BCRF sat down with Lewis C. Cantley to discuss his current work and interest in breast cancer research. Read on to learn more.
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?
A: My first love was chemistry, so I did my doctorate in Physical Chemistry at Cornell University. But once I started doing research, I realized that all the excitement surrounded biology, because biology is chemistry in action. I went from trying to understand how cells make an energy source called ATP, to how cells regulate the uptake of molecules like glucose or sodium or potassium, which then led me to signaling pathways, and then to cancer research and biology.
In the course of this work, I discovered an enzymatic activity that led to tumor formation in laboratory models. The chemical reaction carried out by this enzyme (called PI3-kinase, or PI3K) had not been found before in nature so this discovery opened up a new field of cancer research. The signaling network controlled by PI3K is complex and akin the complex wiring diagram of your computer or radio. We have been chasing down all the wires (i.e. signaling pathways) going in all directions inside the cell that are controlled by PI3K in order to understand how it causes cancer and how best to intervene with drugs. It turns out that the PI3K signaling network is the most mutated in breast cancers and is commonly mutated in the majority of other cancers. More recently, we began to focus much of our research towards drugs that target PI3K, some of which are now going to clinical trials.
Currently, there are roughly 20 PI3K inhibitors in clinical trials. This has set a record for a drug target where no drug has yet been approved but almost every pharmaceutical company simultaneously has at least one drug in the clinic that targets PI3K. The reason is that PI3K is the most mutated pathway in all cancers. Yet, it is also clear from early studies that this is not going to be simple. So the responses being observed in early-phase clinical trials have everyone very excited, but it is still not clear how to identify the patients who are most likely to respond.
Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?
A: BCRF is helping us with preclinical studies that predict the biomarkers likely to tell us which patients are going to respond to the novel PI3K inhibitors and how to use these drugs. We are collaborating with two different labs: Gerburg Wulf at Beth Israel Deaconness and Charles Sawyers at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Wulf and I are giving drugs to laboratory models that are genetically engineered to have the same mutations that we commonly find in human breast cancer. We are trying to figure out which mutations generate tumors that respond to PI3K inhibitors as single drugs and which require that we combine PI3K inhibitors with other drugs. Dr. Sawyers and I have several grants together, including one on prostate cancer, which is another disease with many mutations in the PI3K pathway. In the case of prostate cancer, the mutations are more frequently in an enzyme called PTEN, which is a braking system to PI3K.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advances can help to enhance your progress?
A: What we are doing today could not possibly have been done ten or even five years ago. First and foremost is our ability to sequence the human genome, which now has become cost-effective enough to identify mutational events that occur in genes and cancer genes in every patient. Decoding the genetic mutations of patients allows us to predict who is likely to benefit or not on standard of care and who should be in what clinical trial. In some cases, drugs that have been approved for other cancers might be appropriate for a patient. This is an example of personalized cancer in a very accurate and detailed way.
Breast cancer has really led the way in personalized therapy. Breast cancers have been divided into subsets (estrogen receptor positive [ER+], HER2+, triple negative) and distinct therapies have been developed for each subset, rather than treating all patients in the same way. This really is the reason why so much progress has been made in this disease. But we need to further divide the disease into additional subsets, and genomic sequencing technology is making that feasible.
Another type of technology that has helped us to tease out which drugs are likely to work in which particular mutational background is the engineering of laboratory models that mimic the exact same types of cancers seen in the clinic. This advance has made it possible for us to do what we call "co-clinical trials" in the lab. It saves people from going on inappropriate trials. We want every patient going on a trial to either benefit from the trial or at least to teach us something if the treatment does not demonstrate benefit.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: Every cancer patient will eventually be analyzed for all mutations in the oncogenes and tumor suppressor genes that s/he has. This analysis will help determine which drugs are likely to work for the individual. Because there will be circumstances where an unexpected form of mechanism of resistance to therapy will come about, I envision that we will develop self-learning computer programs that are able to suggest drug combinations based on the individual's set of mutations. The patient will go on this regimen, and then there will be a follow-up to see whether a patient is responding to that therapy. At that point, if it is clear that the patient is not benefiting from treatment, then the computer can generate a second choice, and one could then go in with that therapy very quickly. This way, we do not spend months on therapies that are unlikely to work and can switch to a new one as quickly as possible. The successes and failures will then be fed back into the computer, allowing it to be smarter in predicting the correct therapy for the next set of patients.
Q: What other projects are you currently working on?
A: My laboratory is mainly focusing on cancers with aberrations in the PI3K pathway. We have an NCI funded P01 grant in prostate cancer with collaborators at Beth Israel Deaconess, Dana-Farber Cancer Institute, and MSKCC. We are also participating in P01 and SPORE grants in the area of colorectal cancer, lung cancer, melanoma, and pancreatic cancer, and a Stand Up To Cancer grant in the area of breast, endometrial, and ovarian cancers. These are all cancers where we know that the PI3K pathway plays an important role, yet they are all somewhat different: in some cases it may be mutations in PTEN; in others, mutations in PI3K are turned on by mutations in EGFR or HER2 or KRAS. Hence, they are unlikely to respond to the same drugs. By generating laboratory models, we can figure out ultimately what drug combinations are more likely to work.
Q: How close are we to preventing and curing all forms of breast cancer?
A: It is very exciting how much progress has been made in breast cancer over the last 15 years. The progress is coming from novel targeted therapies and figuring out how to use them at the right stage. For example, trastuzumab (Herceptin®) was originally approved for end-stage disease and demonstrated a rather minor effect, extending life by 3-4 months. But then, it became clear that by prescribing it to patients in the adjuvant (post-surgery) setting for a year, recurrence rates in patients would begin dropping dramatically. Now that took years to figure out because recurrence might take five years, so you have to look over seven years or so years to determine whether the subset who were taking this drug had a lower rate of recurrence. That process is too long. Analyzing the patients' genes, we can get the right drugs to the right patients earlier.
Also, these targeted therapies, as opposed to systemic ones such as radiation or chemotherapy, cause fewer side effects. These very aggressive chemotherapies and radiation treatments can themselves turn on new cancers, and so the hope is that these targeted therapies will not have the secondary damaging effects of chemotherapies and radiation therapy that can actually initiate new cancers. But we have to figure out which ones are going to be effective in these adjuvant therapies. At the end, that is I think where we will have the impact.
Another challenge is that, although we have a rationale for adjuvant therapies and drug combinations in ER+ and HER2+ breast cancers, we have not made as much progress in triple negative disease. It is more difficult to figure out what the best targets for drugs are in triple negative breast cancer than the other subtypes. But we have initiated some very exciting trials that could be very promising in triple negative setting, and they again use PI3K inhibitors in combination with a second drug.
I do not want to say that we are going to cure all cancers or all breast cancers, but I think that the odds of recurrence after surgery are going to drop precipitously over the next ten years as we figure out how to use drugs better in the adjuvant setting, and that is where we are going to see an impact.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: I like to think of our efforts in cancer research as comparable to our efforts in going to the moon. If we had decided to go to the moon in 1930, we would have had no prayer of achieving it, because nobody had figured out the physics yet or had rockets or jet propulsion systems. We did not know what would be required. By 1960, we knew exactly how to achieve going to the moon, and it became a matter of engineering to make it happen. I think we are at the same position right now in cancer where we do not yet know everything, but we know what we should be doing. There is a logical approach we can take. Every clinical trial should be scientifically designed so that you learn something from your failures as much as from your successes. And what BCRF has done for us at this time, when we really know efficiently how we should be spending our money, is providing it to us at a time when the National Cancer Institute is reducing funding. The real dollars we have from the NCI to do research right now are less than what we had ten years ago. And that never happened before, in real dollars where actually we have less to work with, at the time when we know how to use the money correctly. For BCRF to step up and help fill that gap and move us forward at a time when we most know how to use that money is just fantastic.
Read more about Dr. Cantley's current research project funded by BCRF.