Context of Vulnerability: A Powerful New Paradigm for Targeted Drug Development

A Q&A with Daniel Von Hoff, M.D.

Introduction

Success developing targeted therapies in oncology depends on the ability to identify new targets and develop agents that hit those targets. Renowned cancer researcher Dr. Daniel Von Hoff and his team at the Translational Genomics Research Institute in Phoenix and Scottsdale, Arizona have been using this approach to develop novel therapies for patients with pancreatic cancer. They are guided by a rationale dubbed the “context of vulnerability.”

In this issue of Peer Perspectives in Oncology, Dr. Von Hoff explains how this powerful paradigm has already led to promising discoveries and is changing the future of oncology drug development.

About Dr. Daniel Von Hoff

Daniel Von Hoff, M.D.

Daniel D. Von Hoff, M.D. is Senior Investigator and Head of Translational Research at the Translational Genomics Research Institute’s (TGen) Translational Drug Development Division and Head, Pancreatic Cancer Research Program in Phoenix, Arizona. He also serves as Chief Scientific Officer for U.S. Oncology and the Scottsdale Clinical Research Institute, and is a founding shareholder of Medelis.

Dr. Von Hoff’s major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents we now use routinely, including mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, CPT-11, gefitinib and others. At present, he and his colleagues are concentrating on the development of molecularly targeted therapies.

Dr. Von Hoff’s laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient. He and his laboratory are now concentrating on discovery of new targets in pancreatic cancer. Dr. Von Hoff has published more than 529 papers, 129 book chapters, and more than 891 abstracts.

Dr. Von Hoff was appointed to President Bush’s National Cancer Advisory Board from June 2004 – March 2010. He is the past President of the American Association for Cancer Research, a Fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology. He is a founder of ILEX Oncology, Inc. (recently acquired by Genzyme). He is founder and Editor Emeritus of Investigational New Drugs – The Journal of New Anticancer Agents as well as the Editor-in-Chief of Molecular Cancer Therapeutics. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows.

Context of Vulnerability: A Powerful New Paradigm for Targeted Drug Development

Medelis: Judging from trials coming online, more and more companies appear to be positioning themselves as targeted therapeutic companies. Are the days of shrinking tumors with cytotoxic agents numbered?

Dr. Von Hoff: There aren’t many groups developing cytotoxic agents now, mostly because the therapeutic index is not as great as it is for some of the cytostatic agents such as Tarceva® or AVASTIN®. Cytostatic agents are associated with less bone marrow suppression, and they’re usually oral agents, which may be preferable for daily regimens. Now that doesn’t mean there won’t be some big hits with cytotoxic agents again, but there just aren’t that many being brought forward any more.

Medelis: What’s the big research focus these days?

Dr. Von Hoff: Today, people are focused on identifying a biologic target, then designing a drug that hits that target by searching chemical space with supercomputers. It’s totally different from more empiric-based cytotoxic drug development. With cytostatic agents, we say, “what makes the cancer cell a cancer cell versus a normal cell?” And if it is an exaggerated target, you characterize it, and then try to find something that hits it.

Medelis: You use a phrase, “context of vulnerability,” which you have described as an important key to cytostatic, or targeted, drug development. Can you explain what this means?

Dr. Von Hoff: The term was coined by Spyro Mousses, Ph.D., Director of Pharmaceutical Genomics Division at the Translational Genomics Research Institute. It refers to the genetic configuration in a patient’s tumor that makes it susceptible to a specific drug. In other words, “context of vulnerability” provides the genetic rationale for a targeted therapy. Other people have described it as “oncogene addiction” — if we can take away the “heroin,” the cell dies.

Medelis: How do you establish a patient’s context of vulnerability?

Dr. Von Hoff: One way to establish the context of vulnerability is to work backwards from the result. For instance, in a phase I or phase II trial, you treat a certain number patients, and when someone responds, you have to ask yourself, “Why did that patient respond? What was the vulnerability in this specific tumor or patient?” The patient either had a genetic lesion or tumor stroma that was susceptible to the drug in some way.

It gets down to taking a good history and physical, both of which provide clues to the genetic underpinnings of the cancer. For instance, it’s well known that if a patient has an Ashkenazi Jewish background, you have to consider BRCA1 and BRCA2. The second important piece of information comes from profiling patients’ tumors. For instance, if there is a mutation in epidermal growth factor receptor (EGFR) then that would warrant treatment with Tarceva.

Medelis: How does context of vulnerability change drug development?

Dr. Von Hoff: If you let context of vulnerability guide drug development, you would put only those patients who have the appropriate susceptibility to the drug on trial. This optimizes your chance of seeing efficacy with a much smaller n. It’s essentially how Herceptin® got approved with an n of 480. If they hadn’t pre-selected patients for the context of vulnerability, estimates say that it would have taken about 23,000 patients to get the drug approved.

Medelis: You have also described the context of vulnerability as the oncologist’s sixth vital sign. Can you explain this concept?

Dr. Von Hoff: The five vital signs that oncologists already use are blood pressure, pulse, respiratory rate, temperature, and level of pain, which is a recent development. We proposed context of vulnerability as the sixth vital sign and believe it holds a key to optimizing therapy for an individual patient.

For instance, if an Asian woman presents with bronchoalveolar carcinoma, you would put her on an epidermal growth factor-receptor (EGFR) antagonist such as Tarceva. Her genetic vulnerability gives her an 80% chance of experiencing tumor shrinkage.

On the other hand, if a patient has advanced stage colon cancer, it’s more challenging to determine the context of vulnerability. You need to study the tumor and the patient to determine what he or she has had and whether there is, as an example, an enzyme deficiency associated with the cancer.

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.

Medelis: How has the FDA responded?

Dr. Von Hoff: I think they’re encouraging this. Frankly, everybody should be encouraging it, because it establishes criteria for patient selection, which in turn optimizes chances of success.

Medelis: What kind of feedback are you getting from national and international groups?

Dr. Von Hoff: Obviously, we are not the only ones pursuing this strategy.

Medelis: What’s the real promise and potential of this approach? Can it help win the fight against cancer?

Dr. Von Hoff: People say we have lost the war on cancer and it is so discouraging to the people who deliver the care every day, the people who are seeing those curves turn around.

The fact is that the rising tide of cancer deaths hasn’t just been stemmed – it’s been turned around. Mortality, in terms of absolute number of deaths, has been down for two years in a row. It should have been going up like a rocket because we’re all aging.

Medelis: Are investors and sponsors starting to see big opportunity, then, because the field really has turned a corner?

Dr. Von Hoff: Yes, and I have direct evidence of this. The bottom line for me is I will never take another drug into patients, ever, unless I know the genetic or genomic context of vulnerability. Why? Because I’ve tasted high success.

We just need to keep working incredibly hard to find the contexts of vulnerability in the more common tumors. This whole idea of finding the context of vulnerability — it’s so gratifying. It’s a way of truly helping people who seemed to have reached a dead end.

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