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Medelis: From the sounds of it, perhaps context of vulnerability should be the first vital sign — something you think about right from the outset.
Dr. Von Hoff: That would be ideal, but it can be challenging to implement because of the reality of treatment.
Here’s an example. It’s 4:30 on a Friday afternoon and you’re the only partner left in the office. Your last patient of the day arrives - a thirty-year-old man with a gigantic tumor in his abdomen. His pathology indicates a rare tumor, a myxoid liposarcoma. The NCNN guidelines say, “Treat the patient with Adriamycin® or Adriamycin® plus ifosfamide.”
You check the five vital signs and then you remember some doc saying something about checking the sixth vital sign. By this point, it’s now 6:00 PM and the easiest thing to do would be to have the patient return on Monday to implement the NCNN guidelines. But instead, you start thinking about the sixth vital sign — “Is there anything special about this patient and this tumor? Anything about the genetics or pathology?”
Sure enough, a recent article in The Lancet showed a drug called ecteinascidin-743 (ET-743) resulted in dramatic responses in over 50% of patients with myxoid liposarcoma because they have translocations involving chromosomes 12 and 16. So you send his tumor for a 12, 16 translocation analysis and get busy trying to secure ET-743 for this man.
That’s great care, and if you aren’t matching the context of vulnerability to available therapeutics, you aren’t doing the best you can for your patients. It takes more time and thinking but you’re doing the best thing for your patient and for new agent development.
Medelis: Is it further complicated by the fact that there may be more than one context of vulnerability?
Dr. Von Hoff: Yes. The rare tumors appear to have just a single vulnerability that you can exploit. But with the more common solid tumors, it takes longer to find out what the multiple contexts, or pathways, are because there are so many backup systems.
Medelis: What is the potential for context of vulnerability to dramatically transform oncology therapy in the immediate future? Or are we still limited by the lack of genetic information about the targets themselves?
Dr. Von Hoff: That’s a limiting factor, but all the work that Dr. Mousses is doing with Pharma teams is starting to yield results, and clinical trials are just starting.
Medelis: Context of vulnerability is another way of saying mechanism of action. Often though, a CMO is putting a drug into development without knowing how or why it works.
Dr. Von Hoff: That’s why you try to get more of a patient mix and observe closely for the sixth vital sign during the phase I trial. The science is at a point where it’s not purely empiric.
There’s almost always some hint in the phase I. If I get a response during the trial, I have learned to ask incessantly, “Why that specific person? Is it because they have, for example, mesothelioma? Is it because they have mesothelioma with a certain genetic mutation?”
At that point, you start lining up animal models with different mesotheliomas and then test your drug, looking for the specific genetic lesion that explains the response you saw in some patients.
It seems obvious in some ways, but it’s not the usual approach. Most people perform a phase I trial just to get through it. They take a dose and run with it without probing the hints of activity.
Medelis: Do we currently have adequate therapeutics for the different contexts of vulnerability that could potentially exist?
Dr. Von Hoff: No, not even close. It will probably take about five years to get enough therapeutics to address the known contexts of vulnerability. There are about 400 new therapeutics available now and probably 150 known targets, and there is a high degree of mismatch between those. We only have a rudimentary understanding of how these anticancer agents work.
Medelis: What’s the focus of your research now, in regards to context of vulnerability?
Dr. Von Hoff: Dr. Mousses is looking at siRNA, trying to establish which genotype increases tumor sensitivity. I am concentrating on pancreatic cancer, trying to determine which patient population would be responsive to various agents such as an aurora kinase inhibitor.
Medelis: Context of vulnerability flips the drug development paradigm; you know what you’re targeting, you just need to find the agent, the arrow. How can CMOs orient their thinking to accommodate this new approach?
Dr. Von Hoff: No matter how you cut it, the data always counts. The CMO’s job is to help identify the context of vulnerability through careful analysis of the preclinical data and observation of patients. It is then the clinician’s responsibility to match drugs to contexts of vulnerability.
This where the translational investigator comes in — the M.D., Ph.D. or M.D. with laboratory experience who is steeped in the preclinical milieu and will not stop asking “why?” They’re in big demand now because they can dramatically shorten development time. They can also make a watertight argument for reimbursement — insurers will pay if it works.
Medelis: Are targeted therapeutics the future of oncology?
Dr. Von Hoff: I think that every drug we have is targeted and that it’s only a matter of time before the target is found for a drug a CMO may have under development.
Adriamycin, a powerful cytotoxic, is a good example. It was used across the board until it was discovered that it works through topoisomerase II. Studies show that if a woman’s tumor does not possess topoisomerase II, there is no point to using Adriamycin. In the case of basal cell carcinoma, we showed that patients who had mutations in the PATCHED gene would have a high response rate.
Targeted therapeutics are catching on first in the rare tumors because they don’t have as much genetic diversification as the more common solid tumors. However, an important story emerging now is that if a patient has BRCA1 or BRCA2 breast or ovarian cancer, she will respond to PARP (poly[ADP-ribose] polymerase-1) inhibitors.
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