Context of Vulnerability: A New Paradigm in Oncology Drug Development

Medelis, Inc.

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“Context of Vulnerability” –
A Powerful New Paradigm in
Targeted Drug Development
A Q&A with renowned oncology investigator Daniel D. Von
Hoff, M.D., who advocates for “context of vulnerability,” a
powerful new paradigm that is leading to promising
discoveries and is changing the future of oncology drug
development.
Welcome
This presentation is based on our February 2009
issue of Peer Perspectives in Oncology, a free Q&A
series focused on issues that face Chief Medical
Officers today: rising costs, optimum patient accrual,
targeted therapeutics, patient safety, FDA
regulations, efficacy, budgets, and timelines.
You can sign up to receive an email notice for future
issues at www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug development
services from preclinical through NDA. Download our abstracts or read our blog at
www.medelis.com.
Context of Vulnerability: A Powerful New Paradigm
in Targeted Drug Development
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.
www.medelis.com.
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, ludarabine, 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. (acquired by Genzyme). He is founder and Editor
Emeritus of Investigational New Drugs The Journal of New Anticancer Agents as well as the Editorin
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 postdoctoral fellows.
www.medelis.com.
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?
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.
www.medelis.com.
What’s the big research focus these days?
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 empiricbased 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.
www.medelis.com.
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?
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.
www.medelis.com.
How do you establish a patient’s context of
vulnerability?
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.
www.medelis.com.
How does context of vulnerability change drug
development?
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 preselected patients for
the context of vulnerability, estimates say that it would
have taken about 23,000 patients to get the drug
approved.
www.medelis.com.
You have also described the context of vulnerability as the
oncologist’s sixth vital sign. Can you explain this concept?
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 factorreceptor (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.
www.medelis.com.
From the sounds of it, perhaps context of vulnerability should
be the first vital sign — something you think about right from
the outset.
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 thirtyyearold 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 ecteinascidin743 (ET743) 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 ET743 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.
www.medelis.com.
Is it further complicated by the fact that there may be more
than one context of vulnerability?
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.
www.medelis.com.
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?
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.
www.medelis.com.
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.
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.
www.medelis.com.
Do we currently have adequate therapeutics for the different
contexts of vulnerability that could potentially exist?
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.
www.medelis.com.
What’s the focus of your research now, in regards to
context of vulnerability?
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.
www.medelis.com.
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?
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.
www.medelis.com.
Are targeted therapeutics the future of oncology?
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[ADPribose]
polymerase1) inhibitors.
www.medelis.com.
How has the FDA responded?
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.
www.medelis.com.
What kind of feedback are you getting from national
and international groups?
Obviously, we are not the only ones pursuing this
strategy.
www.medelis.com.
What’s the real promise and potential of this
approach? Can it help win the fight against cancer?
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.
www.medelis.com.
Are investors and sponsors starting to see big opportunity, then,
because the field really has turned a corner?
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.
www.medelis.com.
About “Peer Perspectives in Oncology”
In Peer Perspectives in Oncology, Medelis brings together some of the
industry’s most respected researchers to talk about the issues facing
Chief Medical Officers today. They’re issues we all face on a daily basis:
Rising costs. Optimum patient accrual. Targeted therapeutics. Patient
safety. FDA regulations. Efficacy. Budgets. Timelines. In this Q&A
series, we’ll discuss these challenges with leading experts who deliver
practical, frontline insights gleaned from years of experience bringing
new drugs to market.
To download additional issues in the series, please visit
www.medelis.com/oncology_abstracts.html.
www.medelis.com.
About Medelis
Medelis, Inc. is a singlesource provider for oncology CRO and drug
development services, providing a total solution for biotechnology and
pharmaceutical companies seeking rapid drug development and approval.
Medelis' medical founders, team physicians and clinical trial management
physicians are internationallyrecognized oncology thought and opinion leaders
who understand the future of personalized medicine and threshold of credibility
trials. Offerings include strategic plans for regulatory approval from phase I
through NDA and complete clinical trial design, management and execution.
Medelis is privatelyheld and located in Phoenix, Arizona with other U.S.
locations in Nashville, Boston and Reno. Medelis Europe oversees projects for
European & Asian sponsors and is headquartered in Port Vendres, France.
www.medelis.com.

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