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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 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 and advisory board member 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.
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