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Promise and Progress - Cover Story Sidebar: A New Paradigm for Cancer Drug Discovery

The Time is Now: 2010-2011

Cover Story Sidebar: A New Paradigm for Cancer Drug Discovery

By: Valerie Matthews Mehl
Date: November 11, 2010

Nilofer Azad and David Cosgrove
Nilofer Azad and David Cosgrove, co-leaders of the Clinical Trials Program.

The cancer world has created a schism among researchers working to fight cancer.  The science and corresponding treatments have been put in silos related to the place in the body where a cancer starts—there is one for lung cancer, another for breast cancer, yet another for colon cancer, and so on.

This seemed to make sense prior to recent advances in cancer genetics that clearly show the genetic fingerprint of a cancer may reveal more about how the cancer will behave than its location in the body. It also explains why patients with seemingly similar cancers, originating in the same place in their bodies, often have very different responses to treatment.

Increasingly, experts have grown to believe that this fractionation by cancer site is counterproductive. Kimmel Cancer Center Director William Nelson believes it could also be a key reason that drug research is so costly and frequently fails.

“Often in trials, drugs do not look impressive, but that’s because we test them on everyone,” says Nelson.  “We need to start testing them on patients, based on the genetic profile of their cancers, not their locations.  These are the patients where they are likely to work.” Nelson believes this shift in the drug discovery paradigm will not only ensure that the best treatments get to the right patient, but will also speed new drug development and slash the cost.

“Right now it takes $1 billion and 15 years to develop a drug.  We may be able to make that a few years and a couple of million if we change the way we do clinical trials,” says Nelson. “Now that we can get genomic information on everyone’s cancer, we should begin testing drugs on the populations they are likely to help—those with the genetic alterations targeted by the drug.”

 He points to Avastin as an example.  Currently, the drug is mired in controversy related to its use in breast cancer.  Does it work or does it not? Some women are benefitting, but when the data for all breast cancer patients is analyzed, it appears to be largely ineffective.  Nelson believes researchers must look at the women it has helped, decipher the mechanism, and get it to those patients where it is likely to make a difference. “If we treat those it will benefit, and only them, the data immediately look better, we improve patient outcomes, and save money. This is what personalized medicine is all about.”

It is a model Nelson would like to see adopted across all drug trials, and one he is working towards at the Kimmel Cancer Center.

One example is the Center’s restructured Phase I Clinical Trials Program, shepherded by cancer drug discovery experts Michael Carducci and Michelle Rudek and co-lead by clinician-scientists Nilofer Azad and David Cosgrove.  The trials are designed more around the cellular characteristics of tumors rather then cancer type and have a patient mix with many different kinds of cancers, a feature Carducci says is likely to become more common with personalized cancer medicine.

“We talk about cancer being hundreds of diseases, but based on our new genetic understanding, it may actually be 500 diseases,” says Nelson.  “When defined by genetic characteristics, breast cancer alone is six distinct diseases.”

The expanded drug development model provides greater access to new drugs for all patients, but particularly for patients with the worst cancers.  Most of the patients receiving drugs in Phase I trials have cancers that have spread and are unlikely to be helped with standard therapies.

Among the15 or more studies up and running is a trial of IGF (insulin-like growth factor) inhibitors.  Researchers have found that the IGF pathway is altered in many cancers.  Cosgrove describes it as a pro-survival pathway that helps tumors grow. They have trials targeting epigenetics, angiogenesis (the formation of new blood vessels), and other common cancer-related targets, including the hedgehog pathway and the bcl-2 gene.

 “We are bridging basic science and clinical science,” says Azad.

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