|
 Discussion
DR. SAXMAN:
Are there any questions, discussion for Enrique or David?
DR. BALL: I
have a question for Dr. Rozengurt. In terms of focusing attention
on anti-receptor strategies, do you take into account the heterogeneity
of receptor systems such as GRP in small cell? Are the broad spectrum
neuropeptide antagonists really broad enough to account for the
repertoire of the changing face of small cell lung cancer and its
growth factor repertoire?
DR. ROZENGURT:
Up to the point that we have tested and others have tested, those
inhibitors really bind to GRP, to a suppressing galanin
CCK receptors. Their IC50 for each receptor is not the same, and
that really reflects the fact that they have the IC50. For example,
vasopressin receptor could be 10 times lower than for example, a
galanin receptor, but they definitely
target a very broad spectrum type of neuropeptide. One point that
I didn't discuss yesterday morning is there is also an increasing
realization or at least some papers in which some of the neuropeptide
receptors are up regulated in endothelium of cancer cells. So while
it is entirely logical to think that we are targeting the cells
themselves, I think that we might have additional benefit with these
molecules, and we might be targeting up-regulated neuropeptide receptors
coming into the tumor. Thus we have an antiangiogenic effect additionally
to the effect that we are having on the cells themselves.
The mechanism
of action is complex. I think that we understand that there is an
element in that which builds with the ability of these compounds
to reduce a variety of autocrine loops and results in growth inhibition
and results in apoptosis. But there are other ways in which these
compounds could actually act in which these compounds might have
some agonist activity for pathways, while other pathways are not
stimulated. This is something that was also mentioned yesterday
in the session, and it could be an additional level of complexity
that actually adds to the mechanism of action for these compounds.
So I think
that my impression is that we have many different types of small
cells which have a very different type of repertoire of receptors,
and the invariable result for all of us has been inhibition. So
I think that that is the bottom line.
DR. BUNN: The
bottom line is I don't know necessarily that we really understand
how these things work. If you take 13 small cell lines, they have
marked heterogeneity of receptor expression, but if you give bradykinin
antagonist dimers, which work in the same mechanism as the substance
P derivatives, they inhibit all 13 of the cell lines. And the IC50
is very tight. They inhibit cells that express and don't express
MDR, and if you give them with standard cytotoxic agents, they potentiate
the effect of the standard cytotoxic agents. Although the substance
P derivatives don't work very well on non-small cell lines, the
bradykinin antagonist dimers actually inhibit some of the non-small
cell tumors that have neuroendocrine features. Of course, it is
true that if you give a high enough dose, you know we can inhibit
BEAS 2B and other sorts of normal cells, except, for whatever reason,
we have never been able to hurt a mouse, and we have inhibited human
tumors in mice in every instance.
So that is
a real problem, but we seem to inhibit every small cell line no
matter what their expression is. Now, I think Gary has done some
studies in cells that have no neuropeptide receptors with the Substance
P derivatives— or haven't you tried to do that, Gary? If you
don't have neuropeptide receptors, these things probably don't work
very well.
DR. G. JOHNSON:
It is hard to find cells that don't have neuropeptide receptors.
We have screened, and we have resorted to fibroblasts. We express
the GRP receptor and the substance P receptor, and these cells do
not respond to normal agonists. When you put these receptors in
with standard transduction methods, the substance P antagonist that
induces apoptosis in small cells regulates a subset of signaling
pathways that the normal agonist activates, as well as the normal
agonist over the activated additional pathways. We have published
this.
Our model for
how these things work is that they behave as antagonists in terms
of competition of binding normal agonists. You can show that they
will activate G12, G15 which really means that there is a couple
of these receptors. We have shown that they stimulate oxygen radical
generation in cells, and that oxygen radical generation is involved
in the response. You can detect the cells with apoptosis with scavengers
for these oxygen radicals—but we have called it biased agonism.
So the broad spectrum antagonists interact with local neuropeptide
receptors that have a limited agonist activity.
DR. GAZDAR:
I would like to address the point about the new cell lines. Many
of these cell lines that you are currently using indeed started
20 years ago or 15 years ago or more, but they haven't been in continuous
culture. They have been frozen away and deposited in the ATCC within
a few months of being established, a few months of continuous passage.
Therefore, I think when you go back to frozen stock, you are really
going back to a culture that is a few months old or a year old,
not 20 years old, and I think you and Paul Bunn have studied the
endocrine properties of these lines for many years. Have they changed?
DR. ROZENGURT:
I think that the point that was made in the session was slightly
different. It was no doubt that those were excellent models. The
point that was made is that, as time goes by, the actual small cell
lung cancer that is presenting nowadays might not be exactly the
same as small cell cancer that presented 20 years ago. The idea
was that we might be studying small cell cancer 20 years ago rather
than the small cell cancer that is presenting now, and there was
a feeling that it would be nice to have new cell lines coming which
would be compared with the old ones and which we could actually
have more studies. That was the point that was made.
DR. GAZDAR:
Okay, I missed that point. That is a good point. However, I think
if you start new cell lines, we have an enormous database from hundreds
or dozens of investigations throughout the world. On 69345, you
know the complete genotype. You know the phenotype. You even know
whether they are tumorigenic in nude mice. So if you start new cell
lines you have got to generate this enormous database before you
can interpret your data.
DR. BUNN: The
fraction of cells that respond to these peptides in the same cell
line over 20 years hasn't changed much. If you look at 345 or SHP
77, SHP 77 only responds to bradykinin, but 80 percent of the cells
respond to bradykinin. That never changes.
DR. MABRY:
It sounds to me like people pretty much agree that the cells aren't
drifting, but then again, the question is, "Has the cancer changed?"
Amongst the clinicians with gray hair in the room, is there any
sense that the small cell lung cancer now is different than it was
20 years ago?
DR. GANDARA:
I don't think we have put enough evolutionary pressure on the small
cell to have it change.
(Laughter.)
DR. D. JOHNSON:
No, I agree with that, but I do think, personally, there has been
a subtle change. Some of that may simply be the way that we define
and identify the disease, the fact that we now have some subsets
that are newly identified. The large cell neuroendocrine tumor takes
certain elements out. There are some subtle changes, and even clinically
one can see these very subtle changes. Some of them are the result
of a different type of evolutionary pressure, I think, namely, our
ability to stage these patients, diagnose these patients, lots of
other issues that go into modifying “the disease.”
DR. B. JOHNSON:
And the other thing is that if you take a look at the SEER data,
the median survival of small cell lung cancer has gone up about
2 months in the last 20 years. So patients are doing a little bit
differently in the broad group, but that is the glass half full
kind of thing.
DR. D. JOHNSON:
Even though the treatment hasn't changed in that interval, right?
DR. GUMERLOCK:
I have a question for Enrique. The targeted signal transduction
pathways, the neuropeptides, the tyrosine kinase, the ras pathway
with FTI, those are all growth proliferative pathways. Was there
any discussion of targeting an apoptosis pathway to trigger it in
some way?
I understand
that often apoptosis can be triggered while there is the conflicting
cell cycle arrest in the face of continued cell proliferative signals.
So inhibiting cell growth may in fact work against you in terms
of trying to trigger apoptosis in a cancer cell. Some growth pathways
I think branch out into both an apoptosis pathway and a proliferative
pathway. There is some evidence that the HER-2 pathway can lead
to apoptosis in some circumstances and cell proliferation in others.
Was there any discussion of that?
DR. ROZENGURT:
The discussion was actually centered around neuropeptide antagonists,
and Gary Johnson already has made his comments a while ago about
the possibility of induction of apoptosis with some of these agents.
That could also be the same incidentally with herceptin and you
mentioned HER-2, and there is potentially the same type of probability
of inducing apoptosis with some of those agents.
We did not
discuss a great deal about inhibition of growth, as opposed to apoptosis,
as an aspect that actually could interfere with apoptosis in great
detail. But certainly there is a very valid point. As I mentioned
briefly, we were discussing the issues of what does cytostasis mean,
and the point was made referring to some work that myc transformed
cells for example. That we associate primarily with proliferative
cells under certain conditions are committing essentially apoptosis.
That work came originally from Jerry Avan and other people, in which
you put a myc oncogene on the cells essentially in a situation in
which it doesn't actually allow them to progress through the cell
cycle. They move very quickly into apoptosis.
So that was
most of our deliberations on that issue.
DR. GUMERLOCK:
So, in addition, the cell cycle analysis is a surrogate marker in
the cytostatic setting. We had better be looking at apoptosis markers
as well.
DR. ROZENGURT:
Correct.
DR. BUNN: I
think you missed Gary's point. I mean, if you want to make small
cells apoptose, give them Taxol. There is nothing that makes small
cells apoptose more than Taxol. But if you look at the substance
P derivatives through the bradykinin antagonist dimers, it is not
that you just see cells that are not in S phase. The cells undergo
marked apoptosis, and what Gary was telling you was sort of the
mechanism for that. Now, if you need to get higher than Taxol for
apoptosis you can give substance P derivatives or bradykinin antagonist
plus Taxol. That is where you are going to get the highest apoptotic
rate.
Now, you know,
exisulind is sulindac sulfone which is supposed to work by inducing
apoptosis. However, these compounds produce a much higher apoptotic
rate in small cell than exisulind, not that exisulind doesn't do
anything, but we think that this apoptosis is a big thing.
DR. DENNIS:
There are actually some inhibitors that are available that can help
distinguish the pathways in a sense that you can use inhibitors
of, for example, the map kinase pathway, and see in vitro what you
would call a G1 arrest. At the same time, if you use inhibitors
in PI3 kinase AKT pathway, you actually induce apoptosis. That pathway,
although it is nowhere near clinical application at this point like
substance P, when you target this pathway, you can dramatically
potentiate other cytotoxic insults like chemotherapy and irradiation.
So you may
be able to tease apart proliferative pathways from survival pathways
and as opposed to, no one argues with the immediacy and the availability
of GRP and substance P as targets right now. The advantage of looking
further downstream is actually that you may be able to block more
pathways, stimulated by many types of receptors and growth factors.
In fact, the one thing that Dr. Johnson didn't mention from yesterday
is that there may be similarities in the biology of non-small cell
and small cell. Given the availability of greater tissue for non-small
cell, the question was raised as to whether or not for signal transduction
inhibitors that work further downstream, would it be easier or even
more prudent to try to establish some proof of principle in non-small
cell.
DR. ROZENGURT:
Just to mention one thing about the clinical possibilities of these
inhibitors, I would like to reiterate the fact that there is a new
antagonist for myc-1 coming from Parke Davis. They published a paper
in Nature Medicine in which they use it for colon cancer, and it
apparently was very well tolerated, and they have good regulation
of what they call tumor burden in their paper, indicating that there
is movement on that front as well.
DR. MOODY:
Yes, we have seen for the VIP receptor antagonist that they actually
potentiate the action of chemotherapeutic drugs, and this is what
Paul has seen also for the bradykinin dimers. So the high doses
of these peptide antagonists probably induce apoptosis by themselves.
But one of the key facts is they potentiate the action of the chemotherapeutics.
They work in a synergistic manner so that the end result is that
one could even use less chemotherapeutic drug when treating the
patient when using these peptide antagonists.
PARTICIPANT:
I would like to comment. Regarding the signaling pathways, there
is also a link between the signaling pathways and drug resistance
as far as drug transport mechanisms go. We recently demonstrated
that RLP-7, which is a protein which is supposed to link the ras
and the Ro pathways, a protein for which there was no previously
defined effector function is actually a transporter of adriamycin
and of glutathione conjugate. Since glutathione conjugates are formed
as a result of oxidative stress, lipid and glutathione conjugates,
per se, interference with the function of this protein may also
be involved in the apoptotic mechanisms, particularly those having
to do with drug resistance, and it is a very direct way of increasing
the cytotoxicity of chemotherapeutic agents.
PARTICIPANT:
I don't think anybody will argue that there are lots of ways to
induce apoptosis especially in small cell. I think perhaps what
Paul was getting and something that I have worked on as well, that
perhaps the apoptotic pathways themselves appear to be deregulated
in small cell lung cancer, and we may not be getting as much apoptosis
as we perhaps could. Dr. Minna mentioned the bcl-2 over-expression
in 60 to 80 percent of small cell lung cancers and bcl-2 and perhaps
other elements of apoptotic systems might be very reasonable targets.
The antisense
work done in Europe is very intriguing in that they also appear
to be active in cells that don't over-express bcl-2 such as HH2
cell line, but even agents such as Taxol that Dr. Bunn mentioned
do have an effect on this pathway, and there is evidence of phosphorylation
of bcl-2. We worked with dolostatin-10, another microtubule active
agent that phosphorylates bcl-2. It is still unclear whether or
not that actually affects the activity, but it is a potential small
molecule way of interacting with an apoptotic pathway to lower the
apoptotic threshold and perhaps increase the activity of other apoptotic
stimulating molecules. So I think we have to still not only concentrate
on the proliferative pathway and inhibiting those but also optimizing
the apoptotic balance within the cell so that it will respond to
the apoptotic signal appropriately. Nobody knows why small cell
lung cancers are resistant when they relapse. That hasn't been really
talked about at all. We don't know what those mechanisms are, but
perhaps the apoptotic pathway or the lack of a functional apoptotic
pathway is something that we should target a little bit more aggressively.
PARTICIPANT:
These cell lines, were there varying cell lines among these cell
lines that you studied, like H82—did it respond?
PARTICIPANT:
Yes.
DR. G. JOHNSON:
That is the one unique aspect with cell lines that are resistant
to a lot of other drugs. The problem with these things is that they
are peptides. They are very expensive to make, and they are degraded
One of the best ways I think to move this field forward with these
neuropeptides and these drugs is we need an alliance with biotech
pharmaceuticals and chemistry to try to find small peptide mimetics.
The smallest peptide that I am aware of that is really effective
is 5-amino acids, and that is too big to model. So you are really
required to do some reasonably modest or high-throughput screening.
There have been great advances in the last few years with small
molecule inhibitors or agonists. I think most academics don't have
the chemistry access to be able to deal with this.
DR. D. JOHNSON:
We have some industry representatives. Mack is one. Are there opportunities
to forge those alliances?
DR. HUMPHREY:
Within Bristol it is certainly an opportunity to speak with the
basic scientists about their interests and 5-amino acids is actually
a pretty reasonably sized peptide if you think about insulin. So,
depending on the strength of the basic science and how it fits into
the portfolio, etcetera, it absolutely is something possible.
DR. HEASLEY:
This is different from these peptides, but one target that we didn't
talk about yesterday was the non-steroidal anti-inflammatory drugs
which seem to have a lot of excitement in the colon cancer field.
I know that Paul Bunn's group and mine have examined these with
Rake Niminoff at the Health Science Center and looked at the effect
of these kinds of drugs on lung cancer cell growth in vitro and
in nude animal studies, and they show good effects in those kinds
of systems as well. So it is one promising area that we didn't discuss
yesterday.
One question
is, "Is there any anecdotal type evidence for the effects of these
drugs in lung cancer frequency or growth?"
DR. D. JOHNSON:
I take an aspirin a day, and I don't have small cell.
(Laughter.)
DR. D. JOHNSON:
So far it works.
DR. MILLER:
We have reviewed this, and I think there is pretty good epidemiologic
evidence for about a 50 percent reduction in cancer in frequent
aspirin users. So this could be a tremendous chemopreventive thing
right now.
PARTICIPANT:
That is my understanding—that that works very well for colon,
but I don't know of any data for lung.
DR. D. JOHNSON:
There is actually some data from the Tennessee Medicaid database.
There has been an analysis done—it hasn't been published—which
shows a reduction in lung cancer, and breast cancer as well as colon
cancer, in people who are frequent users of NSAIDs.
DR. BRAUN:
I was going to say that probably the best example is in head and
neck cancer, where there is a bona fide clinical response to prostaglandin
antagonists and to some of the newer COX2 inhibitors. Whether that
would be applied in small cell, of course, remains to be seen.
DR. D. JOHNSON:
Actually, there is some intriguing data, I mean all kinds of suggestive
data about COX inhibition, not necessarily COX2, per se. There is
a paper out of Scandinavia that was published several years back
now in Cancer Research in which indomethacin was given in a randomized
fashion to terminally ill cancer patients who received no other
therapy. The survival of those who received the indomethacin was
statistically superior to those who got no further therapy other
than “supportive care” without NSAIDs.
The breadth
of tumors in that was huge. I mean, it was colon and lung and breast
and many other diseases.
DR. MOODY:
We have done a lot of research on the cell lines and in my experience
the cyclooxygenase pathway is utilized much more in non-small cell
lung cancer than small cell lung cancer.
Small cell
lung cancer seems to shuttle the arachidonic acid metabolites through
the lipoxygenase pathway. So drugs such as NDGA seem to be much
more effective at inhibiting small cell lung cancer growth than
the cyclooxygenase inhibitors.
DR. DENNIS:
There has been a recent paper from Vogelstein's group showing that
one possible mechanism of inhibition of COX2 is the fact that it
tends to shuttle the prostaglandins to actually generate ceramide
which is one signaling pathway that we actually didn't talk about
yesterday to increase the activity of sphingomyelinase to generate
ceramide, which is a pro-apoptotic lipid. So it is something else
that was not discussed.
DR. HEASLEY:
I think for non-steroidals, the mechanism of action is poorly defined,
but despite that, they are very effective on small cell and cancer
lines in vitro and in nude animal studies.
So, I mean,
we don't know exactly how they work perhaps, but they are effective.
DR. BRAUN:
I could just also point out that oxygen radical scavengers seem
to attenuate some of the effects. There is now EM data that suggests
that these cells are under oxygen stress when you use those inhibitors
which may be one of the mechanisms.
DR. ASWATHI:
The curfuminoids in particular have a very good antioxidant effect.
These are non-steroidal anti-inflammatories that do inhibit cyclooxygenase.
They have an interesting property that, unlike probably any other
non-steroidal anti-inflammatory, they have no pain-relieving properties.
DR. SAXMAN:
We charged this group at the beginning to take the biology and begin
to strategically plan clinical trials. Where are we? Where do we
need to go? What is ready to go?
I think the
small group breakout sessions have done that nicely, but now that
we are all together again and we have all heard the presentations
from the breakout groups, I think the question still remains, "What
should the priorities be? What is ready for testing and in what
fashion?" I told Dave Johnson that I was going to ask him this,
so I will start with David.
David, from
what we have heard this morning when you go back and talk with your
Phase I people at Vanderbilt, what are you going to tell them that
you think is ready for Phase I type testing in lung cancer? What
is ECOG going to be ready to do in a Phase II or Phase III fashion,
if anything at all, based on what we have heard this morning? For
the biologists, what do you think the biologists need to go back
and work on more before it is ready to come out of the laboratory?
DR. D. JOHNSON:
Part of what one decides to do is a little bit based on what is
available to test, but the things that are out there and are available
for us to use are some angiostatic agents. And matrix metalloprotease
inhibitors are available. They are being studied. Farnesyl transferase
inhibitors are available, and they, too, are being studied. So those
are the things that are all of interest personally to me, and I
think that those products can and are being tested now.
Based on what
I have heard here, I like the idea of looking at the neuropeptide
inhibitors. I think they sound very intriguing. We may not know
exactly how they work, but I like the idea.
Candidly, what
I would like to begin to address is the fact that I think there
is often a disconnect between those individuals who work principally
in the lab and those of us who work principally in the clinic, in
the sense that those of you who are in the lab understandably want
to understand the mechanisms as precisely as one can define them.
Those of us who work in the clinic are more interested in the end
result and often go back and figure out why it is something worked.
Candidly, what I am interested in doing is moving ahead and beginning
to even combine some of these products, not just with chemotherapy
but without chemotherapy, angiostatic agents with immune compounds,
for example. I think that would be of interest to me in beginning
to see what kind of result we get.
I would like
to see that done in pre-clinical models. We will see if it happens,
but I will tell you right now what we are doing at Vanderbilt. We
have an FTI study underway in chemosensitive relapsed patients.
We have done anti-VEGF studies, albeit not in small cell. We have
done three different MMPI’s, one of which we are doing in small
cell lung cancer. We are doing anti-ras in sensitive— that
is a misnomer—relapsed non-small cell. We are working on trying
to get the antisense bcl-2 for small cell.
DR. SAXMAN:
Does anyone else in the group have any thoughts? Paul, do you?
DR. BUNN: I
worked on my list. I think that randomized clinical trials are underway
with at least two MMPIs in small cell lung cancer, which is important.
A randomized trial is underway with BEC2/BCG in small cell lung
cancer, and I think that this trial needs more institutions. I don't
know how to get more institutions, but as the MMP trials finish,
it would be nice if there were some effort to have those institutions
enrolling in those trials go over to BEC2/BCG and get that trial
done in a timely manner.
Personally,
I think one could start a randomized trial, probably with anti-VEGF,
if we actually could get the company to tell us what happened in
trials that have been completed for a year. So there are compounds
that we are discussing here that are ready for randomized clinical
trial.
For Phase II
trials, you know the list is actually quite long. There is the GD2/GM2
bivalent vaccine. There are two Sugen compounds. There are two anti-VEGF
antibodies and a KDR antibody. There is the substance P derivative
that is being only studied and very slowly in England. There is
a new MMPI from Bristol. There is UCN01 with platinum. There are
the FTIs and I think Dave Parkinson left, but I actually think that
Novartis has a C-kit receptor tyrosine kinase inhibitor that is
ready for clinical trial. Also COX2, and that is in addition to
injecting genes into subcutaneous nodules.
So I think
there is actually quite a large number of agents, and the question
is, "Are there enough patients, and how do we study these things?"
I think one
of the problems is: for the Phase I and Phase II trials it is very
difficult for a single institution. I can go out and negotiate with
a pharmaceutical company and be pretty sure if I am doing non-small
cell we are going to complete the trial in a timely manner. I have
trouble talking to these companies about small cell because I have
to say, "We cannot do that trial because we don't have enough patients."
Therefore, these Phase II trials, as somebody mentioned, oftentimes
with the surrogate end points and so on are expensive and a little
bit complicated and we don't really have a good mechanism. Even
though David Johnson and I probably see each other once a month
at some meetings, we have never actually worked out a mechanism
for doing trials together, although we have done some pharmaceutical
trials together just out of, you know, they came to both of us.
But to a certain extent we need some way of really getting two or
three institutions together to do these Phase II trials because
it is hard at a single institution in small cell.
Do you have
enough, Corey, to do a Phase II trial in small cell?
DR. LANGER:
Only in relapsed or refractory patients. Those are the patients
that we see, at least in centers, and I think that is probably reflected
around the table right now, that in the communities people get combination
A. They usually then get combination B or single agent B, and after
they have failed three or four separate regimens they land on our
doorstep. I have to echo Dave's comment about what is available,
but I think we also have to consider toxicity, particularly when
we start looking at combining these new agents with standard chemotherapy
and consider whether that is a route we should go. Certainly that
is what we have done with anti-VEGF, and you know we have seen some
unusual toxicities that we hadn't anticipated, and yet compared
to conventional cytotoxic chemotherapy, a relative dearth of toxicity,
which as a clinician we love and patients particularly love.
DR. D. JOHNSON:
Unfortunately, all the data I brought on all the studies we have
done is on a zip disk. So I don't have a zip drive, so I cannot
show any of the data, but we have combined, as you know, anti-VEGF
with chemotherapy. We know some of the toxicity data. I have some
update on that. We have combined FTI with carboplatin and taxol.
So we know about that. That Phase I is still in progress, but we
at least know at some level that for the most part the MMPIs—with
the exception of some mild thrombocytopenia which we have seen and
which is not clinically relevant—we have not had any difficulty
with combinations, whether you give it with thrombocytopenic producing
regimens like carboplatin plus taxol or gemcitabine containing regimens
or not.
So I mean most
of these at least thus far that we have tested have not been overly
problematic to combine with chemotherapy. Now, the question is,
"Will it make any difference?" Obviously, that remains to be seen.
DR. ARBUCK:
I am glad that the issue of patient numbers came up because while
I am sure that that wasn't the main purpose of the meeting, I think
this issue of patient numbers is truly a critical issue because
we have heard lots of interesting lists to which we could add some
more agents that are currently available. We could talk about how
long it has taken to just find out, and I don't even know yet if
topotecan is active in small cell lung cancer.
DR. D. JOHNSON:
Right after the meeting, come to me and I will tell you.
DR. ARBUCK:
Okay, but that is the point. The same with taxol. It takes us a
while to identify a drug, and then, when we do, it takes us forever
to mount and complete a Phase III trial.
I think there
are lots of good ideas that are coming out. There are many interesting
drugs that we have available now, and we are going to have more.
I think the issue of skipping Phase II or some kind of screening
approach is a non-issue because you just cannot test these drugs
directly in Phase II in any kind of meaningful way. We are going
to miss the opportunity to do a lot. So what I would like to propose
is that some people start to really take this in hand. I really
think that it is going to involve getting out and working with this
and letting patients know about some of the opportunities because
no matter how much work is done scientifically and how much discussion
we have about what the priorities are, I think that that is a real
limiting factor now. So I am not sure precisely how to pursue it,
but I really do believe it is essential.
DR. D. JOHNSON:
Actually, I think, and I am sure my NCI colleagues will throw all
kinds of objects at me when I say this, but I have been thinking
about this for a long time, and as a member of a large cooperative
group, I worry about what I am about to say. But for these new products
I have thought about having something like the small cell lung cancer
working group. It would take institutions like Paul's and Bruce
and others who have a specific interest in this disease to pool
their resources of that for the purposes of the early testing fairly
quickly.
We need some
statistical help. I think we have to develop some new models from
our statisticians and look at it. I am trying to figure out why
it is I cannot use a person that failed an antisense to ras, why
I cannot use that same person afterwards to test another signal
transduction agent. Maybe there is a good reason, but I just don't
understand. I sort of vaguely understand it in chemotherapy, but
I don't know that I understand it in these products. I think a working
group of about maybe 10 institutions can use "sensitive relapse"
and even up front patients.
It is not that
we don't see them. It is just that we see as many as our colleagues
in the community do, which is to say that everybody sees two or
three a month, and that is about it. It is not like you see 70 untreated
patients a year, which we used to see at our institution. So that
is what we are talking about. Plus, there are many more studies
ongoing now, and so the competition for the number of patients that
are out there is much greater. As you said, there are two ongoing
Phase III trials with MMPIs. There is an intergroup Phase III trial
ongoing. Each of the cooperative groups has at least one, if not
two, pilot studies. That is where the patients are. It is not that
they don't exist. It is that they are being soaked up by these multiple
opportunities.
DR. ARBUCK:
Do you think there is an opportunity, though, to reach more of the
patients to let them know about these clinical trials?
DR. D. JOHNSON:
Yes, through a working group.
DR. BUNN: Yes,
and I think the Internet is potentially a useful tool. What happened
is that, as we train good medical oncologists, and I don't think
any of us think that the medical oncologists in the community aren't
good, but they are a lot busier. These are complicated randomized
clinical trials that they don't necessarily want to do. It
is like lymphomas, you know. Small cell just became a stable patient
population for private doctors. It is part of their stable and they
don't want to lose them.
DR. AWASTHI:
I would like to address that issue, also. I work for US Oncology,
and I have been asked by the lung cancer trials director to increase
the number of trials that are ongoing for small cell lung cancer.
I think right now the only thing that we have active in US Oncology
is the marimastat and the Bayer trial for small cell lung cancer
and US Oncology has over 800 physicians, around 800 oncologists
around the country and getting a trial activated through US Oncology
as part of the collaborative effort would not be difficult. We see
a lot of patients that have Medicaid that have small cell lung cancer
that used to be in the past referred to the county hospitals or
other institutions.
DR. BUNN: Just
on a local issue, there are 60 of your colleagues in my city, and
when they are ready to participate in any of these trials, let me
know. We will allow them to put on any of our trials, but we are
ready to go.
DR. SAXMAN:
I would just like to reiterate very quickly what Susan said. I think
that getting more involved with the patient advocacy group is extremely
valuable. I talked with Betty Layne, who has been at this meeting.
I personally think the challenge for their group, the charge for
their group, is not so much education in terms of clinical trials
but truly is promotion. I believe that education is the wrong word,
and I have talked with her about that, and I think that it is up
to us to help them in that effort. I don't know, Betty, if you would
like to say anything about that or I don't want to put you on the
spot, but I do think it is a two-way street in that regard. I think
that we need to charge you with that. I think that your organization
needs to help us in those efforts.
DR. D. JOHNSON:
This is which organization?
DR. SAXMAN:
ALCASE (Alliance for Lung Cancer Advocacy, Support and Education).
DR. BUNN: Two
comments about ALCASE. One, send money. Two, we had a nice discussion
with them about randomized trial of preoperative chemotherapy plus
surgery versus surgery alone. The initial thought of a group like
that was well, the trouble with that is some people get surgery
alone, therefore, how could we support such a trial because we all
know everybody ought to get chemotherapy and radiation. When we
mentioned the fact that most patients don't actually get treated
and if you actually believe that the treatment is better, the fastest
way to get the people treated is with a positive randomized trial.
You know it was easy to convince them of the importance of promoting
even randomized clinical trials to get the answers and so, I think
they will help us promote. Part of their problem is they don't have
enough money right now to do all the promotional things that they
like to do.
DR. CHRISTIAN:
I just wanted to make one comment. Someone raised earlier the issue
of industry collaboration for the development of neuropeptide mimetics,
et cetera. Just to remind people that there are a number of early
drug discovery new initiatives in the developmental therapeutics
program, molecular targeted drug discovery and other things, the
purpose of which is to make available some of these combinatorial
libraries, et cetera. So if that is an interest to remind people
that Ed Sausville can point them in the right direction within that
program and also to tell you that, as I mentioned yesterday in the
session that I attended, we are actually developing new initiatives
to facilitate some of these arrangements to allow you and Dave to
work together on clinical trials and other things, Paul. So we will
be in touch with you about those, but there are resources that the
institute is developing that I want to encourage people to either
stay in touch with people they have met here or check websites
because they will be coming out over the next several months.
DR. HUMPHREY:
And actually if I could elaborate on earlier comments, and I am
glad Michaele brought this up again. Not only is there the RAID
mechanism, but in terms of collaborating with industry, I think
it is important that people be aware that major pharmas all have
licensing teams or licensing departments, and for some companies,
such as Bristol, we have a dedicated oncology licensing team. Frequently
what happens is that people who have a strong desire to promote
a particular compound in development will come and actually make
a presentation to the oncology licensing team. Among the things
that you really need to be aware of is that if the compound has
no patent protection or it doesn't have a means of patent protection,
it is really a major strike against it.
The company,
as a large company, has a much greater interest in an uninteresting,
unexciting but patented anti-hypertensive "me-too" drug than they
would potentially in an interesting novel approach to cancer which
has no patent protection. It is just a fact of life and the way
industry operates. But within every major pharma, there should be
a licensing team that you can go to and actually present the data
and try to influence their interest in a particular approach to
the treatment of cancer. I would encourage that if anybody really
feels strongly that they have something very interesting they would
like to see move forward with industry. That they find out who that
person is within each big pharma and make those presentations.
DR. MABRY:
I think there is one point though that cannot be reiterated enough,
and that is the access to patients so that one can get studies that
have sufficient power so a conclusion can be reached. I cannot claim
that I know all about all the trials that are going forward for
cancer registration, but I can certainly say that small cell lung
cancer, as a registration strategy, there are very few of those.
So I think what we are really talking about, in addition to some
very neat biology by a lot of different and very good people, is
that the ability to design and implement a clinical trial to give
a definitive answer for even one of those products is a very difficult
thing to do.
DR. D. JOHNSON:
Let me remind you of topotecan just approved by the FDA for small
cell lung cancer, and so, it is possible. You have to design and
strategize in a manner that will provide you that window of opportunity.
Designing studies for registration is a bit of a challenge I think,
but there are windows and opportunities there to do this that aren't
so huge in this new era.
DR. MABRY:
That is true, but what I was getting at is that people in my situation
have responsibility to stockholders and the pension funds for the
widows and orphans and so forth, and so when we look at the ability
to register a molecule given a burn rate or amounts put into development
costs for non-small cell lung cancer, if we are going to be a cancer
company and we look over and we look at small cell lung cancer,
the decision is very easy based on that. So if we really want to
test molecules in small cell lung cancer, then what Susan was talking
about is that we really do need to establish a network for patients
and their physicians who are in fact informed very rapidly and in
fact have bought into the idea that clinical trials are important
for patient benefit.
DR. ELIAS:
You also have to be somewhat cognizant of course of the number of
patients who are untreated. So the opportunities to do trials by
that very nature are going to be limited, depending on setting we
choose drugs to be tested in. Therefore, to a certain extent, one
is going to have to be at the clearinghouse area, and you have to
be cognizant of how many trials you have in a particular setting
and how many patients you eventually have in that setting. I think
that is one of the issues.
DR. B. JOHNSON:
I think the point I want to make is to reiterate what Susan said.
Paul gave a list, I think, of 12 things that are ready for trial.
I would say realistically we have been doing Phase II of a size
of 40 or 50 patients where you would build in an end point of say,
10 percent of the patients. We probably only have the ability to
do about three a year across the existing mechanisms, and so we
cannot do 12, let alone in Phase III. So at the current rate, we
probably would complete one Phase III every 2 years within the existing
accrual. So I do think some thought has to be given to what we can
really do and accomplish especially if we are going to take a look
and find out if what we think we are doing is effective. Those of
us who have done some of these things in the past, in terms of getting
tissue, know how to do that and do need to get together and work
it out between the institutions. I think one thing that happens
is that—for those of us who do this—if you run a trial
comparing an old cytotoxic with or without etoposide platinum, the
patients don't come and your staff members don't put it in. If you
have an interesting agent for which you can ask the question, the
staff members and the patients will find it, and you can increase
patient numbers by a factor maybe of one and one-half or twofold
when you work real hard at it. So I think the idea of this meeting
is a very good one. We need to think very carefully about this and
begin to sort through this at a moderate rate. We also need to think
about what questions we want to ask, and that is going to have to
be driven by the folks who think it is important to ask those questions
because it is the only way it is going to get done.
DR. D. JOHNSON:
Which goes back to what I was saying earlier.
DR. SAXMAN:
I want to thank everyone for coming and participating. I also want
again to thank the presenters from yesterday morning and the people
who chaired the breakout sessions and thank all of you very much.
(Thereupon,
at 12:22 p.m., the meeting was adjourned.)
TOP
|
DR.
SAXMAN: The final session of this morning will be the summary of
the signal transduction/cellular growth pathways breakout group.
The chairpersons for this group were Dr. Enrique Rozengurt, Professor
Of Medicine at UCLA School of Medicine in Los Angeles, and Dr. David
Johnson, who is Director of the Division of Hematology Oncology
at Vanderbilt University and also Chairperson of the Thoracic Oncology
Committee in the Eastern Cooperative Oncology Group. 
The
other issue that came up is that we have talked many times about
cytostatic and cytotoxic agents, and we feel that there is a need
to really define cytostatic a little bit more precisely. Cytostatic
can be either a cell that is blocked in G1 and is not growing or
a population that is not growing, but equally well cytostatic. By
this I mean a steady state of cells that are actually undergoing
growth and apoptosis. When we talk about cytostatic, we don't really
understand many times whether we are having a dynamic population
which is actually growing and dying or whether we are having a population
that is actually not growing at all and blocked at one point of
the cell cycle. I think that these are very important distinctions.
So
in terms of more specific signal transduction, we were having a
long very stimulating discussion about which are the most immediate
targets and which we really think will be able to move into clinic
much more rapidly than targets that will require much more development.
One thing that came through the discussion is that signal transduction
branches very quickly and that the receptors remain the preferred
target for most of us in the session. That has been expressed by
a number of people. Gary Johnson really talked very forcefully about
this point. 
We
also discussed at great length questions concerning downstream targets.
First of all, we felt that the FTIs should really be tested. Whether
or not ras is involved FTIs probably work through other mechanisms,
and we discussed the fact that there is some data that FTIs are
working through a small G protein role. Gary Johnson made a point
that FTIs also work through interfering with the lipidation of the
gamma subunits of the heterotrimeric G proteins. 
DR.
D. JOHNSON: There is a lot of redundancy in the presentations, as
well as the systems, in terms of the clinical issues and, of course,
some of the issues that we discussed related to how one assesses
the activity of these various agents and compounds and the relevant
end points in bringing forward to clinical study a particular product
like a tyrosine kinase inhibitor or a broad spectrum neuropeptide
inhibitor. How does one assess the biological activity, not so much
in the cell culture but in the patient himself or herself? How do
we know, for example, that the product is even being absorbed if
it is an oral agent? This is a problem with some of the MMPIs, for
example. I won't reiterate the discussions that have already been
had vis-a-vis response rates, although I will just interject a personal
bias I had that it is a bias to assume that these products won't
cause tumor regression. 
Again,
we talked about trial design, and I won't belabor the point. Do
we do classic Phase I studies? Do we do classic Phase II studies?
I think these issues that have been discussed earlier in the morning
session all apply to signal transduction perturbing compounds.
In
an attempt to try to answer some of the questions that were posed
to us in advance of our coming to this meeting, like all of you
we received a Xerox and a faxed copy of questions. 
Again,
we are coming back to the study design questions which we could
dwell on a bit more. We felt with some of these products a maintenance
approach might be reasonable. This has already been utilized with
marimastat and the Bay 12-9566 product. There is a little bit of
a problem there if one is doing a full randomized Phase III trial.
They are lengthy. There is a need for large numbers.