Dear Dr. [GOG
Investigator],
I'm a medical oncologist in Robert and I co-founded Oncotech in
1985.
I was the Laboratory Director at
My greatest contribution to the field of cell culture drug
resistance
assays,
You would be surprised, I think, to evaluate the whole of the
literature
which
In 1990-91 Nagourney and I proposed
to
the GOG a head to head comparison of
Since 1991, I've worked full time providing DISC, MTT, ATP, and caspase
3/7
It is very difficult to obtain publishable results in the setting of
a totally
One of the JNCI reviewers of my rejected manuscript said that the
"only
study
As I said, we do these assays better and differently than anyone
else,
although
I am not a corporation or even a company. I am simply an
MD/PhD
medical
I am determined to carry out a prospective, randomized trial of
empiric
versus
I'd be very happy to travel tomorrow to Please let me know if there is anything I can do to compete for the
opportunity
Hopefully yours,
Larry Weisenthal
mail@weisenthal.org, lab phone: 714-596-2100, mobile phone:
714-931-6842,
home
http://weisenthal.org/vitae.htm
References cited above:
(rejected) JNCI paper on platinum resistance in ovarian cancer,
along
with
(rejected) ONCOLOGY review on cell culture drug resistance testing,
along with
Branch at the NCI at a time when the Branch Chief was Bob Young; I
was a couple
of years behind Bob Ozols. Both
may remember me, or at least be somewhat
familiar with my work. I met Robert Nagourney
when he was an intern rotating
through Hem/Onc in my first job as an
attending/Asst
Prof at the
VA/UC Irvine.
Oncotech from 1987-91. I "converted"
the "clonogenic/thymidine incorporation
chemosensitivity assay" into the "extreme
drug resistance (EDR) assay" by noting
that patients with assay results falling
a standard deviation below the median
virtually never responded to chemotherapy. Everyone at Oncotech
opposed the
"switch" from a chemosensitivity assay
to a drug resistance assay at the time,
but I eventually prevailed, and my term "EDR" was adopted as the flag
ship
product of Oncotech. (Kern DH and
Weisenthal
LM. Highly specific prediction of
antineoplastic drug resistance with an in
vitro assay using suprapharmacologic
drug exposures.J Natl
Cancer Inst 1990; 82: 582-588).
however, was my going against the then-existing grain in 1981, with
my
description of an assay technology based on the concept of total cell
kill
(cell death), as opposed to cell proliferation. Alas, timing
is everything; at
the time, no one had heard of apoptosis, and everyone thought that
cell death
was too crude an endpoint to be valid. I originally presented
my technology
and data at the combined plenary ASCO/AACR session in 1981 and in a
series of
papers published in Cancer Research and elsewhere in the early to
mid-80s.
Since then, everything I published has
been independently confirmed by many
other investigators; some with my originally-described technology (the
DISC
assay, or, as Nagourney calls it the
"ex vivo apoptosis assay"), or with other
cell death endpoints which were first compared with the DISC assay
in their
original publications and where the assay conditions were modeled after
those
used in the DISC assay. These other endpoints included MTT, ATP,
and
fluoresceindiacetate.
Most recently, the GYN-ONC group at Yale has described
the "Yale Apoptosis Assay," which is simply measuring caspase
3/7 activity, and
which correlates precisely with the findings in the DISC, MTT, and
ATP assays
(in our laboratory, we use ALL of these latter endpoints (DISC, MTT,
ATP, and
caspase 3/7).
exists to validate these cell death endpoints. I wrote an invited
review for
ONCOLOGY (American, not Swiss version of the journal) several years
ago; alas,
it wasn't published because it was judged by the editors to be "too
controversial" (web reference below, along with peer reviews).
Taken in their
entirety, the data are extensive, consistent, not at all controversial,
and
quite compelling.
DISC, ATP, and "EDR" assay endpoints in ovarian cancer, while we were
both
still at Oncotech. We wrote the
original draft of the protocol. Subsequently,
both of us left Oncotech to start up
our own labs, free of the constraints of
the venture capitalists who ended up in control of Oncotech.
I recruited my
own replacement, another NCI trained med oncologist named John
Fruehauf,
who
had also been one of my house officers during his medicine residency.
Basically, Oncotech quickly moved to
form a tight association with Gyn/Onc
at
UC Irvine, and appointed UCI Cancer Center Director Frank Meyskens
to its Board
of Directors. Nagourney and I were
frozen
out of the study we had originally
proposed and designed, and evaluations of the DISC and ATP assays were
dropped
from the study. To my knowledge, results of the "EDR" component
of the study
were never published.
assays as a service to oncologists and patients. At Oncotech,
each assay would
require about 5 minutes of my time. The way that I do it here,
with multiple
endpoints and many more drugs tested at multiple concentrations, each
assay
requires a minimum of 2 hours of my own time and an average of 3
hours.
My
"niche" is to do the most careful, exacting, and comprehensive job
of testing
of each specimen. I love my job. I view each specimen as
holding the secrets
to a human life, and it is my job to unlock those secrets and come
up with a
treatment which works. Several members of my own family have
been treated on
teh basis of our assay results, including
my brother, treated for massive
mediastinal Hodgkin's Disease with mitoxantrone, vinorelbine, vincristine,
dexamethasone, and bleomycin
(a unique regimen designed "on the fly" on the
basis of our testing) and my sister, an MD currently battling
platinum-resistant
ovarian cancer, who was treated up front with assay directed
gemcitabine/carboplatin/vinorelbine,
followed
by Doxil/interferon gamma,
followed by Taxol/vinorelbine/high
dose tamoxifen.
She was initially platinum
resistant in our assays. Such patients have a poor prognosis,
as described in
the paper referenced below (1).
independent laboratory, but I've made the best effort I can.
The paper
referenced below (1) was submitted to the JNCI, but rejected (peer
reviews are
self published on the web, along with the paper). I reported
our findings that
previously-untreated patients were significantly more
platinum-sensitive
than
previously-treated patients, that patients relapsing within 6 months
of
platinum-based therapy were more platinum resistant than were late relapsers,
that pre-treatment platinum-sensitivity/resistance correlated
strikingly
with
long term survival in poorly-differentiated tumors, but not in moderate
to well
differentiated tumors, that poorly-differentiated tumors were more
sensitive/less resistant to platinums
than were moderate to well differentiated
tumors. These latter data were interesting, because the original
GOG trials of
platinum based therapy (Bruckner, et al)
showed a much greater advantage for
platinum-based therapy in poorly differentiated tumors than in moderate
to
well-differentiated tumors. I think that platinum resistance,
along with
optimum surgery are the most important factors governing survival in
poorly
differentiated tumors, while surgery and tumor biology (and not
platinum
sensitivity) are the most important factors governing survival in
moderate
to
well differentiated tumors). I think, of course, that everyone
should be
treated with assay-directed therapy. In the absence of assays,
poorly
differentiated tumors should be treated with single agent carboplatin,
while
moderate to well differentiated tumors should be treated with
non-platinum-based combination chemotherapy, e.g. taxane/vinorelbine,
taxane/gemcitabine, etc.
worth publishing" would be a prospective, randomized trial of
empiric vs
assay-directed therapy. He suggested that I do the trial in
platinum-resistant
ovarian cancer. Taking him at his word, I analyzed our data and
submitted an
abstract to the SGO meetings (ref below). My plan was to get
the data out to
the GYN oncologists for the purpose of convincing them to support such
a trial.
Being objective, I think that it was a pretty good abstract. Afterall,
we
reported a median survival which was twice as good as anything ever
achieved in
GOG trials of platinum-resistant disease, along with some interesting
tumor
biology data. Alas, it was rejected, not only rejected for
presentation
at
their meetings, but it wasn't even accepted for publication in the
proceedings
of the meeting! I can't, for a moment, understand the certitude
(that we can't
possibly be correct) which goes into such a decision.
our methods are entirely public domain and non-proprietary. I'd
be happy to
train a Fox Chase investigator, were one interested. We test
each specimen with
at least 3 (and sometimes 5) different assay endpoints.
Unlike Oncotech,
we
test drugs at two concentrations, and we test many more drugs.
While Oncotech
brags misleadingly that they are the only Medicare-approved laboratory,
two of
our assays (DISC and MTT) were approved by Medicare for reimbursement
at the
same time that Oncotech's were
approved
and are reimbursed at the same level
(we do much more work, however, and are grossly underpaid, but many
oncologists
feel
that way these days; so I don't complain about it). One of the
other things we
do which is unique is to compare
"apples
to apples," instead of "apples to
oranges." We obtain careful biometrics of things such as the
ratio of viable
tumor cells post-culture over pre-culture, strength of metabolic signal
post-culture, degree of tumor three
dimensionality
in culture, etc. All of
these are variables which correlate with in vitro drug effects, along
with
intrinsic chemosensitivity/drug
resistance.
By making these apples to apples
comparisons, biological and clinical correlations are improved.
oncologist who has devoted his career since 1978 to the study and
application
of cell culture drug resistance assays in human cancer. I have
a solo,
laboratory based medical practice, where the only thing I do each day
is to
perform these assays on a hands-on basis. If one makes a long
focused effort
at a task which is basically a bioengineering challenge, then it is
indeed
possible to make progress.
assay directed therapy before my career ends. To this end, I
have recently
obtained an equity line of credit on my personal residence
to support
this trial. I would be amenable to almost any trial design you
would propose.
If you want gemcitabine/carboplatin
to be the standard therapy arm of the trial
(or any other combination) that is perfectly fine with me. If
you need some of
my credit line money to defray GOG expenses, that is fine also. I
help
patients with
my work; I save and prolong the lives of patients with ovarian cancer
and other
neoplasms. I know this; the
oncologists
who have loyally provided me with
referrals over the years know this also. I want to submit our
methods to a
rigorous test to show the world that our (non-proprietary) technologies
work.
If the study is positive, I'll be happy to train GOG institutions in
our
methodology. I want to do all these things, but the ability to
do good
laboratory work and the ability to organize clinical trials are not
skills
inherited on the same chromosome. So I need help; your help,
if possible, to
get this done.
with you, if this would be possible. I am very worried that the
GOG is going
to, at long last, do a randomized trial of assay-directed therapy,
and I am
fearful that the better technology will not be given a chance.
Note that I
could, myself, perform the Oncotech
"EDR" assay, if I chose to do so. I
supervised 10,000 of these while at Oncotech.
I don't do it, not because it
isn't valid (it is valid), but because there are better ways to obtain
more
useful information.
of participating in the GOG trial of assay-directed therapy of
platinum-resistant ovarian cancer.
phone: 714-846-7560
reviewer's comments and also (rejected) SGO abstract describing our
results in
platinum-resistant ovarian cancer: http://weisenthal.org/w_ovarian_cp_toc.html
reviewer's comments: http://weisenthal.org/oncol_t.htm
,
http://weisenthal.org/onc_rev.htm