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SLIDES
& TRANSCRIPTS
Friday,
December 13, 2002
NCI
Kidney/Bladder Progress Review Group
Nicholas
Vogelzang, M.D.
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| Slide
1: |
 I'm
going to try, in a very short period of time, to summarize this
book. There were almost 20 urologists and chairmen of urology
departments that have participated in this kidney and bladder
review group.
TOP
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| Slide
2: |
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 The
issue, as Marston said to you, is pretty obvious. Prostate cancer
causes 31,000 deaths, but combined, kidney and bladder are not far
behind.
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| Slide
3: |
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 One
of the striking features, the kidney and renal is a major cause
of average years of life lost, because kidney and renal cancer is
a disease of 50 year olds. Whereas, you will notice on this slide
from the NCI, bladder and prostate have the lowest numbers of years
of life lost.
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| Slide
4: |
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 So
we were impacted, obviously, by the Weinberg hypothesis, namely,
that cancer needs a whole variety of things to grow, but there are
generally six such factors. The basic scientists were very impressed
with this construct.
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| Slide
5: |
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 We
also were informed by the fact that renal cancer is now a set of
diseases with distinction genetic fingerprints, and that each one
of these -- this slide is stolen from Marston -- shows a different
chromosome, a different gene, a different histology. And we believed
that these different genetics were going to have a major impact
on the biology of the disease.
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| Slide
6: |
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 That
has already been demonstrated. As we know, in VHL, where the VHL
complex being disrupted, leads to up-regulation, or accumulation
of hypoxia inducible factor- alpha, which, in turn downstream leads
to excess VEGF production, increased PDGF, as well as increased
glucose transport.
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| Slide
7: |
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Peter's role in this was to look at the bladder story. The bladder
story is not quite as distinct as the kidney story in terms of genetics,
particularly family genetics, but we can see chromosome 9, 11, and
17 are all well defined.
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| Slide
8: |
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 And
there are very clear pathways within progression patterns that are
related to chromosomal differences, namely the chromosome 9 for
low grade, whereas, the p53 and RB pathway for carcinoma-in-situ
and dysplasia. So again, the theme was that genetics matter.
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| Slide
9: |
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One of the problems though is that methylation patterns where genes
are silenced without being mutated is a dark horse for bladder cancer,
and for kidney cancer. And this may mean that we don't have nearly
the full story on the genetics.
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| Slide
10: |
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 So
what did we decide we needed? When we got together we said we needed
to understand the pathways for all tumors. We need to understand
if it is mutation that causes silencing or methylation that does.
We need longitudinal studies, better animal models, tailored therapy,
and earlier detection.
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| Slide
11: |
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 This
is our algorithm. You can find this in the book. We broke it down
into discovery, treatment, translation, and cancer control. And
we came up with 13 endpoints.
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| Slide
12: |
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 Number
one, understand the biologic mechanisms underlying the two diseases.
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| Slide
13: |
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 Number
two, understand the global genetic mechanisms. And by the way, we
argued over these for four hours the last day of the last meeting.
It was quite an interesting experience in the politics of science.
You can read
this, but we felt that it was critical to develop fingerprinting
of a variety of tumors to show how these tumors, at their genetic
or methylation pattern level have a role in subsequent progression,
response to therapy, and maintenance of subtypes.
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| Slide
14: |
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There was a lot of interest in organogenesis. What are the molecular
underpinning of the development of the kidney, the development of
the bladder? Are these kidney and bladder stem cells relevant? How
relevant are they? There is little known about them, and we must
spend more time at them.
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| Slide
15: |
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 And
then an alternative or corollary of this was then to develop transgenic
models. There are remarkably few transgenic models of bladder, or
of kidney cancer. I have heard of several that have been sort of
published or at least are starting to be published. But we are very,
very far behind in the development of transgenic models for these
diseases.
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| Slide
16: |
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The translational group wanted us to really get on the stick for
proteomics, to develop and examine the urine, to look at these endpoints
in the setting of clinical trials to predict not only response,
but also resistance and progression. So for bladder cancer, it's
nice to know that BCG and interferon works, but tell us why, is
the question. Tell us why. Don't just make an observation, explain
the mechanism.
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Slide 17: |
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 To
facilitate the development of non-invasive techniques. A big push
here for radiology, for PET scan, for MRI, for markers. We need
better markers.
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| Slide
18: |
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 Find
the agents that are going to target the pathways that have been
discovered, and use them.
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| Slide
19: |
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 And
these will in turn, lead to innovative therapeutic strategies that
are focused on mechanism-based agents. These should allow us to
have novel delivery strategies, et cetera.
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| Slide
20: |
Going back to this algorithm that the NCI has discovered,
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| Slide
21: |
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 you
should be aware that anti-VEGF now has established itself as a major
player with this 10 percent response rate. That seems like a trivial
response rate, but the high dose antibody, without any other treatment,
has an activity.
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| Slide
22: |
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 And
it not only has an activity, it impairs time to progression. You
can see that there.
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| Slide
23: |
|  That
was Jim Yang's work by the way, from the NCI.
Treatment -
Develop innovative approaches for both localized and advanced disease,
taking into account stage and molecular factors.
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| Slide
24: |
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The prognostic sets for genes for renal cancer, shown here on data
from the Vinanal(?) Institute in Bintay(?) can be well defined.
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| Slide
25: |
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It can be cancer chip. A bladder cancer chip is needed.
I saw in Cancer Research this past week, a microarray of cell lines.
We need microarray of the tumors themselves.
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| Slide
26: |
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 This
is the data from UCLA and Drs. Zinsman and Belledegrun. Look at
the metastatic patients -- see the asterisks. Metastatic patients
are found in group 3, group 4, and group 5. Not all metastatic patients
do badly. There are clearly differences here that we must understand
the molecular biology of.
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| Slide
27: |
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 Treatment,
nine. We need the protein signatures, and we need markers.
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| Slide
28: |
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 Number
ten was looking at palliative care.
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| Slide
29: |
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 From
a medical oncology perspective, hypercalcemia, brain mets, pathologic
fractures are a major portion of our work, and consume immense amounts
of patient and human suffering.
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| Slide
30: |
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You will hear about myeloablative therapy. This is a non-myeloablative
allo-stem cell transplant. And you will see that now in four studies
published, the response rates, although low, are inducing long-term
cure of these patients. And we think this should be more widely
applied.
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| Slide
31: |
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 Describing
the impact and quality of life. You have already heard about this
large pool of patients. There was a lot of support for looking at
the health-related quality of life in these patients. So, one of
the cancer control foci will be to fund research that looks at those
long-term survivors.
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| Slide
32: |
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 We
estimated 500,000. You heard Mike O'Donnell say pretty much the
same.
The second malignancy
risk you heard Harry Herr just say 20 percent of preserved bladders
get a second malignancy. What about chemoprevention? We know of
only several chemoprevention trials in the United States. There
must be more going on.
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| Slide
33: |
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 We
lack investigators and instruments. We need to look at the role
of smoking both in kidney and bladder.
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| Slide
34: |
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 This
would be to now take those markers that have been identified, and
apply them as prevention strategies, using transgenic models if
needed, but also to try to reduce progressive disease.
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| Slide
35: |
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 And
I'm going to just point out that kidney cancer is shown on this
upper score localized disease. Look at this increasing rate of kidney
cancer since 1975. There is something that we haven't yet figured
out.
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| Slide
36: |
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 We
believe that screening works for bladder cancer. It may work for
subpopulations of genetically identified renal cancer patients.
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| Slide
37: |
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 And
lastly, there are huge gaps in the standards of care that exist
in bladder and kidney cancer patients.
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| Slide
38: |
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 For
example, Harry Herr pointed out that women experience substantially
more delays, are nearly 50 percent more likely to die of bladder
cancer, and their death rates from bladder cancer has not declined.
Likewise, elderly
patients, remarkable under-treatment and under-diagnosis of elderly
patients with bladder cancer. We all are to blame at some level
for this. And African American men particularly, have an extremely
quick rising rate of renal cancer and death.
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| Slide
39: |
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| Slide
40: |
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 Resources.
We thought that the centers of diseases Specific clinical research
need to be expanded. Many of us come from institutions, where we
are, as one of my colleagues says, one cell thick. There are two
or three of us at an institution. That is not enough for a SPORE.
So we need to develop multi-institutional consortia. We need animal
and cell-based models. We clearly need better training. Marston
has been very vocal about this at the national level.
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| Slide
41: |
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 Validated
input for RNA and DNA screening trials, and non-invasive modalities
need to be done.
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| Slide
42: |
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 Enormous
opportunities exist for defining the biology of the disease, which
will in turn lead to better staging, better treatment, and improve
populations outcome. We call this an ecosystem for urologic oncology.
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| Slide
43: |
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 Twenty-four
thousand Americans die every year of two diseases. The death rate
from bladder cancer has declined. It can be reduced from renal cell.
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| Slide
44: |
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TOP
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| Slide
45: |
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 Here
is our group. We had about 45 people. Almost 20 of these were urologists.
The PRG participants, 120 came from all over the country and world.
Jorge Gomez did a great job of keeping us on track. We had 13 science
writers that turned this thing around in about three months. And
we had tremendous support from the NCI.
Thanks a lot.
Sorry to make this so rushed.
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