“Context of vulnerability” and its role in targeted drug development

Dan Von Hoff
Renowned cancer researcher Dr. Daniel Von Hoff and his team at TGen are fervent believers in a new approach to developing novel therapies for patients with pancreatic cancer. Their rationale, dubbed “context of vulnerability,” is a powerful new drug development paradigm that’s generating impressive results.

Medelis has just published a free downloadable interview with Dan (download it here) as part of our “Peer Perspectives in Oncology” series.  In the abstract, Dan explains how this model has already led to promising discoveries and is changing the future of oncology drug development. 

“Context of vulnerability,” a term coined by TGen’s Spryo Mousses, Ph.D., refers to the genetic configuration in a patient’s tumor that makes it susceptible to a specific drug.  “Context of vulnerability provides the genetic rationale for a targeted therapy,” Dan explains.

In the abstract, he provides examples of context of vulnerability in use.  “One way to establish the context of vulnerability is to work backwards from the result,” he says.  “For instance, in a phase I or phase II trial, you treat a certain number of 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.”

Dan explains that context of vulnerability can improve a sponsor’s chance of seeing efficacy during an early-stage trial with a much smaller n.

“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,” he emphasizes.  “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.”

Throughout the interview, Dan addresses many of the questions and opportunities presented in this model:

  • How context of vulnerability provides a genetic rationale for a targeted therapy;
  • How to establish a patient’s context of vulnerability;
  • How using context of vulnerability to guide drug development can improve your chance of seeing efficacy with a much smaller n;
  • Incorporating context of vulnerability as the oncologist’s “sixth vital sign;”
  • A case study of context of vulnerability in use and how it improves patient care and new agent development;
  • The gap between known contexts of vulnerability and available therapeutics;
  • How CMOs can flip their drug development planning to leverage this approach;
  • Feedback from the FDA, national and international groups;
  • Targeted therapeutics and the future of oncology.

The abstract is the fifth in Medelis’ “Peer Perspectives in Oncology” series, and you can download the entire series here.  You’ll receive email notices when future issues are published as well.