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00:00:15 --> 00:00:19
While she's writing that up,
I also wanted to clarify a point

2
00:00:19 --> 00:00:23
that was raised by a TA last time at
the end of last lecture.

3
00:00:23 --> 00:00:27
Some of you might have thought
about this fact,

4
00:00:27 --> 00:00:32
and it's important to clarify at
least as best we can.

5
00:00:32 --> 00:00:36
I told you last time that people who
inherit a defective copy of the RB,

6
00:00:36 --> 00:00:41
retinoblastoma tumor susceptibility
gene are highly predisposed to the

7
00:00:41 --> 00:00:46
development of retinoblastoma,
a tumor of the eye.  Actually, these

8
00:00:46 --> 00:00:50
patients end up getting bilateral
retinoblastoma,

9
00:00:50 --> 00:00:55
affecting both eyes,
and typically have about a dozen

10
00:00:55 --> 00:00:59
tumors, independent tumors.
And, if you recall,

11
00:00:59 --> 00:01:03
those tumors arise through the loss
of the normal copy of the RB gene in

12
00:01:03 --> 00:01:07
the cells that give rise to these
tumors.  And I also told you that

13
00:01:07 --> 00:01:11
the RB gene is a critical regulator
of cell cycle progression.

14
00:01:11 --> 00:01:15
And so you might have wondered why
don't these people get all sorts of

15
00:01:15 --> 00:01:19
tumors?  Why are they predisposed
only to retinoblastomas?

16
00:01:19 --> 00:01:23
Why not breast cancer,
lung cancer, pancreatic cancer and

17
00:01:23 --> 00:01:28
so on?  We don't actually know in
complete detail why that is,

18
00:01:28 --> 00:01:33
but we suspect that there's a
fundamental difference between

19
00:01:33 --> 00:01:38
retinal cells and other cells with
respect to their requirement for RB

20
00:01:38 --> 00:01:43
gene function.
So I told you previously that RB is

21
00:01:43 --> 00:01:47
a regulator of the cell cycle.
Specifically it regulates the entry

22
00:01:47 --> 00:01:52
of cells from the G1 phase of the
cell cycle into S phase.

23
00:01:52 --> 00:01:57
It blocks.  And it has to,
itself, be inactivated for tumor

24
00:01:57 --> 00:02:02
development.
Or rather for normal cell cycle

25
00:02:02 --> 00:02:06
progression.  An we think that in
retinal cells this is the key

26
00:02:06 --> 00:02:10
regulator of S phase progression,
of S cell cycle entry, so that if

27
00:02:10 --> 00:02:14
you get rid of it you now have
deregulated cell cycle control and

28
00:02:14 --> 00:02:18
tumor development.
And we suspect that in other cells

29
00:02:18 --> 00:02:23
where RB is almost certainly
important --

30
00:02:23 --> 00:02:30
-- there are probably other factors,

31
00:02:30 --> 00:02:34
let's call them X, which can also
regulate cell cycle progression.

32
00:02:34 --> 00:02:38
So that even if the cell were to
lose RB, there are other factors

33
00:02:38 --> 00:02:42
that can, in a sense,
back it up.  And in these cells,

34
00:02:42 --> 00:02:46
in most of your cells, although RB
loss might contribute to tumor

35
00:02:46 --> 00:02:50
formation, it's not sufficient.
In these cells other events must be

36
00:02:50 --> 00:02:54
necessary to inactivate,
one way or another, these X

37
00:02:54 --> 00:02:59
functions.  OK?  So hopefully
that helps clarify.

38
00:02:59 --> 00:03:03
Now, I told you last time,
the last two times that we now think

39
00:03:03 --> 00:03:07
of cancer as a clonal progression
from normal cells to tumor cells.

40
00:03:07 --> 00:03:11
The acquisition of mutations in
cellular genes,

41
00:03:11 --> 00:03:15
oncogenes, tumor suppressor genes,
and collectively these give rise to

42
00:03:15 --> 00:03:19
cells that are malignant and
potentially life-threatening.

43
00:03:19 --> 00:03:23
This is interesting information
from a scientific point of view,

44
00:03:23 --> 00:03:27
but is it useful?  Why do we want to
understand these cancer-associated

45
00:03:27 --> 00:03:32
genes?
Why do we want to understand these

46
00:03:32 --> 00:03:36
mutations?  Well,
there are a variety of reasons why.

47
00:03:36 --> 00:03:41
We're going to focus today on
therapy which is directed against

48
00:03:41 --> 00:03:45
the mutations that arise in cancers.
But there are other purposes that I

49
00:03:45 --> 00:03:53
just want to mention to you.

50
00:03:53 --> 00:03:57
Early detection.
Cancer is most easily treated when

51
00:03:57 --> 00:04:01
caught early.  If we know somebody
has cancer, before the cancer has

52
00:04:01 --> 00:04:05
spread, they have a much better
chance of curing that individual.

53
00:04:05 --> 00:04:10
And so it's desirable to have tests
for early detection.

54
00:04:10 --> 00:04:16
And increasingly there are
PCR-based tests looking for cancer

55
00:04:16 --> 00:04:21
cells in bodily fluids.
Sometimes the blood, urine or other

56
00:04:21 --> 00:04:27
tissues.  PCR-based tests looking
for mutations in the

57
00:04:27 --> 00:04:32
cancer-associated genes,
looking for cells that have a Ras

58
00:04:32 --> 00:04:38
mutation or have a p53 mutation or
have an RB gene mutation and so on.

59
00:04:38 --> 00:04:44
So this is not commonplace,
but there are now tests,

60
00:04:44 --> 00:04:50
commercially available tests that
are based on PCR looking for such

61
00:04:50 --> 00:04:56
mutations.  There are also blood
tests for what we call

62
00:04:56 --> 00:05:01
cancer markers.
You've probably heard of the PSA

63
00:05:01 --> 00:05:05
test for prostate cancer.
There are certain other tests for

64
00:05:05 --> 00:05:08
other types of cancer.
These are blood tests that detect

65
00:05:08 --> 00:05:11
inappropriate levels of something,
often something produced by the

66
00:05:11 --> 00:05:15
cancer.  And, again,
increasingly, as we understand what

67
00:05:15 --> 00:05:18
happens in cancer cells,
we'll have more and more precise

68
00:05:18 --> 00:05:21
cancer makers that will be
detectable in the blood in a very

69
00:05:21 --> 00:05:25
simple screening test so that you
can go to the doctor every year,

70
00:05:25 --> 00:05:28
go through one of these tests and
know whether or not you have an

71
00:05:28 --> 00:05:32
early form of one or another
type of cancer.

72
00:05:32 --> 00:05:36
That's not, again,
happening today, at least in a

73
00:05:36 --> 00:05:40
widespread way,
but it will happen in the years to

74
00:05:40 --> 00:05:44
come.  And when it does,
we will be in a position to do what

75
00:05:44 --> 00:05:48
we call cancer prevention.
Rather than waiting until somebody

76
00:05:48 --> 00:05:52
has a full-blown tumor and trying to
treat it, which is difficult,

77
00:05:52 --> 00:05:56
we will hopefully detect those
tumors at a very early stage and

78
00:05:56 --> 00:06:00
then prevent their progression.
So this is not treating cancer

79
00:06:00 --> 00:06:05
really, but treating the
hyperplasias I told you about.

80
00:06:05 --> 00:06:11
Or early lesions,

81
00:06:11 --> 00:06:15
benign lesions before they progress
to true cancer.

82
00:06:15 --> 00:06:19
And we think that this will be
easier to do because those cancer

83
00:06:19 --> 00:06:23
cells will have acquired fewer
mutations.  And,

84
00:06:23 --> 00:06:27
therefore, it will be easier to
design very specific agents that

85
00:06:27 --> 00:06:31
will effectively limit their
proliferation or possibly

86
00:06:31 --> 00:06:35
even kill them.
OK.  Today we're going to focus on

87
00:06:35 --> 00:06:41
the use of this information for
better therapies,

88
00:06:41 --> 00:06:47
ways to design more effective,
more specific anti-cancer agents.

89
00:06:47 --> 00:06:52
And I'll come towards the end to
using this information and related

90
00:06:52 --> 00:06:58
information to do better diagnosis
to try to distinguish two people who

91
00:06:58 --> 00:07:03
have clinically similar tumors.
But those tumors might actually be

92
00:07:03 --> 00:07:08
quite different at the molecular
level, and we'd like to understand

93
00:07:08 --> 00:07:13
that.  OK.  Before we get into sort
of the New Age cancer treatments,

94
00:07:13 --> 00:07:18
I thought I should at least mention
to you conventional therapies.

95
00:07:18 --> 00:07:34
Right now, if you have to have

96
00:07:34 --> 00:07:38
cancer treatment,
you might get one of the drugs that

97
00:07:38 --> 00:07:42
I'm going to tell you about later in
the lecture, but more likely you're

98
00:07:42 --> 00:07:46
going to get what we call a
conventional anti-cancer treatment.

99
00:07:46 --> 00:07:50
And these anti-cancer treatments
have actually been around for quite

100
00:07:50 --> 00:07:54
some time, and they do work.
They do work, but they don't work

101
00:07:54 --> 00:07:58
as well as we need them to work.
Radiation is a very common

102
00:07:58 --> 00:08:02
anti-cancer agent, as you
probably are aware.

103
00:08:02 --> 00:08:07
And there are a variety of drugs
that we list along with radiation

104
00:08:07 --> 00:08:13
like Adriamycin,
Cisplatin.  And there are a variety

105
00:08:13 --> 00:08:18
of other chemical agents,
which together are grouped because

106
00:08:18 --> 00:08:24
they cause DNA damage.
These are DNA damaging agents,

107
00:08:24 --> 00:08:30
and they're also effective
anti-cancer agents.

108
00:08:30 --> 00:08:34
There's another category of
anti-cancer agents which is

109
00:08:34 --> 00:08:39
exemplified by a drug called Taxol,
and there is a series of

110
00:08:39 --> 00:08:43
Taxol-related compounds.
And these are microtubule

111
00:08:43 --> 00:08:48
inhibitors.  Microtubule inhibitors.
And these therefore, microtubules

112
00:08:48 --> 00:08:53
are important in mitosis,
if you'll remember the mitotic

113
00:08:53 --> 00:08:58
spindle.  So these are
anti-mitotic drugs.

114
00:08:58 --> 00:09:06
And these drugs do work.

115
00:09:06 --> 00:09:10
And we think that they work in part
because cancer cells are rapidly

116
00:09:10 --> 00:09:14
dividing cells compared to most
normal cells in your body.

117
00:09:14 --> 00:09:18
And, therefore, if you damage their
DNA or you block their ability to

118
00:09:18 --> 00:09:22
divide you'll more effectively block
cancer growth compared to

119
00:09:22 --> 00:09:26
normal cell growth.
Now, overall, in the context of

120
00:09:26 --> 00:09:31
cancer, what we're looking for,
and actually in the context of other

121
00:09:31 --> 00:09:36
diseases as well is something called
a therapeutic window.

122
00:09:36 --> 00:09:42
A therapeutic window is defined as
a difference in the concentration of

123
00:09:42 --> 00:09:47
a drug necessary to kill the cell of
interest versus normal cells in the

124
00:09:47 --> 00:09:52
body.  These drugs,
anti-mitotics and DNA damaging

125
00:09:52 --> 00:10:00
agents will kill normal cells.
So if you look at a graph of percent

126
00:10:00 --> 00:10:10
killing versus drug concentration,
normal cells will eventually die.

127
00:10:10 --> 00:10:21
The hope is that cancer cells will
die sooner.  And this difference is

128
00:10:21 --> 00:10:33
defined as the therapeutic window.

129
00:10:33 --> 00:10:37
And that does exist for many of
these drugs for many different types

130
00:10:37 --> 00:10:41
of cancer.  And so these agents will,
in fact, give initial responses.

131
00:10:41 --> 00:10:46
Unfortunately, they tend not to be,
tend not be durable.  That is

132
00:10:46 --> 00:10:50
patients tend to relapse.
Not always but tend to relapse in

133
00:10:50 --> 00:10:55
response to these agents.
This slide just makes the same

134
00:10:55 --> 00:10:59
point that many of the drugs that we
know about affect the cell cycle

135
00:10:59 --> 00:11:03
either in S phase during DNA
synthesis or in M phase

136
00:11:03 --> 00:11:08
during mitosis.
And this also points out that many

137
00:11:08 --> 00:11:12
of these agents cause the death of
cancer cells by inducing apoptosis,

138
00:11:12 --> 00:11:17
inducing the death of cells.  In
contrast to most,

139
00:11:17 --> 00:11:21
but not all, most normal cells in
the body, which in response to that

140
00:11:21 --> 00:11:26
same concentration of drug,
will not die.  And instead those

141
00:11:26 --> 00:11:30
cells will arrest at some point in
the cell cycle and repair

142
00:11:30 --> 00:11:34
the damage.
And the difference,

143
00:11:34 --> 00:11:38
what makes up the therapeutic window
in many cases,

144
00:11:38 --> 00:11:41
is that the cancer cells are dying
at a given concentration,

145
00:11:41 --> 00:11:44
the normal cells are staying alive
and simply arresting.

146
00:11:44 --> 00:11:48
However, there are other cells in
the body that in response to the

147
00:11:48 --> 00:11:51
same drug at the same concentration
will undergo apoptosis.

148
00:11:51 --> 00:11:54
And you actually know what those
cells are if you've thought about

149
00:11:54 --> 00:11:58
cancer chemotherapy before.
It's the cells that support the

150
00:11:58 --> 00:12:02
hair follicles.
Those cells die in response to these

151
00:12:02 --> 00:12:06
drugs.  And that's why cancer
patients lose their hair.

152
00:12:06 --> 00:12:10
It is cells in the blood,
in the bone marrow which will die in

153
00:12:10 --> 00:12:14
response to these concentrations.
And that's why cancer patients get

154
00:12:14 --> 00:12:19
anemic.  And in cells of the lining
of the stomach and intestine which

155
00:12:19 --> 00:12:23
will die in response to these drugs.
And that's why cancer patients feel

156
00:12:23 --> 00:12:27
sick, feel nauseous.
So there are side effects in

157
00:12:27 --> 00:12:32
response to these drugs.
And that's because many cells,

158
00:12:32 --> 00:12:36
some cells in your body will also
die by apoptosis.

159
00:12:36 --> 00:12:40
Now, we've learned,
actually my lab has participated in

160
00:12:40 --> 00:12:44
this process, that the p53 tumor
suppressor gene that I've told you

161
00:12:44 --> 00:12:49
about is actually quite important in
guiding the responsive cells to

162
00:12:49 --> 00:12:53
these drugs.  Many normal cells turn
on p53 in response to this damage

163
00:12:53 --> 00:12:57
and arrest.  Those other cells that
I just told you about will

164
00:12:57 --> 00:13:01
turn on p53 and die.
And cancer cells,

165
00:13:01 --> 00:13:05
likewise, if they have a functional
p53 gene will turn it on.

166
00:13:05 --> 00:13:09
And this will induce apoptosis.
And it's the difference between

167
00:13:09 --> 00:13:13
cancer cells turning on p53 and
dying compared to normal cells

168
00:13:13 --> 00:13:16
turning on p53 and resting,
it gives the therapeutic window.

169
00:13:16 --> 00:13:20
Unfortunately, as I've mentioned to
you, about 50% of human cancers

170
00:13:20 --> 00:13:24
carry p53 mutations.
And given that p53 is important in

171
00:13:24 --> 00:13:28
this response,
if you don't have p53 then you won't

172
00:13:28 --> 00:13:32
die, or won't die as effectively,
and that limits the therapeutic

173
00:13:32 --> 00:13:35
window.
And this is one of the reasons why

174
00:13:35 --> 00:13:39
cancer therapy is not as good as it
should be and why cancer cells will

175
00:13:39 --> 00:13:43
sometimes come back,
because they're now no longer

176
00:13:43 --> 00:13:47
responsive to the drug,
at least especially responsive to

177
00:13:47 --> 00:13:51
the drug.  So we'd like to do better,
and we think we can do better by

178
00:13:51 --> 00:13:55
taking advantage of the information
that we've gained over the last 30

179
00:13:55 --> 00:13:59
years about cancer-associated
mutations.

180
00:13:59 --> 00:14:02
And I'm going to review for you in
detail the first three of these new

181
00:14:02 --> 00:14:05
agents, all three FDA approved in
the last five years or so for the

182
00:14:05 --> 00:14:09
treatment of one or another type of
cancer.  And I'll also mention

183
00:14:09 --> 00:14:12
anti-Ras therapies,
although we don't have an FDA

184
00:14:12 --> 00:14:16
approved drug for those.
If there's time I'll mention

185
00:14:16 --> 00:14:19
inhibitors of an enzyme called
telomerase, as well as

186
00:14:19 --> 00:14:23
anti-angiogenesis.
There are other therapies,

187
00:14:23 --> 00:14:26
not drug-based therapies but other
therapies that are under

188
00:14:26 --> 00:14:30
consideration, and in
some places in use.

189
00:14:30 --> 00:14:34
Gene therapy, replacing cancer
mutation genes.

190
00:14:34 --> 00:14:39
Immunotherapy, trying to convince
your immune system to attack your

191
00:14:39 --> 00:14:43
cancer.  And also cancer prevention
strategies, which I mentioned

192
00:14:43 --> 00:14:48
actually last time,
trying to make vaccines against

193
00:14:48 --> 00:14:53
viruses that are associated with
certain types of cancer including

194
00:14:53 --> 00:14:57
human papillomavirus and cervical
cancer.  So Ras is the first one

195
00:14:57 --> 00:15:02
that I'd like to mention to you.
And it's an example of where we

196
00:15:02 --> 00:15:06
haven't done enough.
We don't know enough.

197
00:15:06 --> 00:15:10
Even though we know that Ras is
mutated in 30% of human tumors,

198
00:15:10 --> 00:15:14
30%, 90% of pancreatic cancers carry
Ras mutations.

199
00:15:14 --> 00:15:18
Pancreatic cancer is one of the
worst killers in the cancer category.

200
00:15:18 --> 00:15:22
If you get pancreatic cancer,
of a particular type at least, it's

201
00:15:22 --> 00:15:26
a very, very, very serious disease.
We know that these tumors carry

202
00:15:26 --> 00:15:30
mutations in the Ras gene but we
cannot do anything about

203
00:15:30 --> 00:15:36
it at the moment.
So, as I've told you,

204
00:15:36 --> 00:15:43
Ras proteins are involved in
signaling proliferation.

205
00:15:43 --> 00:15:50
And this takes place through kinase
cascades, phosphorylating enzymes

206
00:15:50 --> 00:15:56
that phosphorylate other enzymes in
a cascade.  When you have a mutation

207
00:15:56 --> 00:16:03
in Ras, it turns the protein on in a
constitutive fashion leading to

208
00:16:03 --> 00:16:10
increased signaling down these
pathways and increased

209
00:16:10 --> 00:16:16
proliferation.
We know some of these enzymes.

210
00:16:16 --> 00:16:21
I've told you about Raf and MEK and
MAP kinase.  And so many drug

211
00:16:21 --> 00:16:26
companies are now trying to find
inhibitors that might block those

212
00:16:26 --> 00:16:31
enzymes, small molecule
inhibitors, drugs.

213
00:16:31 --> 00:16:42
And because these are kinases,

214
00:16:42 --> 00:16:47
the approach is to try to find ATP
analogs.  Drugs that look like ATP,

215
00:16:47 --> 00:16:53
can get into the active site of the
enzyme and compete for ATP,

216
00:16:53 --> 00:16:58
and thereby block enzyme function.
Some of these drugs work, at least

217
00:16:58 --> 00:17:02
in cells in culture.
There's a bit of a fear that these

218
00:17:02 --> 00:17:06
pathways are so commonly used in
normal cells that the drugs might be

219
00:17:06 --> 00:17:10
highly toxic and therefore not
tolerated.  And,

220
00:17:10 --> 00:17:14
importantly, we don't understand
what these arrows mean well enough.

221
00:17:14 --> 00:17:18
We have some basic ideas, but we
don't have enough detail to know

222
00:17:18 --> 00:17:22
exactly which kinase to inhibit in
exactly which type of tumor.

223
00:17:22 --> 00:17:26
So this is in progress but it's not
quite there yet.

224
00:17:26 --> 00:17:30
I'll come back to another couple of
stories related to ATP analogs that

225
00:17:30 --> 00:17:34
do work and are now in use
in cancer treatment.

226
00:17:34 --> 00:17:38
Before I do, I want to mention
another class of inhibitors,

227
00:17:38 --> 00:17:50
and these are antibodies.

228
00:17:50 --> 00:17:54
Antibody-directed therapy.
Cancer cells often up-regulate

229
00:17:54 --> 00:17:58
proteins on their surface.
I mentioned one last time in the

230
00:17:58 --> 00:18:02
context of breast cancer.
It's a protein called HER2.

231
00:18:02 --> 00:18:07
I mentioned the fact that 30% of
breast cancers have an amplification

232
00:18:07 --> 00:18:12
of the HER2 gene and,
therefore, make more of this HER2

233
00:18:12 --> 00:18:17
receptor on their cell surface.
So, in contrast to normal cells

234
00:18:17 --> 00:18:22
which will have a certain
concentration of this receptor on

235
00:18:22 --> 00:18:27
their surface,
cancer cells, breast cancer cells

236
00:18:27 --> 00:18:32
that carry this amplification will
have a much higher density.

237
00:18:32 --> 00:18:37
Maybe ten times or a hundred times
the level of this receptor on their

238
00:18:37 --> 00:18:42
surface.  And they are using that
increased level of receptor to

239
00:18:42 --> 00:18:47
increase the signal downstream of
that receptor to promote

240
00:18:47 --> 00:18:52
proliferation.
Now, the receptor is responding to

241
00:18:52 --> 00:18:57
ligands as it would normally do.
And therapy is based on the fact

242
00:18:57 --> 00:19:02
that the ligand has to bind to the
receptor in order to activate it.

243
00:19:02 --> 00:19:07
And so what was done by a company
called Genentech out in California

244
00:19:07 --> 00:19:12
was to make antibodies that block to
the receptor, that bind to the

245
00:19:12 --> 00:19:17
receptor and block the binding of
the ligand to the receptor.

246
00:19:17 --> 00:19:22
So these are anti-HER2 antibodies.
And this drug, which is now

247
00:19:22 --> 00:19:28
approved by the FDA, is
called Herceptin.

248
00:19:28 --> 00:19:34
And it works.  For those breast

249
00:19:34 --> 00:19:38
cancer patients who have
amplification,

250
00:19:38 --> 00:19:41
too much of this receptor on their
surface, Herceptin works and can

251
00:19:41 --> 00:19:45
give them months,
sometimes years of symptom-free

252
00:19:45 --> 00:19:48
survival.  It's not curative,
unfortunately, but it does extend

253
00:19:48 --> 00:19:52
life.  And it's therefore an
extremely important drug.

254
00:19:52 --> 00:19:55
This is just a blocking antibody.
There's nothing attached to the

255
00:19:55 --> 00:19:59
antibody.  It's just blocking the
binding of the receptor to its

256
00:19:59 --> 00:20:03
ligand and thereby blocking the
function of the receptor.

257
00:20:03 --> 00:20:09
But antibodies can also be linked to
toxins or radionuclides,

258
00:20:09 --> 00:20:15
and thereby deliver bad stuff to the
tumor cell, either a toxin or

259
00:20:15 --> 00:20:21
something that will irradiate this
cell.  And these are being tested

260
00:20:21 --> 00:20:27
currently.  There are no FDA
approved versions of this,

261
00:20:27 --> 00:20:34
but I suspect that will change in
the years to come.

262
00:20:34 --> 00:20:37
So Herceptin is an effective
antibody-based therapy.

263
00:20:37 --> 00:20:40
There are a couple more now,
but it was the first.  And this is

264
00:20:40 --> 00:20:43
actually from the Genentech website
which gives you a little bit of

265
00:20:43 --> 00:20:46
information about Herceptin and
shows you a bottle of Herceptin as

266
00:20:46 --> 00:20:49
you would see in the pharmacy.
And this diagram is just a

267
00:20:49 --> 00:20:52
reiteration of what I've told you
already.  Normal cells have low

268
00:20:52 --> 00:20:56
levels of the receptor on their
surface, cancer cells have higher

269
00:20:56 --> 00:20:59
concentrations of the receptor on
their surface,

270
00:20:59 --> 00:21:02
and the antibody binds to the
receptor thereby blocking

271
00:21:02 --> 00:21:06
its function.
OK?  So this is a clear example.

272
00:21:06 --> 00:21:10
We learned that Herceptin was
over-expressed in cancer,

273
00:21:10 --> 00:21:14
breast cancer and ovarian cancer.
The company made an antibody and it

274
00:21:14 --> 00:21:24
works.

275
00:21:24 --> 00:21:29
Another story,
my favorite story relates to a

276
00:21:29 --> 00:21:34
disease called chronic myelogenous
leukemia --

277
00:21:34 --> 00:21:51
-- or CML.  CML is a disease that

278
00:21:51 --> 00:21:57
affects young adults,
adults and children.  Child patient

279
00:21:57 --> 00:22:02
shown here.
It is leukemia so it's a disease of

280
00:22:02 --> 00:22:06
the blood.  It affects both the
blood, as well as the bone marrow.

281
00:22:06 --> 00:22:10
And we've learned a lot about this
disease over the years.

282
00:22:10 --> 00:22:14
It's not a very common disease.
It only affects about 4,000 or 5,

283
00:22:14 --> 00:22:18
00 people in this country per year.
And it falls in stages.  Initially

284
00:22:18 --> 00:22:22
the person is diagnosed with CML
based on relatively low

285
00:22:22 --> 00:22:26
concentrations of,
low levels of white blood cells in

286
00:22:26 --> 00:22:31
their circulation.
And then they progress with that

287
00:22:31 --> 00:22:36
phase in what's called the chronic
phase where there are still

288
00:22:36 --> 00:22:40
relatively low levels of white blood
cells, higher than normal but lower

289
00:22:40 --> 00:22:45
than are dangerous.
However, this can progress over

290
00:22:45 --> 00:22:50
time through an accelerated phase
where there's even higher levels of

291
00:22:50 --> 00:22:54
white blood cells in the blood to
the final phase which is called

292
00:22:54 --> 00:22:59
blast crisis where the levels of
white blood cells really shoot up.

293
00:22:59 --> 00:23:04
And this is lethal.
And these patients invariably

294
00:23:04 --> 00:23:08
progress through these stages and
eventually died.

295
00:23:08 --> 00:23:12
So what have we done?
This is a picture of what the blood

296
00:23:12 --> 00:23:17
cells look like in a normal
individual.  This is a white blood

297
00:23:17 --> 00:23:21
cell you could see in a CML patient.
There are higher levels, and they

298
00:23:21 --> 00:23:25
can be even higher than this.
This disease has been studied for a

299
00:23:25 --> 00:23:30
very long time.
And we now know that there's a

300
00:23:30 --> 00:23:34
signature mutation,
a mutation that takes place in

301
00:23:34 --> 00:23:38
almost all CML cases.
It's a translocation that

302
00:23:38 --> 00:23:43
rearranges two genes called BCR and
ABL and places them together on a

303
00:23:43 --> 00:23:47
translocated chromosome.
There's a swapping of genetic

304
00:23:47 --> 00:23:52
information from chromosomes 9 and
22 such that there's production of a

305
00:23:52 --> 00:23:56
new gene called BCR-ABL that results
in a new protein,

306
00:23:56 --> 00:24:00
a fusion protein that has a little
bit of this BCR protein and a little

307
00:24:00 --> 00:24:04
bit of this ABL protein.
And you can see in the karyotypes of

308
00:24:04 --> 00:24:07
these individuals that they have an
abnormal chromosome 9 which is a

309
00:24:07 --> 00:24:11
little shorter,
sorry, a little longer than it

310
00:24:11 --> 00:24:14
should be, and an abnormal
chromosome 22 which is a little

311
00:24:14 --> 00:24:17
shorter than it should be.
And when you look at cancer cells of

312
00:24:17 --> 00:24:21
CML patients you always find that
translocation.

313
00:24:21 --> 00:24:24
It's called the Philadelphia
translocation because it was

314
00:24:24 --> 00:24:28
discovered by researchers
in Philadelphia.

315
00:24:28 --> 00:24:39
And it's sometimes referred to as

316
00:24:39 --> 00:24:43
the Philadelphia chromosome.
And, again, it's a translocation

317
00:24:43 --> 00:24:48
involving chromosome 9 which has a
gene called ABL which is

318
00:24:48 --> 00:24:56
a tyrosine kinase.

319
00:24:56 --> 00:25:03
And so it's a signaling protein.
And chromosome 22 which has a

320
00:25:03 --> 00:25:11
separate gene called BCR.
And, in the development of CML,

321
00:25:11 --> 00:25:19
breaks take place on these two
chromosomes leading to a

322
00:25:19 --> 00:25:27
translocation and the formation of a
new chromosome that has a fusion

323
00:25:27 --> 00:25:33
gene composed of both BCR and ABL.
And this gives rise to a fusion

324
00:25:33 --> 00:25:38
protein with a piece of BCR and the
kinase domain of ABL.

325
00:25:38 --> 00:25:43
And this leads to increased
proliferation,

326
00:25:43 --> 00:25:48
as well as increased survival of the
cells that carry that translocation,

327
00:25:48 --> 00:25:53
more cells in the blood and
eventually leukemia.

328
00:25:53 --> 00:25:58
And the hope is, the hope was,
as this was being worked out,

329
00:25:58 --> 00:26:03
actually important experiments done
at MIT in the early 1980s here.

330
00:26:03 --> 00:26:06
As this was being worked out that
maybe, because it's such a common

331
00:26:06 --> 00:26:10
mutation in this disease,
if you could find an inhibitor --

332
00:26:10 --> 00:26:18
-- maybe you could block the

333
00:26:18 --> 00:26:21
proliferation of these cells or
perhaps induce their death.

334
00:26:21 --> 00:26:25
This just gives you a little a bit,
a sort of cartoon version of BCR-ABL

335
00:26:25 --> 00:26:28
signaling.  I don't want you to
literally pay great attention

336
00:26:28 --> 00:26:32
to this.
Suffice it to say BCR-ABL as a

337
00:26:32 --> 00:26:36
signaling protein stimulates many of
the pathways that you've learned

338
00:26:36 --> 00:26:40
about already in this class and
causes cells to proliferate,

339
00:26:40 --> 00:26:44
as well as to survive better.
So, again, can you find an

340
00:26:44 --> 00:26:49
inhibitor that blocks the activity
of this enzyme and thereby blocks

341
00:26:49 --> 00:26:53
the proliferation of these cancer
cells?  This was undertaken by

342
00:26:53 --> 00:26:57
probably many drug companies in the
world, but a drug company now called

343
00:26:57 --> 00:27:01
Novartis, which has its research
headquarters here in Cambridge,

344
00:27:01 --> 00:27:06
succeeded.
They generated this drug which goes

345
00:27:06 --> 00:27:10
by the name Gleevec.
It has a trade name,

346
00:27:10 --> 00:27:14
the name of which I can never
remember, but everybody called it

347
00:27:14 --> 00:27:18
Gleevec when it was being developed.
It was also called STI571 but

348
00:27:18 --> 00:27:23
Gleevec is the common name.
They found this drug through a

349
00:27:23 --> 00:27:27
screen looking for small molecules
that look a little bit like ATP,

350
00:27:27 --> 00:27:31
although it doesn't look much like
ATP anymore, that can specifically

351
00:27:31 --> 00:27:36
bind to and block the kinase
activity of this particular kinase.

352
00:27:36 --> 00:27:39
And this drug is successful.
It does bind to the kinase and

353
00:27:39 --> 00:27:43
blocks its kinase activity.
And importantly in cell lines,

354
00:27:43 --> 00:27:47
as well as in mouse models, it was
found to be effective in killing CML

355
00:27:47 --> 00:27:51
cells.  It was then used in
treatment of CML patients and found

356
00:27:51 --> 00:27:55
to be effective there,
too.  So the number of white blood

357
00:27:55 --> 00:27:59
cells in these patients dropped
dramatically and the number of

358
00:27:59 --> 00:28:03
Philadelphia chromosome positive
cells likewise.

359
00:28:03 --> 00:28:18
So if you were to plot the number of

360
00:28:18 --> 00:28:23
white blood cells in a normal
patient it would be low.

361
00:28:23 --> 00:28:29
In a CML patient, in the early
phase of the disease it would be

362
00:28:29 --> 00:28:34
down here, and then it would go up
in the accelerated phase and then it

363
00:28:34 --> 00:28:40
would go up still further
in blast crisis.

364
00:28:40 --> 00:28:51
And, as I said,

365
00:28:51 --> 00:28:55
this could take years,
several years to progress.

366
00:28:55 --> 00:28:58
And at this stage, late-stage
disease, this person might have

367
00:28:58 --> 00:29:02
hundreds of thousands of white blood
cells per mill.

368
00:29:02 --> 00:29:06
But when treated with Gleevec the
white blood cell counts dropped to

369
00:29:06 --> 00:29:11
mere normal.  And amazingly the drug
is extremely well-tolerated.

370
00:29:11 --> 00:29:16
So even though all of your cells
have this same ABL kinase,

371
00:29:16 --> 00:29:20
not fused to BCR but the same ABL
kinase unfused,

372
00:29:20 --> 00:29:25
and it's probably doing stuff in
your cells, those cells

373
00:29:25 --> 00:29:30
don't need it.
But the cancer cells,

374
00:29:30 --> 00:29:34
in the context of this BCR-ABL
fusion, are totally dependent on it.

375
00:29:34 --> 00:29:38
And if you inhibit it now the cells
will not proliferate anymore.

376
00:29:38 --> 00:29:42
And, indeed, as you can see how
precipitous this fall is,

377
00:29:42 --> 00:29:46
the cells will actually die,
undergo apoptosis.  So the drug is

378
00:29:46 --> 00:29:50
extremely effective.
As I said, clinical tests were done.

379
00:29:50 --> 00:29:54
Sorry.  This just illustrates a
cartoon version of what we've been

380
00:29:54 --> 00:29:59
talking about.  Here's
the BCR-ABL protein.

381
00:29:59 --> 00:30:03
Here it's in its normal state
binding to ATP and transferring a

382
00:30:03 --> 00:30:07
phosphate to some substrate protein
in the context of signaling.

383
00:30:07 --> 00:30:11
And what Gleevec does is binds to
the ATP pocket and blocks the access

384
00:30:11 --> 00:30:16
of ATP to the enzyme and,
therefore, blocks the kinase

385
00:30:16 --> 00:30:20
activity.  And this is actual
clinical data provided by Novartis

386
00:30:20 --> 00:30:24
in this case.  And what you're
looking at here is the number of

387
00:30:24 --> 00:30:29
Philadelphia chromosome positive
cells in the blood.

388
00:30:29 --> 00:30:33
And what percentage reduction you're
seeing, either somewhat or

389
00:30:33 --> 00:30:38
completely, looking at the accepted
therapy before Gleevec came along,

390
00:30:38 --> 00:30:43
which was not very effective, only
12% of patients showed any response,

391
00:30:43 --> 00:30:48
or rather a major response, and only
3% showed a complete response.

392
00:30:48 --> 00:30:53
That is when you looked in their
blood by PCR you could find no more

393
00:30:53 --> 00:30:58
Philadelphia chromosome
positive cells.

394
00:30:58 --> 00:31:02
But now with Gleevec,
75% of patients showed a major

395
00:31:02 --> 00:31:06
response.  And 54% of patients
showed a complete response,

396
00:31:06 --> 00:31:10
you could not find Philadelphia
chromosome positive cells by PCR in

397
00:31:10 --> 00:31:14
the blood of these patients.
So it really worked extremely well.

398
00:31:14 --> 00:31:26
It gave what we call clinical

399
00:31:26 --> 00:31:32
remissions.  Clinical remissions.
And these patients survived, had,

400
00:31:32 --> 00:31:38
you know, dramatically extended
lifetimes.  This would go on for in

401
00:31:38 --> 00:31:44
some cases as little as a half a
year, in other cases up to ten years

402
00:31:44 --> 00:31:50
increased survival,
especially if the patients were

403
00:31:50 --> 00:31:56
treated early in the disease.
But unfortunately for all the

404
00:31:56 --> 00:32:08
patients the numbers went back up.

405
00:32:08 --> 00:32:12
Clinical relapse.
An all too familiar problem in

406
00:32:12 --> 00:32:16
cancer therapy.
You might see initial treatments,

407
00:32:16 --> 00:32:20
they might even last a while, but
too many patients undergo relapses

408
00:32:20 --> 00:32:24
where their disease comes back.
So what's going on here?  These

409
00:32:24 --> 00:32:28
patients are continuing to receive
Gleevec throughout this course,

410
00:32:28 --> 00:32:33
and yet the tumors are returning.
Why?  What might be going on?

411
00:32:33 --> 00:32:39
Remember that cancer cells acquire
mutations?  Cancer cells are always

412
00:32:39 --> 00:32:45
acquiring mutations.
So what kind of mutation might be

413
00:32:45 --> 00:32:52
taking place in these cells that
would lead them to be Gleevec

414
00:32:52 --> 00:32:58
resistant?  Well,
maybe they're acquiring mutations

415
00:32:58 --> 00:33:04
within the BCR-ABL gene,
that fusion gene, which blocks their

416
00:33:04 --> 00:33:10
ability to bind the drug.
So Charles Sawyers,

417
00:33:10 --> 00:33:15
investigator at UCLA,
took the cancer cells from these

418
00:33:15 --> 00:33:20
relapsed patients,
PCR-ed up the BCR-ABL gene,

419
00:33:20 --> 00:33:25
sequenced it, and lo and behold he
found a bunch of mutations.

420
00:33:25 --> 00:33:30
Individual tumors had one or
another of these point mutations

421
00:33:30 --> 00:33:35
within the ABL kinase.
And the consequence of those

422
00:33:35 --> 00:33:40
mutations was that the drug Gleevec
could no longer bind.

423
00:33:40 --> 00:33:45
And that's illustrated here.
So this is, again, a cutaway view

424
00:33:45 --> 00:33:50
of the BCR-ABL kinase.
Here's Gleevec where it normally

425
00:33:50 --> 00:33:55
sits, but that red dot is a mutation
that sticks an amino acid side chain

426
00:33:55 --> 00:34:00
right in the way of where
Gleevec binds.

427
00:34:00 --> 00:34:05
So now it cannot bind anymore.
The drug cannot bind, it cannot be

428
00:34:05 --> 00:34:10
effective, cancer cells come back.
OK?  So that's a problem.  What are

429
00:34:10 --> 00:34:15
you going to do about it?
What can be done?  What would you

430
00:34:15 --> 00:34:24
do?

431
00:34:24 --> 00:34:30
Maybe we could find a drug that will
bind even if there is a mutation

432
00:34:30 --> 00:34:37
there.  And that actually works and
that's why this Gleevec fits nicely

433
00:34:37 --> 00:34:43
into that pocket and blocks the
activity.  So this enzyme is

434
00:34:43 --> 00:34:50
inhibited.  The problem is that
apparently invariably mutant

435
00:34:50 --> 00:34:57
BCR-ABLs arise which are
Gleevec resistant.

436
00:34:57 --> 00:35:08
So you can have Gleevec around,

437
00:35:08 --> 00:35:13
but it cannot get in there, the
enzyme still functions,

438
00:35:13 --> 00:35:19
it still causes proliferation.
But working with a different drug

439
00:35:19 --> 00:35:24
company, Charles Sawyers screened
new drugs.  And he found a drug

440
00:35:24 --> 00:35:29
which has a similar but slightly
different shape than Gleevec,

441
00:35:29 --> 00:35:35
and it's able to bind to the mutant
BCR-ABLs.

442
00:35:35 --> 00:35:43
This drug is called BMS-354825
produced by Bristol-Myers Squibb.

443
00:35:43 --> 00:35:51
And just in December of this past
year Charles Sawyers reported the

444
00:35:51 --> 00:35:59
first clinical trial with this drug
in patients who had failed Gleevec

445
00:35:59 --> 00:36:07
therapy who had relapsed.
And 31 out of 36 responded.

446
00:36:07 --> 00:36:11
And to my knowledge they are still
in remission.  And the five who

447
00:36:11 --> 00:36:15
didn't respond had a particular kind
of mutation that actually also

448
00:36:15 --> 00:36:19
blocked the binding of this drug.
But the majority of mutations, even

449
00:36:19 --> 00:36:23
though there are several mutations
that will affect Gleevec resistance,

450
00:36:23 --> 00:36:27
the majority of them are still
sensitive to this new drug.

451
00:36:27 --> 00:36:32
So this is smart and smart again.
Smart, understanding how cells can

452
00:36:32 --> 00:36:36
be sensitive.  Then smart again,
finding out how they become

453
00:36:36 --> 00:36:40
resistance.  And then smart for a
third time, finding new drugs that

454
00:36:40 --> 00:36:44
will bind even in the presence of
those resistance mutations.

455
00:36:44 --> 00:36:48
And this, I suspect, is the future
of cancer treatments.

456
00:36:48 --> 00:36:52
Understanding the molecular
signature mutations,

457
00:36:52 --> 00:36:56
finding specific drugs,
and then being prepared to find

458
00:36:56 --> 00:37:00
second-generation drugs that will
still work even if resistance

459
00:37:00 --> 00:37:04
arises.
A very similar story,

460
00:37:04 --> 00:37:09
which I'll have to tell you quickly,
comes from the world of lung cancer.

461
00:37:09 --> 00:37:14
In this case,
several drug companies were trying

462
00:37:14 --> 00:37:19
to find drugs that would block a
different tyrosine kinase.

463
00:37:19 --> 00:37:24
This time a receptor tyrosine
kinase by the name of epidermal

464
00:37:24 --> 00:37:30
growth factor receptor,
EGF receptor.

465
00:37:30 --> 00:37:36
They were motivated to do so because
this receptor is over-expressed,

466
00:37:36 --> 00:37:42
there is too much of it in many
types of cancer, including

467
00:37:42 --> 00:37:50
lung cancer.

468
00:37:50 --> 00:37:55
And so different companies made
different drugs.

469
00:37:55 --> 00:38:00
One of them is called Iressa which
goes by the trade name Gefitinib.

470
00:38:00 --> 00:38:05
Another made by Genentech is called
Tarceva.  And these do function as

471
00:38:05 --> 00:38:10
EGF inhibitors,
anti-EGF receptor inhibitors.

472
00:38:10 --> 00:38:15
They work.  They work in the
test-tube.  However,

473
00:38:15 --> 00:38:20
when tested in clinical trials they
were a spectacular failure.

474
00:38:20 --> 00:38:25
Even for patients who had high
levels of EGF receptor on the

475
00:38:25 --> 00:38:31
surface of their cancer cells,
the drug didn't do anything.

476
00:38:31 --> 00:38:35
And they were almost not going to be
FDA approved for that purpose,

477
00:38:35 --> 00:38:40
except that a very small number of
lung cancer patients responded

478
00:38:40 --> 00:38:45
extremely well to the drug.
about 10% of lung cancer patients

479
00:38:45 --> 00:38:50
showed responses like the one I'm
showing you here,

480
00:38:50 --> 00:38:55
where this, and outlined in red,
is a lung tumor where the tumor is

481
00:38:55 --> 00:39:00
basically filling the entire
lobe of the lung.

482
00:39:00 --> 00:39:04
Six weeks after treatment with this
drug Iressa, you can see massive

483
00:39:04 --> 00:39:08
resolution of the tumor.
The tumor is almost all gone,

484
00:39:08 --> 00:39:12
and that white stuff is probably
just fibrotic tissue.

485
00:39:12 --> 00:39:17
The tumor cells are practically
gone.  A dramatic response.

486
00:39:17 --> 00:39:21
What's going on?  Why do those 10%
of patients respond so well?

487
00:39:21 --> 00:39:25
Well, it turns out that those 10%
of patients carry a mutation in the

488
00:39:25 --> 00:39:30
EGF receptor gene.
In those 10% of patients,

489
00:39:30 --> 00:39:35
one of the ways the cancer cells are
growing and surviving is that they

490
00:39:35 --> 00:39:39
have a mutation that activates this
gene making those tumor cells highly

491
00:39:39 --> 00:39:44
dependent on that particular protein
in the same way that these cancers

492
00:39:44 --> 00:39:49
are highly dependent on BCR-ABL.
And if you deprive those cancer

493
00:39:49 --> 00:39:53
cells of that activity by using
these drugs, the cells will die.

494
00:39:53 --> 00:39:58
So this is a good example of what
will come in the future of

495
00:39:58 --> 00:40:03
individualized medicine.
If you're a lung cancer patient,

496
00:40:03 --> 00:40:07
you shouldn't just indiscriminately
take Iressa because 95% of the time

497
00:40:07 --> 00:40:11
it won't do anything for you.
But if you're one of those 10% who

498
00:40:11 --> 00:40:15
has a mutation in this gene,
you would benefit dramatically from

499
00:40:15 --> 00:40:19
having it.  And that will happen
more and more in cancer and other

500
00:40:19 --> 00:40:23
diseases.  Your tumor will be
molecularly typed to find out

501
00:40:23 --> 00:40:27
exactly what mutations it has to
find out which of a collection of

502
00:40:27 --> 00:40:31
targeted therapies you
should be taking.

503
00:40:31 --> 00:40:34
These patients,
just so you know,

504
00:40:34 --> 00:40:38
tend to be women, non-smokers,
and tend to be Asians for reasons

505
00:40:38 --> 00:40:42
that we don't understand.
Any of those three we don't

506
00:40:42 --> 00:40:46
understand, but the percentage of
EGFR mutant lung cancer patients are

507
00:40:46 --> 00:40:50
higher in those categories of people.
And so they have a greater

508
00:40:50 --> 00:40:54
likelihood of being responsive.
But, in fact, nowadays if you have

509
00:40:54 --> 00:40:58
lung cancer you get your EGFR gene
sequenced.  And if it has a mutation

510
00:40:58 --> 00:41:02
you take this drug.
And it will work.

511
00:41:02 --> 00:41:08
It will resolve your tumor.
Unfortunately, your tumor will come

512
00:41:08 --> 00:41:13
back.  The same story but faster.
These patients tend only to get

513
00:41:13 --> 00:41:18
three months, six months,
maybe a year, two years, three years

514
00:41:18 --> 00:41:24
extra survival,
and then their tumors come back.

515
00:41:24 --> 00:41:29
Same story, the receptors that are
now insensitive to the drug carry a

516
00:41:29 --> 00:41:35
new mutation that blocks access of
the drug to the receptor.

517
00:41:35 --> 00:41:39
Fortunately, just last month there
was a paper that described a new

518
00:41:39 --> 00:41:44
drug that will still work even if
the receptor carries such a

519
00:41:44 --> 00:41:48
resistance mutation.
So there's hope that we'll see a

520
00:41:48 --> 00:41:53
story similar to this one emerging
for lung cancer.

521
00:41:53 --> 00:41:57
Now, I've told you three of,
just a handful of molecularly

522
00:41:57 --> 00:42:02
targeted agents for
therapy in cancer.

523
00:42:02 --> 00:42:06
There are more to come.
Telomerase is an enzyme that cancer

524
00:42:06 --> 00:42:10
cells need, that normal cells or at
least most normal cells don't need.

525
00:42:10 --> 00:42:14
We won't go into the details of
that, but suffice to say this is a

526
00:42:14 --> 00:42:18
promising area for therapy as well.
Angiogenesis, I've mentioned to you

527
00:42:18 --> 00:42:22
before.  Tumors,
solid tumors need a new blood supply.

528
00:42:22 --> 00:42:26
If you can block the ability of the
tumor to recruit a blood supply,

529
00:42:26 --> 00:42:30
you might be able to block the
development of the tumor.

530
00:42:30 --> 00:42:34
And there has recently,
Genentech once again, been an FDA

531
00:42:34 --> 00:42:38
approved anti-angiogenesis drug that
blocks, that prevents progression of

532
00:42:38 --> 00:42:42
colon cancer, and also they just
reported breast cancer.

533
00:42:42 --> 00:42:47
So anti-angiogenesis is a viable
therapy strategy as well.

534
00:42:47 --> 00:42:51
Gene therapy, putting lost genes
back.  Cancer cells have mutations

535
00:42:51 --> 00:42:55
in tumor suppressor genes,
p53, RB I've told you about,

536
00:42:55 --> 00:42:59
and others.
Perhaps you could just put the gene

537
00:42:59 --> 00:43:03
back in, the gene that got lost.
Make a virus that expresses that

538
00:43:03 --> 00:43:07
gene and put it back.
This is being tried.  I'm not super

539
00:43:07 --> 00:43:11
enthusiastic about whether it will
work because I don't know that we

540
00:43:11 --> 00:43:14
can get the virus carrying the good
gene into all the cancer cells.

541
00:43:14 --> 00:43:18
But, nevertheless, it's something
to consider.  Immunotherapy is also

542
00:43:18 --> 00:43:22
a promising area.
It's possible that we can convince

543
00:43:22 --> 00:43:26
your immune system to detect the
abnormal proteins that cancer cells

544
00:43:26 --> 00:43:30
make by virtue of the mutations
that they carry.

545
00:43:30 --> 00:43:33
You can make antibodies or T cells
that eliminate those,

546
00:43:33 --> 00:43:37
and that's underway.  And I've
mentioned already the cancer

547
00:43:37 --> 00:43:41
prevention approaches with vaccines.
I want to draw your attention to

548
00:43:41 --> 00:43:45
the fact that the Cancer Center here
at MIT will have a symposium in June.

549
00:43:45 --> 00:43:49
Many of you will have gone home for
the summer, but some of you may not

550
00:43:49 --> 00:43:53
have.  June 24th.
This is free to MIT students,

551
00:43:53 --> 00:43:57
and actually features many alums of
MIT.  Two of these people were

552
00:43:57 --> 00:44:01
undergraduates here at MIT,
including Dan Heber, the guy who did

553
00:44:01 --> 00:44:05
the EGF lung cancer story
that I just showed you.

554
00:44:05 --> 00:44:08
This is a very great group of people
who will be telling you the latest

555
00:44:08 --> 00:44:12
and greatest about the new science
of cancer therapy,

556
00:44:12 --> 00:44:16
an extension of what I've told you
about today.  All right.

557
00:44:16 --> 00:44:20
Before we finish I want to just
briefly mention that in addition to

558
00:44:20 --> 00:44:24
tracking mutations in
cancer-associated genes,

559
00:44:24 --> 00:44:28
we can also track the expression
patterns, the levels of expression

560
00:44:28 --> 00:44:32
of all the genes in a cancer cell.
And this is done using a technology

561
00:44:32 --> 00:44:36
called array technology where all of
the genes of a cell,

562
00:44:36 --> 00:44:41
the 30,000 genes of a cell can be
assessed based on how much RNA is

563
00:44:41 --> 00:44:45
being produced in those cells at any
given time or at any given sample.

564
00:44:45 --> 00:44:50
This is called a GeneChip or a gene
expression array.

565
00:44:50 --> 00:44:54
And increasingly it's being used to
diagnose cancers.

566
00:44:54 --> 00:44:59
Cancer is typically diagnosed by
histopathology.

567
00:44:59 --> 00:45:02
You look at the tumor,
or the pathologist looks at the

568
00:45:02 --> 00:45:06
tumor in a histological section and
says it's a this or it's a that.

569
00:45:06 --> 00:45:10
The problem is that many cancers
look very similar to the histologist

570
00:45:10 --> 00:45:14
or the pathologist,
but in the underlying molecular

571
00:45:14 --> 00:45:18
level they might be quite different.
Some of them might be fairly benign.

572
00:45:18 --> 00:45:22
Others might be really dangerous.
And maybe you cannot tell that

573
00:45:22 --> 00:45:26
apart by looking at the cells,
but looking at the activity of the

574
00:45:26 --> 00:45:30
different genes inside those cells
you may be able to get to that.

575
00:45:30 --> 00:45:33
So this is done by comparing,
on a glass slide, the levels of

576
00:45:33 --> 00:45:37
expression of all the genes from the
cancer cell compared to some

577
00:45:37 --> 00:45:41
reference RNA,
let's say the normal cell of that

578
00:45:41 --> 00:45:45
tissue.  And then the signal that
you read out by looking at labeled

579
00:45:45 --> 00:45:48
RNAs, the cancer cell being labeled
red, for example,

580
00:45:48 --> 00:45:52
the normal RNA being labeled green,
the signal that you read out from

581
00:45:52 --> 00:45:56
each of those spots using a laser
and a CCD camera to detect the

582
00:45:56 --> 00:46:00
signal coming off of the chip,
the signal that you see can be

583
00:46:00 --> 00:46:03
quantified.
And a red signal would mean there's

584
00:46:03 --> 00:46:07
more RNA in sample one for that
particular gene,

585
00:46:07 --> 00:46:11
a green signal more RNA for sample
two, and a yellow signal roughly

586
00:46:11 --> 00:46:15
equal.  And the pattern that you get
from these chips can then give you

587
00:46:15 --> 00:46:19
information about the state of those
cells, and that information might be

588
00:46:19 --> 00:46:23
extremely important clinically.
And in the last two minutes I'll

589
00:46:23 --> 00:46:27
just tell you a brief story about
how it is being used.

590
00:46:27 --> 00:46:30
This is a collection of 75 breast
cancer specimens,

591
00:46:30 --> 00:46:34
early stage breast cancers,
node negative, lymph node negative

592
00:46:34 --> 00:46:38
breast cancers.
These patients,

593
00:46:38 --> 00:46:42
before this technology,
all would undergo removal of the

594
00:46:42 --> 00:46:45
tumor and then chemotherapy.
But it turns out that only some of

595
00:46:45 --> 00:46:49
them will actually go on to progress.
These patients were followed for

596
00:46:49 --> 00:46:53
ten years after that sample was
taken.  And it was known that some

597
00:46:53 --> 00:46:57
of them progressed,
and those fall over here,

598
00:46:57 --> 00:47:01
progressed in the sense that they
developed metastatic tumors.

599
00:47:01 --> 00:47:05
And others didn't progress.
And so what was done was is to take

600
00:47:05 --> 00:47:09
RNA from these samples at this early
stage, RNA from these samples and do

601
00:47:09 --> 00:47:13
one of these GeneChips and ask,
is the pattern of expression of

602
00:47:13 --> 00:47:17
genes correlative to the outcome,
the eventual outcome?  It might take

603
00:47:17 --> 00:47:21
some years for it to happen.
And what they found was that indeed

604
00:47:21 --> 00:47:25
--
And you can probably see it from

605
00:47:25 --> 00:47:29
where you're sitting,
that this collection of genes in red

606
00:47:29 --> 00:47:33
over here is highly expressed in the
guys who actually do pretty well and

607
00:47:33 --> 00:47:36
is relatively lower expressed in the
guys that don't do well.

608
00:47:36 --> 00:47:40
And this collection of genes is
highly expressed in the ones who

609
00:47:40 --> 00:47:43
don't do well compared to the ones
who do.  And so now there's a

610
00:47:43 --> 00:47:47
clinical test.
You can have your early-stage

611
00:47:47 --> 00:47:51
breast cancer typed by this analysis
and it will tell you with some

612
00:47:51 --> 00:47:54
degree of certainty,
not complete, whether your tumor

613
00:47:54 --> 00:47:58
will eventually,
maybe five year down the road

614
00:47:58 --> 00:48:02
progress into a metastatic tumor.
If you get the signal,

615
00:48:02 --> 00:48:06
if you get the answer yes,
then you have it removed and you

616
00:48:06 --> 00:48:11
undergo therapy.
If you get the answer no,

617
00:48:11 --> 00:48:15
you have a choice.  Perhaps you get
the tumor removed,

618
00:48:15 --> 00:48:20
but you don't undergo what is in
fact quite difficult and sometimes

619
00:48:20 --> 00:48:24
damaging therapy.
So this is an example of,

620
00:48:24 --> 00:48:29
again, stuff to come, molecule
medicine, specific patient-oriented

621
00:48:29 --> 00:48:32
medicine.