Panel (Proteus Syndrome Foundation Family Conference)

Uploaded by GenomeTV on 12.10.2011

Female Speaker: I think -- oh, yeah [inaudible].
Male Speaker: Kim's question was, "How should we do this
Female Speaker: I don't like to put [spelled phonetically]
things [unintelligible].
Female Speaker: Okay, I'll go first. [unintelligible] not
going to sleep, went to the bathroom at 3:00 and wrote everything down. So not necessarily
knowing [unintelligible] asking the questions as much as I guess [inaudible]. You know [spelled
phonetically], the first conference that you guys had [unintelligible]. So we started with
you guys in 2001 -- February of 2001. [unintelligible] Way too many things going on. The first family
conference we came to was in the fall of 2004 --
Male Speaker: Your daughter can do it so you can too.
Female Speaker: Oh, my daughter, yeah. So the first family
conference we came to was in 2004 and that previous winter I had lost my husband. So
I came to this conference to learn how to deal with Proteus syndrome on my own, which
-- it was wonderful to meet all these families and, you know, you left there, everything
felt good. We came to the next conference; everything was wonderful leaving there. Kathy
was talking about us trying to find, you know, the doctor who's supposed to be taking care
of our children. I don't think she realizes it's you guys.
You guys open up your hearts to our children. You know their condition; you know what's
going on, and we trust them with you. So now we're in the present day conference and we
have found the cause. But my concerns on leaving here is Julie's going to be calling some people;
we don't know who -- for you guys to ask us to put our children on a drug. And that's
kind of nervous and questions and for some of us Proteus isn't a horrible thing. But
can the side effects of the drugs make it worse? Can it make it -- so what I think I'm
asking is between now and Julie's phone calls, what do we need to be doing? What are the
type of questions that we need to be thinking about to be asking you guys to put our children
on this? Does that make sense?
Male Speaker: State your name [inaudible] --
Female Speaker: Well, I figure Julie will be the one calling
everyone to say okay --
Leslie Biesecker: As Groucho Marks [spelled phonetically] said,
I represent that comment.
So, yeah. So therapy is a mixed blessing. And the hope is that it will be 100 percent
effective and have no side effects, although that is generally not how medicine works.
And I would actually say, though, that the situation that you're describing is actually
the same as what you all have been doing all along, because the royal we [spelled phonetically],
mainly the lady sitting next to me, have been doing some fairly risky things with many of
our patients over the past -- how many years ago did you first start?
Female Speaker: 2000, 2001?
Leslie Biesecker: 10 to 12 years. And so there's a -- we've
been making those decisions along with you all about whether, and if so when, to operate
on a patient with Proteus syndrome, and we scare the pajamas off of you about all of
this DVT [spelled phonetically] stuff all the time, and so those are real risks. And
we had a great question yesterday about something even as apparently mundane as an X-ray; that
has risk. And we are in a situation everyday with every decision we make about every one
of these kids is whether to do something or whether to keep an eye on it and see how things
And we make those calls all the time and they all involve trade-offs and when we're making
them we don't have, necessarily, all the information to allow us to be certain that we're making
the right choice, so that causes you all anxiety and it causes us all anxiety as well. And
so, we've been actually living in that world for a long time and I think we are mostly
comfortable with it; we don't like it, but we're mostly comfortable with it because that's
just the way it is and we have to keep moving forward, and that's the only way we can move
forward is by making those decisions using good judgment and trying to improve things.
And we for sure have improved things since 1996, I mean these things that Dr. Tosi described
that are almost routine, we treat eight-Plates [spelled phonetically] as well, we just do
that now.
Female Speaker: Right.
Leslie Biesecker: We just do that. 12 years ago, we had no clue
about eight-Plates and how incredibly useful they can be. And we didn't know when you put
that first set in if those screws were going to fall out, if that was going to cause the
bones to be fragile and lead to fractures or accelerate the overgrowth; we actually
had no idea. In retrospect now, it seems wonderful, obvious, and now it's routine. We didn't know,
and so we're going to do the same thing with treatment and I think we'll make good decisions
and there is no knowing how it will turn out. And we'll make prudent decisions and go forward
and I think it'll be an exciting adventure. I'm actually very optimistic about it; I don't
have rose-colored glasses about it, but I'm very optimistic. I think things are going
to be better.
Male Speaker: Les, could you address the possibility of
a mouse model in which you could test the drugs on? I mean, there are so many models
that come up all the time for this. What about the possibility of one for Proteus and using
the drugs that way?
Leslie Biesecker: So great question. It --
Female Speaker: [inaudible]
Leslie Biesecker: You didn't hear that? Okay. Mike asked whether
or not we should use a mouse model to test the drug before we put it into people. And
that will depend a lot on what we learn when we go out to meet with the pharmaceutical
companies, because they may have already done quite a bit of work along those lines that
they will inform us of. We currently don't know that. When you interact with pharmaceutical
companies, they have trade secrets and actually -- I mentioned this yesterday -- Julie and
I have spent time with our legal counsel negotiating agreements, we have to sign legal agreements
with the company as to what they'll tell us and what we're allowed to know and what we
can and cannot tell other people so it's really -- it's crazy. But they're going to give us
all this data because we just don't know.
And a substantial amount of this work may have already been done and will be very reassuring
and useful, but it will always be a trade-off as to how long do you want to wait? How sure
do you want to be before you're confident enough to give it a try because you think
the odds are good enough that it's going to help? Which is, to me, the exact same decision
we make with Dr. Tosi every time we take a patient to surgery. Should we do it now or
should we wait until it's more serious, more compelling, or are we potentially losing an
opportunity to make it better now and have a better outcome if we do it now instead of
later? Those are tough trade-offs.
Female Speaker: And I think a number of people in this audience
are particularly aware of how the orthopod [spelled phonetically] is particularly tied
into the growing organism because there's so many things that we can do to manipulate
growth pre-pubertal, and once we get to a certain point, then we're talking about hacking
versus subtle nuance. And my money -- shall we all go to Vegas? -- my money is that if
we can use this drug more safely in a younger child, that that is going to be more effective
simply because so much of the disorder is boney and I've never seen bone turn around.
It's one thing to melt tumors; it's another thing to change bone. So that -- if you look
at my prejudices -- and I always try to be open-minded, but I'm a mother, I'm not -- we're
going to have bigger challenges than ever because I think the drug will be most effective
in the growing individual.
Male Speaker: Any more questions?
Female Speaker: Well I think it's more what do we as parents
right now need to be thinking about if Julie does call?
Female Speaker: [inaudible]
Male Speaker: Stay tuned. We just don't have enough information,
I think, right now, to answer that question because we don't know what the dimensions
of the decision that you will need to make will be. But you will have to be thinking
about --
Female Speaker: [inaudible]
Male Speaker: You might not. But I think it is -- it will
mostly be similar to how we make decisions about surgery. You're doing -- it's an intervention
that has risks and benefits. Some of the risks are known; some of the risks are not known.
Most of the benefits are known; occasionally, some of the benefits are not known. So it's
hard, and that's another decision making process that is intrinsically anxiety-provoking when
you're making a decision and you know you don't have complete information. It's hard.
Female Speaker: [inaudible] ask people to stand up and [inaudible].
Female Speaker: This is basically a re-ask of a question that
I asked earlier today, but I thought many of you may have -- want the same information.
And my question was, now that you've gotten to this point with Proteus, what is the ability
to do additional research on CLOVE or other of those through NIH? Other -- those overgrowth
[low audio]
Male Speaker: Hold the mic closer to your mouth.
Male Speaker: Oh, okay. So, great question. And I think
this is a question that gets to resources and priorities and strategies and tactics
and it's also a hard question. You guys are two for two on tough questions. I think there's
no question that right now, in the current fiscal climate, with resources actually declining,
not staying stable, but actually declining, it's not realistic to think that we could
launch a clinical and molecular research effort on CLOVE syndrome today that would match the
size of what we're doing with Proteus syndrome. That just is not fiscally possible.
Resources are, as I mentioned -- we're lucky if we're flat and we're probably going to
be going downward. So, expanding, doubling the size of our operation to include a CLOVE
study that is as big as Proteus is not going to happen. So we have to be very tactical
about how we do this and we will -- we're already working with a couple of other groups
to help them with some things that are going on with CLOVE syndrome, at least in the molecular
analysis. We are going to evaluate very, very selected patients that have overgrowth disorders
that overlap with Proteus syndrome, but again, it won't be on the scale of what you are all
used to with Proteus syndrome with regular visits and these full week-long evaluations
and things like that, because if we did that, we would have to cut back on what we need
to do with Proteus and that means that we would not be able to do a treatment trial.
And there's just no way we're not doing a treatment trial; we're going to do it.
So, we're going to go forward and we'll be sort of -- try to do pin prick approaches
to CLOVE and other overgrowth disorders that can help advance things, collaborate with
other people; we're not the only research lab in the world who can do this stuff, and
so if other people are interested, our efforts would be better used in helping and encouraging
them instead of trying to replace what they're doing.
Male Speaker: Yes, when you go to look at AKT1, I mean,
there is so much interaction with some signaling pathways like mTOR and rage signaling. And
if you go to look at the probably 50 or 60 things that are connected with it, is it possible
that the approach to CLOVE, at least, and perhaps hemihyperplasia-multiple lipomatosis
might be somewhere on one of those pathways connected to AKT1?
Male Speaker: Yes.
Male Speaker: It might be less work than going through the
whole thing, that's what I was getting at.
Male Speaker: Absolutely.
Female Speaker: I'll just add to that, and several of you
know this already, that I do have quite a bit of information about CLOVE-specific research
efforts that are being conducted at various centers throughout the country so that's something
that I have, so if you want that information you can see me, and I'll get it to you.
Male Speaker: Although I think we should warn folks that
when -- a research program on a disorder doesn't mean the same thing everywhere. And what those
of you who have been to the NIH for the in person research evaluation that includes multiple
clinical, or what we call phenotypic assessments as well as the molecular research, that's
sort of a relatively full package of evaluations and other places, when they say, "We are studying
CLOVE syndrome," what that may actually mean is that if you wish, you can have your doctor
send them a tube of blood or a piece of tissue and that may be all that the study is. And
so you have to investigate it and see what the study comprises and what the components
are and what you have to contribute and what you get back, because a research program on
a disease means different things to different people.
Female Speaker: [inaudible]
Male Speaker: Wait, wait, wait, wait.
Female Speaker: When you were giving your talk, you said something
about the, I'm probably going to say it wrong, the prosthesis leg, and you said it's hard
to fit because of the boney overgrowth that comes out. Can't they do in the top of that
leg a cushion that those boney growths would go down into? I was thinking about that going
down into something hard --
Female Speaker: Absolutely. The challenge -- it's different
if you amputate a child, typically, than if you amputate an adult. So, many adults, sadly,
get amputations either from trauma or very commonly, sadly, from diabetes. They are done
growing and you cut the bone and you bring a flap of, hopefully, has muscle and skin
over, and you hopefully have a relatively flat end. And the way they make the sockets,
most of the pressure actually isn't on the end, but it's actually around the cut part
of your upper lower leg. And with good care, most adults with an amputation have fairly
good results.
Kids are funny. And they're challenging. When we amputate a child, which hopefully we don't
do often, but there are many reasons why it has to happen, we, interestingly enough, try
to, in most cases, amputate them through a joint. So think about, when you go for fried
chicken, you tear apart a joint, the end of the bone is covered with soft cartilage. And
that turns out to be a nice, smooth end, and I bring my skin up over, the child does well.
When I have to amputate through the middle of a long bone, it means I'm going to be coming
back every year or two because children's bone is growing and the bone gets confused
and often the bone will grow these long, sharp swords out the end of the bone. It doesn't
understand that I don't want it to grow anymore.
And so, amputating children is really difficult and even though I work with a prosthesist
to have a nice catch just below the knee so that we're trying to catch the soft tissue
and take most of the weight through there, if I've got swords growing out the end, I've
got a problem. So, you'll watch me always try to nurse almost any deformity I can, through
puberty before I amputate. That's more long-winded, more technical than you wanted, but it's thinking
about that whole issue of growth is the lifeblood of pediatric orthopedic surgeons. And when
I'm thinking about a problem, I'm thinking about where am I in growth. Not that we can't
amputate -- we can always amputate, we often have to amputate -- it's how can I make sure
the child isn't coming back to the OR every year or two? How can I make sure the child
isn't infected because they didn't want to see the doctor and they let a spur give them
a deep ulcer that's now infected?
Male Speaker: I'm actually going to add on to that as well,
a little bit. I know you all met Chris yesterday as well, with the insoles, and I've been talking
to him very closely related to prostheses being a lot of people and a lot of Proteus
people are going to be using them here soon. So what I've decided to do with him is we're
going to try to custom make the where the cup and the socket go into the cup, and it
would almost be like the same process as the insole itself. So, when they do fit down into
the insole, it's almost going to be like the golf ball on the bottom of the foot going
into it, so it can relieve some of the pressure, but as Dr. Tosi also said, when it gets -- when
it needs to get done to get resurgically shaved down, if it needs to be shaved down, then
he can just recustomize the molding for it as well, but we've been talking about different
attribute with that to see how it can help and figure out how to best comfort the people
that have amputations.
Male Speaker: Anybody?
Female Speaker: Okay, there are a couple questions from people
who couldn't make it, so these are questions on behalf of them. The first one -- I don't
know who this is directed to, but -- what is the status of Dr. Everman's [spelled phonetically]
bone scoring study?
Male Speaker: So, David Everman is trying to get that going.
We are dependent upon a collaboration with a German radiologist who is -- has his own
schedule and other projects, so we're trying to negotiate some time with him. He's one
of the best skeletal radiologists in the world and we really need him to be involved with
this, and so David has negotiated with him, and again, it's an issue of funding in that
he was -- this German professor was supposed to have a funded sabbatical to do work at
the Greenwood [spelled phonetically] Genetic Center, where Dr. Everman works. And that
got cancelled because of funding issues, so that set things back a little bit. So we're
always dealing with these realities -- sorry, thanks -- of financial resources versus desires
and we have endless desires and needs for things we want to do and we have monetary
realities. We're working through that the best we can.
Female Speaker: There is a second question from those who
couldn't make it today, so the second question is, "Will a drug only help those who are newly
diagnosed or mildly affected? And how will the drug affect the bones and internal organ
[low audio]
Female Speaker: I think that -- I don't really know the animal
studies, so -- and I think we're all waiting to hear about animal studies, but my expectation,
not my knowledge, but being an orthopedic surgeon is that any drug would -- that affects
bone would affect it best during growth. These are the other problems that we face. Lung
changes, blood clots, the skin -- that, I think, it something I think we will follow
with huge, great interest because we have no idea. Because the interesting -- everything's
always turning over, so even the bone could change, but I don't know how it would. I can't
imagine it changing shape. I can't imagine it rebuilding joints. But there's nothing
to have dissolve. So, with, for instance -- we don't know why everybody's so -- why so many
patients are prone to blood clots, but would this potentially change the walls of the blood
vessels? Would it potentially change the clotting cascade? The list of maybes is huge. Could
-- I mean, we do know that some drugs do melt bad things. Could we see the changes on the
bottom of the feet melt? That's very different than bone. Don't know. Yeah.
Male Speaker: So, in terms of skin, I agree with you; I
think that the skin may be more responsive than the bone to treatment with an inhibitor
of AKT1. So -- and I'll just share with you some experience that I've seen in a different
disorder. It's called tuberous sclerosis complex, but in tuberous sclerosis complex, people
-- they get these very firm lumpy, bumpy skin lesions. Usually they're on the lower back
and on the face, not on the feet or the palms like in Proteus syndrome, but they came up
with a treatment for that based on an understanding of the signaling pathway that was abnormal
in Proteus syndrome just as the similar approach that Dr. Beisecker is using right now.
And in the treatment of that, I thought -- my impression as a dermatologist was that the
redness of the lesions would go away, but probably not the lumpy, bumpy stuff. And I've
been very happy to see that the redness is one of the first things that improves in these
patients, but the lumpy, bumpy, thickened skin also gets thinner; it flattens out. And
that, to me, has been very remarkable and very encouraging, so I don't know what that
means for Proteus syndrome, but it is -- as you were mentioning, it's all a matter of
the remodeling and so you're continuously, in the connective tissue nevus, there's this
making of collagen and breakdown of collagen, and if you could normalize those cells, then
maybe the breakdown will begin to pick up and that deposition of new collagen will slow
down enough to actually see some improvement.
That would be the great news. I don't know if that will actually happen for Proteus syndrome,
but I'm encouraged about the possibility because of what we've seen in tuberous sclerosis.
Female Speaker: Okay. When the drug company comes forward
with the drug, I'm wondering, why wouldn't we let all the Proteus patients decide whether
or not they want to take it? I'm -- and maybe I'm having a misunderstanding, but I think
that I'm understanding that Julie will make phone calls to kids who you think will benefit,
but the reality is the Proteus group is so very small and it just seems like we, as families,
just hang on every hope and, you know, with Dr. Darling having seen what he's seen, I
don't think there's any Proteus family who would not like to see the reduction of that
skin on the feet if there was any hope of having it.
So I guess my question to you is would you consider, or are you considering and I'm simply
misunderstanding, that perhaps all the Proteus families would be invited to say here's what's
up, you need to decide if you want to participate or not, and then just do that very normal
means you may end up with people who don't go forward and you may end up with people
who do go forward. But I thought that I understood that you weren't going to try to have a control
group and again, I could have misunderstood, but -- so I'm thinking that you're not deliberately
going to have some people not have it because there's no -- what's that when you take it
-- placebo -- because there would be no placebo so anyway, what are you thinking?
Are you thinking small group or are you thinking that everybody have a crack, because you know,
once those windows close, you know, and some of us are -- our kids are already in puberty,
and if we're going to have to do mice models and wait and are we going to get in or not
in or have that opportunity or not, you know? Or do we all have to beg you and -- [laughs].
Male Speaker: Another great question. So, when we were -- when
Julie and I were presenting over at the PSF U.K. meeting, I think it was -- was it you
that started the notion of climbing mountains? The metaphor of climbing mountains and there's
this wonderful book by this guy up at Harvard, Paul Farmer, and it's -- the title of the
book is "Mountains Beyond Mountains" and it's about actually trying to implement medical
care in Haiti. Completely different set of challenges than what we face, but as difficult.
And the notion is that you have a lot of mountains that you need to climb, but you can't climb
the second one until you climb the first one, and if you don't get over the first one, you
never have an opportunity to climb the second one, the one that's behind it.
So our goal is to get over that first mountain with the highest chance of success that we
possibly can. And our goal will be to include as many people as we possibly can in doing
that, but the truth is for all of us, that -- remember that these are unapproved today,
these are unapproved drugs, and no one has any access to any of them -- so what we want
to do is do whatever we can to get that situation changed. And we will do just about everything
we can to try and do that. And that may mean that not every single patient who has the
diagnosis of Proteus syndrome will be participating in that first trial. We may not have to use
controls and placebos; there is a variation of a control, where it's called what we call
a cross-over control where everybody gets the drug, but they get it for half of the
time period of the study and you measure how much that person progresses during the time
when they aren't taking it versus when they do, and then you start with half on and half
off and everybody switches place. And that allows you to give the compound to everyone,
but still have a control and the patient is their own control. Ways to do that, and there
are also ways to do studies without formal controls and we have to explore all that.
And as I mentioned yesterday in the small group, it is going to be essential to get
more people involved because again, if not every single person is eligible, we need as
many people to select from and enroll as we can possibly get. As I mentioned yesterday,
as well, that what you all have been involved with is what we call a natural history study,
which is understanding how the disorder evolves and doing what we can symptomatically, and
that's a different kind of clinical research than is a drug trial. And so, you are all
incredibly motivated and committed people and have contributed a lot to this natural
history study that we've been doing, and it's been successful beyond our dreams, as far
as finding the cause, finding treatments, managing complications; it's been phenomenal,
but it's a different business to do a trial.
So we're going to hope and we're going to try and work with you all to recruit even
more people, and I think we can recruit more people because more people, frankly, will
be interested if we have a drug to offer than if we say, "We want to just follow your kid
and see what happens and learn from them." Not everyone is really willing to do that.
If you have a drug to offer, maybe more will be, and so we'll try and recruit more people,
so we will try and include as many people as we possibly can, but our overwhelming goal
is to get over that first mountain, which is to change our situation from one where
there are no drugs available to anyone to where there is a drug that is available that
we can work with. And that's what we need to work toward.
Female Speaker: And just to add to that, I think, as Dr. Biesecker
is mentioning, we've never done this before and we are learning as we are going and that
right now, we're sitting in a place that is not very comfortable for anyone, which is
this place of a lot of uncertainty. We were really just kind of speculating about what
our plans might do and we -- I think that the main point is that we are very appreciative
of all of these concerns. So we've never done it before, but we know enough to know that
this is a big deal, that it's a big deal when you're designing something that's completely
new and when you're asking parents to consider whether or not they want to trade a set of
known issues for a set of unknown risks in hope of possibly achieving a benefit that
is also completely unquantifiable.
We understand that these are big issues and that's what we know and why we hope to continue
to talk with all of you because we're all going to learn kind of how to do this and
how all of these different issues sit with us over time, which is why I think it's more
-- and starting a clinical trial like this is more than just a set of eligibility criteria,
right? I mean, at the end of the day, as Dr. Biesecker mentioned in his talk and as we've
talked with many of you here personally, every patient for whom we reported in our paper,
every number that's in that diagram is a person who helped us to do this, and we appreciate
that all of you are people and that there are personal implications to all of this,
and we hope that we can just continue to learn how to manage all of these things together.
Female Speaker: When you talk about recruiting people for
the drug trials or whatever, and I know you've got a number of steps to go before we get
there, but will you be -- how do you advertise for more people? Are you going to do it on
our website? Do you do it through advertising in different journals? I mean, how are you
going to get more people to, you know, take part? And I know, there are other people out
there that have Proteus that, you know, maybe not part of our group or haven't stayed as
active, but, you know, how do you plan to get them back into the fold?
Male Speaker: So, as I mentioned in one of the small groups
yesterday, we are already starting to get inquiries since the paper was published of
folks who haven't been involved with your foundation or with our research study, and
I think it's -- what's the number?
Female Speaker: Eight, nine, 10 -- it goes up every day.
Male Speaker: Eight to 10 since July, which for us, is a
huge bump. That's a big increment of patients and I think that we should expect that if
we make a trial known that we will get an even larger bump in that number. So I'm very
confident that there are more patients out there, and again, they lack this incredible
attribute that you all have of being so invested in the foundation and the research study already,
they obviously haven't been doing that, but when we offer treatments, they're willing
to put their name forward. And so, yes to all the things you have said, advertisements
in journals, Web, we will post signs at meetings, give seminars on the treatment trial, et cetera,
put the word out any way and every way we possibly can and patients will, I'm sure,
come out of the woodwork.
Female Speaker: Now, are these -- would [spelled phonetically]
these patients have to be -- go through the process again? I mean, [unintelligible] if
you've not had them in your study before, I mean, are you going to have to make sure
that they fit the criteria before, you know --
Male Speaker: So the question was what evaluations and workup
on testing will the subjects for the treatment study have to undergo? And it will probably
not be exactly the same as what you all have done because what most patients who are here
have undergone is a set of individualized or customized evaluations that's based on
a hybrid between what we're interested in studying and the needs and challenges and
problems that you all communicate to us. So the truth is every patient who has been through
our study has had their own research evaluation that isn't exactly the same as anyone else's.
And that situation changes completely with a drug trial. And we will design certain criteria,
and we'll design things in such that if somebody has already undergone some studies, if they've
already had their full body X-ray skeletal survey, then we may not need to do that again,
we can maybe use something that's a little bit older. We may not have to go through the
evaluations, so we'll try and minimize that, but it will be very rigorous, very uniform,
and pretty selective, and we will probably use some combination of the clinical criteria
together with testing for the mutation in the gene that we have described, and it'll
be some combination that will make people eligible.
Because again, we don't want to risk the trial failing because we've mixed in people who
have something different going on for which this treatment would be expected not to work.
That would dilute the effect, the trial will fail, and we'll be back to square one, which
we definitely do not want to have happen; that's again, that first mountain we have
to get over.
Female Speaker: So, in the talks yesterday, I know you mentioned
that in some of the tissues that you have tested for the AKT1 mutation that some of
the tissues that you found that there wasn't a mutation -- I know this was a small subset
-- and I know there might be many different reasons for why you didn't find the mutation,
but one of these possibilities could be that there is another mutation for Proteus out
there. As far as, you know in regards to this, do you think you'll continue looking for another
mutation or do you think, you know, you're done searching for the Proteus gene?
Male Speaker: Great question. So, the most likely explanation
for the patients we have so far evaluated and who have had a negative test result is
that we have, in fact, in our laboratory, the wrong specimen or a sample that has an
amount of variation in it that's too low to detect. So since that is the most likely explanation,
our efforts would be best effective if we work on solving what we think is the most
likely problem, which is that we need another specimen that's more clearly affected, or
we need better detection techniques to find that it's actually there.
But we will continue to work along that avenue until we do enough work that we begin to be
convinced that actually that the answer isn't that it's that alteration that is just not
being detected and that it's some other one, and then we change, we jump horses and get
on a different horse, and we say okay, then what else is it? And we will look for other
alterations in the same gene first and then we will do what Dr. Cohen just suggested which
is to look for alterations in other genes in that pathway, and then the third thing
we will do is what we did with the 17 samples at the beginning of this study, which is we
will sequence everything. And so, we do it in a step wise fashion to use the least amount
of research resources, i.e. Julie's time and Marge's time and your colleagues in the laboratory
to get to the answer that we want.
Female Speaker: Okay, I have two questions. The first would
be is there funding available and in place at the NIH to launch a clinical trial of the
magnitude that you're, you know, looking to do? And second, you've alluded to making this
visit to a drug company that, you know, hopefully there can be a promising relationship with.
If that somehow falls apart or fails to go forward, what's plan B?
Male Speaker: So, for the resources, I can't answer your
question precisely right now because it's a sort of circular thing, because I don't
know exactly yet what the scale and scope of the trial will be so I don't actually know
if we have enough resources to do it. Certainly we will be, as part of those meetings, learning
and interacting and negotiating what the scope of the trial will be, as well as -- the companies
always have to contribute resources to these efforts as well; it won't just be NIH that's
paying for this, so that will be a negotiation as well as how much resources the company
will contribute to this effort. And so we'll be doing -- that whole, very complex negotiation
will be initiated at this meeting two weeks from yesterday.
I'm pretty -- I'm very optimistic that we will be able to marshal the resources that
we need to do this trial. I think it is very doable and it's the kind of a thing that the
NIH has set as a goal, which is not just to find causes of disease, but to treat disease.
So that is clearly and important -- you'll hear about that tonight at dinner as well.
NIH is serious about that and we'll hold them to that, so I'm very optimistic that we will
be able to do such a trial. That is not to say that we'll be able to do everything that
we want to do, and it's not to say that we'll be able to do everything that you all want
us to do, but what we are committed to do is to do enough to get us over that first
mountain to where we have something that we know works. And I think there's every reason
to be optimistic for that, with again, the help of this group.
One of the things that we will need, as we've said, is more people from whom we can select
and in a trial we will be seeing patients on a very regular, scheduled basis and those
folks will need to be traveling to NIH and they're going to need support and encouragement
to do that, and that's something where the foundation can help enormously.
Female Speaker: Plan B?
Male Speaker: Oh, plan B. That's a great question. So there's
at least two, and maybe three, compounds out there to be considered, so plan B may be company
two or company three, so we have that to pursue, so that's a good thing. One can also take
the pathway of identifying new compounds, which there are pathways now to develop. That
is a much, much longer road. Starting from trying to identify a chemical that has an
effect to making a drug can take from 10 to 15 years, and that's why we were so excited
to learn, this summer, that there was something that they had already done most of the upfront
work; that was just a phenomenally fortunate occurrence for all of us, and so that may
allow us to skip over a decade of work, which is fantastic.
So, I would call that, though, starting from scratch, plan D. I think we've got a B and
a C that we can work on that are much nearer term than that. But there's lots of ways forward,
and whatever way forward there is that's the best way, that's where we're going.
Female Speaker: This one's just a quickie. If there's more
than one drug, would you be able to run two drug --
Male Speaker: I hadn't considered that embarrassment of
riches [spelled phonetically], to be honest with you. I would bet that it's likely, logistically,
that we would run into problems with numbers, with taking our available patients and dividing
them in half yet again. Many trials require -- and this is again, part of the negotiation
with setting up the trial -- that the patients are, in the drug company language, na久e
to treatment. That is, they haven't been exposed to another treatment, especially another experimental
treatment, and so, we don't want to mess things up and limit how many people we can treat
by having more than one compound, because you can't just go from one to the other, necessarily.
So, again, we've got to find out what our best bet is and put all of our chips on that
Female Speaker: The lady with all the questions, I am, I am.
Okay, I know that you all have a million questions in your mind, as I do, and hopefully I will
hit some of them. First of all, we are so thrilled that the gene has been located. So,
your daily plan, now that you've got this gene, and we're thinking oh my goodness, now
he's got this time he's going to another something. But I know that's not the case because there's
a lot more to do now that you've found this. You'll still be seeing new prospective Proteus
children for patients, et cetera. You'll still be seeing some of the children here, I'm assuming.
And on top of that, you're going to be working with the drug companies to have them come
up with this treatment.
There -- the current medicine that they're -- or the current drug that they're talking
about is the drug that will treat the growth part of cancer is my understanding, and if
I'm wrong, you know, because of the growth. This is like the overgrowth of the bone in
relationship to the overgrowth of the tumor in breast cancer. That's what I'm understanding,
and like I said, I may be wrong. So, we know what you're up against. I know you're up against
a large amount of unknown, but knowing your history, that's no problem. But what can we
do, now, to help you? Where should we direct our efforts? Yes, we'll still be there for
you, our kids and whatever you want of us, we will do. But what more can we do to help
Male Speaker: So I think as I said yesterday in the small
group session, I think the top three priorities are recruit, recruit, recruit. So, as many
people as we can have available to participate in the next phase, success will almost certainly
depend on numbers. We need numbers to make this work, and the more numbers we have, the
more likely it is that it will succeed. And so, yes, there's a lot of unknowns, you know,
that's why it's research. We're not looking for things we know are there; we're looking
for unknown things, and there's a lot -- there's always open questions and we'll need to design
the trial in such a way to minimize the unknowns and the surprises, but there will be some
along the way, you can be sure, just like there have been in the past 15 years.
Your first part of your question was, I think, directed towards are we going to stop the
natural history trial when we start a treatment trial? So the answer to that is no. We are
still interested in seeing patients and evaluating them to do what we have been doing in the
past, and I am sure that those patients will end up in Dr. Tosi's clutches down at Children's
Hospital. They will also be seeing Dr. Darling and getting care and advice about their dermatologic
issues so those things will continue. They will be affected by the treatment trial, though.
And when a patient is on a treatment trial, there are considerations for what you can
and can't do for that person if they need to stay on the trial.
So, for example, I'm using the analogy of a treatment trial for cancer chemotherapy,
that a person can't go to their -- if they're on a study drug, they can't go to their private
physician and receive a prescription and undergo an additional chemotherapy on their physician's
recommendation because that will then make them ineligible to stay on the trial, because
that confuses the analysis and doesn't allow us to figure out what the experimental treatment
is doing. So those things -- those are real issues, and I think that gets to your question
earlier is, you know, what does this mean for our kids, and it means that, and that'll
be complex and we'll have to negotiate that and be very, very mindful and -- not to fear
that it will endanger the children, because there are, not only all of our philosophy
but as well, the regulatory groups that oversee us, will not allow us, even if we wanted to,
which we don't, to compromise a patient's clinical care in order to make the study work.
What we want to do is make sure we set things up so that we are in that situation rarely
or never, and that requires a lot of thought in how we get this set up so we minimize that
conflict, but it's an important question.
Female Speaker: Could you talk about cancer versus overgrowth
and treatment?
Male Speaker: [inaudible]
Female Speaker: Yeah.
Male Speaker: The other part of your question was about
treating a cancer versus treating an overgrowth. And one thing about a cancer is that it's
usually no just one mutation in a cancer, it's multiple, and so even when you find a
mutation that may be driving the growth of the cancer, when you target that one part
of a signaling pathway, the cancer has, always, other ways of getting around it. And so, it
actually turns out to be more difficult to target a cancer because they have those multiple
mutations versus an overgrowth, where presumably, it's just that one thing. And we're just targeting
that one thing to normalize the cell.
Male Speaker: I know this is probably impossible to answer,
but if somebody puts their child in your study, are you anticipating that it's going to be
a six month, a one year, a five year -- do you have any anticipation of length of time?
Male Speaker: I can't answer that numerically right now,
but I can tell you sort of how we will get to the answer. The answer is determined by
finding a couple of what we call clinical end points, which are something that we can
measure that we expect to change in the absence of treatment for the worse in the patients.
So something that will get measurably worse over some period of time that, if you were
to have a treatment that would stop it, you would be able to, by measuring that change,
show that it's not getting worse.
So what we do is we back calculate the time of the study, from first deciding what the
end points will be and how much we predict they will change and then having a time interval
sufficient that that change is significant and measurable, and then that will be the
end point. So we don't design the length of the study for any reason other than getting
enough of a change having gone by that we can measure. And so it's always designed to
be the minimum, because everyone benefits from the trial being as short as it possibly
can because you want to get to the answer as quickly as you can, not only for your considerations,
but it costs money and it costs more money the longer it goes on. But you want to have
it be long enough that you're confident that you would expect to see a change if your treatment
wasn't effective. So it's all back calculated based on those considerations with lots of
input from statisticians.
Female Speaker: We have time for one more question and then
we're going to do the breakout sessions and -- [unintelligible] --
Male Speaker: The lady in the back hasn't got to ask her
question yet.
Male Speaker: Sorry [unintelligible]. You've had your one,
you're cut off.
Female Speaker: So in the last 16 years, I was to believe
that my daughter had Proteus and now we don't know and she got tested and we find out she
doesn't have it, where do I go from there?
Male Speaker: So for the past 15 years we've been in the
difficult position of what we've called undiagnosing patients. And the first time we did it, back
in 1996 at the meeting -- and this is where clinicians and researchers can get a little
silly and self-absorbed, we were very proud of ourselves, Mike and I, for having, what
we thought, discovered separate disorders within what was previously called Proteus
syndrome and we thought that was incredibly important, useful, helpful, and even went
so far as to think, I assumed, I don't know what Mike thought, wouldn't that be a great
thing, to be able to tell one of these patients, no, actually you don't have Proteus syndrome,
you have something that's not as severe, but oh, by the way we don't actually know what
it is.
And that turned out to be an intellectually satisfying thing for us to do. Yes, yes, it
was about 35, 40 percent of patients, and it has been at least that over the years from
the inquiries we've gotten in the project. But it turns out that that was emotionally
very, very difficult for the families, and we've incorporated -- Julie has incorporated
that into her counseling approach for this, because it's a big deal because it feels like
we're pitching you back into the unknown, which we really don't like to do, and we recognize
the adverse consequences now of doing that, and so Julie works with the folks that we
see to minimize that and help people anticipate that this might happen, but now that we're
making progress on the molecular delineation, I think it will be a much shorter interval
for new patients whose diagnosis is changed, we can figure out what they do have.
And I actually anticipate within even the next year that we will see discoveries of
other genes in this pathway as Dr. Cohen was just saying, that are the explanation for
these overlapping disorders and that we'll be able to nail these down quite quickly.
So I have a lot of hope about that, and so if we do it, please don't despair; there will
be an an answer coming pretty soon for most people. I'm very optimistic. Mike, do you
want to comment?
Male Speaker: In a discussion that I had with Kim a long
time ago, the question was that some people were approaching her that we later found out
didn't have Proteus syndrome, but they're here at the meeting and we welcomed them because
it's important to have support for these families. I'm sorry.
I spoke to Kim a number of years ago about this because she was contacted by a number
of people that had serious problems, but they weren't Proteus syndrome, and they are -- she
welcomed them as part of this group, and some of them are here today. And the idea here
is that we need family support for such people, because they can't get in anywhere else, and
so they're welcome here. I want to say that if we make the diagnosis of Klippel-TrOaunay
Syndrome, on the other hand, they're better off with that society because that society
is at least 10 times the size of ours, so they're well off there.
Female Speaker: Okay. We're just going to take a 10 minute
break and then we'll be back in here -- I have the sheet so if you can't remember who
you signed up for -- and there are still some openings in all the [unintelligible] --