, which is not yet life-threatening, generally rarely releases its DNA into the blood. So one could take a glass half empty or glass half full approach. With half of the early-stage tumors able to be detected and most late-stage tumors able to be detected, we hope that looking in the blood of a patient is useful. The patient could get a simple blood test to detect mutated DNA that is indicative of a tumor and if we can use this to detect cancer earlier, that can improve outcomes.
Cancer Network: How do you see circulating tumor DNA assays being translated into the clinic? Is there a specific function that you discussed that this type of assay would work better for?
Dr. Kinzler: Yes. The circulating tumor DNA will first translate into the clinic in situations where you would want to monitor a patient who has an existing cancer. That is easier to do now, and it is also easier to demonstrate the value of this. We want to make sure that anything we introduce into the clinic is of good value, because we want it to be cost-effective and careful of our resources. Monitoring patients is probably going to be the earliest adopted application of this technology.
Cancer Network: Lastly, how do the circulating tumor DNA assays compare with the assays that detect circulating tumor cells?
Dr. Kinzler: In the studies that we have done and the cases we have looked at, circulating tumor cells are not the source of the circulating tumor DNA. Tumor DNA is distinct, and there are two potential sources of the tumor DNA in the blood. One is from tumor cells, and one is from cell-free DNA that was released by dead or dying tumor cells. When we have studied this, there is much more cell-free circulating DNA than tumor cells. It seems to be that circulating tumor DNA may be a much more sensitive assay.
Cancer Network: Thank you so much for joining us today, Dr. Kinzler.
Dr. Kinzler is a consultant for Sysmex Inostics and a cofounder of Personal Genome Diagnostics, companies focused on genetic analyses of cancer. Dr. Kinzler is also entitled to a share of royalty and milestone payments received by Johns Hopkins University on sales of products related to research described in this podcast. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies.