1 00:00:00,090 --> 00:00:02,490 The following content is provided under a Creative 2 00:00:02,490 --> 00:00:04,030 Commons license. 3 00:00:04,030 --> 00:00:06,330 Your support will help MIT OpenCourseWare 4 00:00:06,330 --> 00:00:10,720 continue to offer high quality educational resources for free. 5 00:00:10,720 --> 00:00:13,320 To make a donation or view additional materials 6 00:00:13,320 --> 00:00:17,280 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,280 --> 00:00:18,450 at ocw.mit.edu. 8 00:00:26,770 --> 00:00:30,030 PROFESSOR: Last time I told you about oncogenes. 9 00:00:30,030 --> 00:00:36,430 Oncogenes-- we discussed the fact that these were gain 10 00:00:36,430 --> 00:00:40,150 of function mutations that occur in cancer cells-- 11 00:00:40,150 --> 00:00:43,480 that occur in normal cells as they develop into cancer cells, 12 00:00:43,480 --> 00:00:46,060 and then occur in cancer cells. 13 00:00:46,060 --> 00:00:49,210 And we discussed the fact that these are dominant mutations. 14 00:00:52,400 --> 00:00:55,240 And this was exemplified by the Weinberg experiment in which he 15 00:00:55,240 --> 00:00:59,920 transferred a dominant oncogene into a "normal cell' and caused 16 00:00:59,920 --> 00:01:02,620 that cell to become transformed despite the fact that it had 17 00:01:02,620 --> 00:01:05,950 normal copies of the same gene in its genome-- 18 00:01:05,950 --> 00:01:08,590 definition of a dominant mutation. 19 00:01:08,590 --> 00:01:10,760 We also talked about tumor suppressor genes. 20 00:01:22,990 --> 00:01:26,230 And tumor suppressor genes importantly, 21 00:01:26,230 --> 00:01:30,010 carry within them loss of function mutations 22 00:01:30,010 --> 00:01:31,930 in the context of cancer. 23 00:01:31,930 --> 00:01:35,800 Loss of function mutations, as such, these mutations 24 00:01:35,800 --> 00:01:45,260 are recessive mutations at the cellular level. 25 00:01:45,260 --> 00:01:47,680 It's necessary to inactivate both copies of a tumor 26 00:01:47,680 --> 00:01:49,930 suppressor gene in order to give rise 27 00:01:49,930 --> 00:01:52,990 to a cell that's lacking that function altogether. 28 00:01:52,990 --> 00:01:56,830 And that's a cell that is on its way to becoming a cancer cell. 29 00:01:56,830 --> 00:01:59,605 And these loss of function mutations can be various. 30 00:02:06,155 --> 00:02:09,030 You might find nonsense mutations 31 00:02:09,030 --> 00:02:10,339 in a tumor suppressor gene-- 32 00:02:10,339 --> 00:02:11,880 blocks the production of the protein. 33 00:02:17,367 --> 00:02:18,450 You might find a deletion. 34 00:02:18,450 --> 00:02:21,590 It takes out the entire gene, or a big portion of the gene. 35 00:02:28,390 --> 00:02:30,520 You might find a frame shift mutation-- again, 36 00:02:30,520 --> 00:02:33,370 that blocks the ability to make any protein, or much protein. 37 00:02:38,130 --> 00:02:40,870 And I also told you about chromosome loss events. 38 00:02:40,870 --> 00:02:42,666 The loss of the chromosome that carries 39 00:02:42,666 --> 00:02:44,290 the normal copy of the tumor suppressor 40 00:02:44,290 --> 00:02:48,970 gene as a frequent second event to lose the remaining wild type 41 00:02:48,970 --> 00:02:50,659 copy of the gene. 42 00:02:50,659 --> 00:02:52,450 OK, so this is just a little bit of review. 43 00:02:55,021 --> 00:02:57,270 Now, I framed the discussion about oncogenes and tumor 44 00:02:57,270 --> 00:03:00,240 suppressor genes from the point of view of cell division 45 00:03:00,240 --> 00:03:03,730 control and the production of more cells 46 00:03:03,730 --> 00:03:05,620 through the action of these mutations. 47 00:03:08,470 --> 00:03:12,070 And indeed, cancer is a product of inappropriate cell division. 48 00:03:19,780 --> 00:03:24,400 And the two genes that we discussed in some detail 49 00:03:24,400 --> 00:03:25,390 regulate this process. 50 00:03:28,570 --> 00:03:32,890 The RAS gene and the product oncogene 51 00:03:32,890 --> 00:03:36,350 stimulate cell division. 52 00:03:36,350 --> 00:03:41,010 The RB tumor suppressor gene inhibits cell division. 53 00:03:47,324 --> 00:03:49,490 When we consider the kinds of mutations that we have 54 00:03:49,490 --> 00:03:53,790 in these genes that regulate the cell division process-- 55 00:03:53,790 --> 00:03:59,460 in the case of the RAS gene, we find activating mutations. 56 00:03:59,460 --> 00:04:01,740 And in the case of the tumor suppressor gene RB, 57 00:04:01,740 --> 00:04:03,870 we find inactivating mutations. 58 00:04:06,690 --> 00:04:09,710 RAS is in oncogene. 59 00:04:09,710 --> 00:04:11,920 RB is a tumor suppressor gene. 60 00:04:11,920 --> 00:04:14,410 Activating mutations in the oncogene. 61 00:04:14,410 --> 00:04:17,860 Inactivating mutations in the tumor suppressor gene. 62 00:04:17,860 --> 00:04:19,899 But cancer isn't only about cell division. 63 00:04:19,899 --> 00:04:22,480 It's really about cell number-- inappropriate cell number. 64 00:04:22,480 --> 00:04:24,130 And there's another important process 65 00:04:24,130 --> 00:04:25,465 to remember in this context. 66 00:04:31,620 --> 00:04:34,470 Apoptosis-- program cell death, which 67 00:04:34,470 --> 00:04:37,680 I've referred to many times in many different contexts. 68 00:04:37,680 --> 00:04:45,370 Apoptosis, which results in dead cells. 69 00:04:45,370 --> 00:04:47,840 And failure to undergo apoptosis properly 70 00:04:47,840 --> 00:04:51,230 will likewise result in too many cells, which 71 00:04:51,230 --> 00:04:52,605 again can be cancer causing. 72 00:04:55,670 --> 00:04:57,990 We have genes that regulate this process. 73 00:04:57,990 --> 00:05:01,640 For example, the P53 gene, which we'll 74 00:05:01,640 --> 00:05:06,800 discuss in some more detail, positively regulates apoptosis. 75 00:05:06,800 --> 00:05:11,750 And another gene called BCL-2, which 76 00:05:11,750 --> 00:05:16,200 negatively regulates apoptosis. 77 00:05:16,200 --> 00:05:19,950 Is P53 an oncogene or a tumor suppressor gene? 78 00:05:22,610 --> 00:05:23,930 Oncogene? 79 00:05:23,930 --> 00:05:25,280 Tumor suppressor gene? 80 00:05:25,280 --> 00:05:26,360 Good. 81 00:05:26,360 --> 00:05:30,320 P53 is a very important tumor suppressor gene. 82 00:05:30,320 --> 00:05:34,100 It is inactivated in the context of cancer 83 00:05:34,100 --> 00:05:36,770 because you want to get rid of apoptosis 84 00:05:36,770 --> 00:05:39,860 as you are developing cancer cell. 85 00:05:39,860 --> 00:05:45,860 Is BCL-2 an oncogene or a tumor suppressor gene? 86 00:05:45,860 --> 00:05:48,470 It's an oncogene. 87 00:05:48,470 --> 00:05:52,160 We find gain of function mutations in BCL-2, 88 00:05:52,160 --> 00:05:54,710 producing more of this inhibitor of apoptosis 89 00:05:54,710 --> 00:05:57,010 in the context of cancer to block 90 00:05:57,010 --> 00:06:00,890 apoptosis leading to an increased number of developing 91 00:06:00,890 --> 00:06:02,390 cancer cells. 92 00:06:02,390 --> 00:06:04,850 OK, so oncogenes and tumor suppressor genes 93 00:06:04,850 --> 00:06:07,520 can regulate these two processes differently. 94 00:06:07,520 --> 00:06:11,240 As you can see, inhibitors in this case, stimulator's 95 00:06:11,240 --> 00:06:15,960 in this case, in the context of tumor suppressor genes. 96 00:06:15,960 --> 00:06:17,760 All right, a little bit more about P53, 97 00:06:17,760 --> 00:06:21,690 which is probably the most important cancer gene of all. 98 00:06:21,690 --> 00:06:27,490 It's mutated in at least 50% of all human tumors. 99 00:06:27,490 --> 00:06:32,980 And P53 is known to function as a molecular policeman of sorts. 100 00:06:32,980 --> 00:06:36,790 It's sensitive to various perturbations within the cell. 101 00:06:36,790 --> 00:06:38,140 For example, DNA damage. 102 00:06:42,350 --> 00:06:54,420 DNA damage will feed into the P53 regulated pathway, 103 00:06:54,420 --> 00:06:59,100 as will a fascinating process, which is still incompletely 104 00:06:59,100 --> 00:07:02,400 understood, where the cell can recognize that it's 105 00:07:02,400 --> 00:07:04,500 dividing inappropriately. 106 00:07:04,500 --> 00:07:07,600 Abnormal proliferation-- cells dividing when it shouldn't. 107 00:07:07,600 --> 00:07:10,260 This gets detected, and this, too, 108 00:07:10,260 --> 00:07:13,350 can feed into the P53 pathway. 109 00:07:13,350 --> 00:07:18,210 And this leads to an increase in the levels of the P53 protein. 110 00:07:27,350 --> 00:07:29,670 P53 is a transcription factor. 111 00:07:29,670 --> 00:07:32,390 It regulates the expression of other genes. 112 00:07:32,390 --> 00:07:38,440 And the genes that it regulates fall into two broad categories, 113 00:07:38,440 --> 00:07:44,900 some of which cause the cell to undergo cell cycle arrest. 114 00:07:44,900 --> 00:07:46,730 When the P53 pathway is activated 115 00:07:46,730 --> 00:07:49,805 under certain circumstances, the cells are instructed to arrest. 116 00:07:56,810 --> 00:07:58,700 During which time, whatever the damage is 117 00:07:58,700 --> 00:08:01,580 can be fixed before the cell continues to cycle. 118 00:08:01,580 --> 00:08:05,540 If there's DNA damage, the cell might arrest, fix the damage, 119 00:08:05,540 --> 00:08:06,580 and then continue on. 120 00:08:09,270 --> 00:08:11,730 In addition, P53 regulates apoptosis, 121 00:08:11,730 --> 00:08:18,160 as I mentioned a few moments ago, causing the cells to die. 122 00:08:18,160 --> 00:08:19,885 Causing the damaged cells to die-- 123 00:08:27,430 --> 00:08:31,120 and that's good because dead cells make no tumors. 124 00:08:31,120 --> 00:08:34,480 This is a sacrifice by the individual cell who 125 00:08:34,480 --> 00:08:38,710 has been damaged, basically saying, I'm in trouble, 126 00:08:38,710 --> 00:08:43,799 killing itself, and allowing the organism to survive. 127 00:08:43,799 --> 00:08:46,990 OK, and this is a very important process in cancer prevention 128 00:08:46,990 --> 00:08:47,890 we now know. 129 00:08:47,890 --> 00:08:49,690 And I'll tell you some examples of how 130 00:08:49,690 --> 00:08:52,840 we know that momentarily. 131 00:08:52,840 --> 00:08:56,660 OK, so I've introduced you to a couple of different oncogenes 132 00:08:56,660 --> 00:08:59,835 and a couple of different tumor suppressor genes. 133 00:08:59,835 --> 00:09:01,210 I want to focus a little bit more 134 00:09:01,210 --> 00:09:03,085 on the tumor suppressor genes in one respect. 135 00:09:06,647 --> 00:09:08,605 We touched on this last time, but very briefly. 136 00:09:18,770 --> 00:09:22,380 Tumor suppressor genes is sporadically occurring cancers. 137 00:09:22,380 --> 00:09:31,040 And sporadic means that the individual 138 00:09:31,040 --> 00:09:34,280 has no family history of that particular cancer type-- 139 00:09:34,280 --> 00:09:36,350 sort of a chance event. 140 00:09:36,350 --> 00:09:41,930 And tumor suppressor genes in sporadic cancers 141 00:09:41,930 --> 00:09:46,100 require two mutational events. 142 00:09:46,100 --> 00:09:47,620 And I described these as hits. 143 00:09:47,620 --> 00:09:49,550 And we typically do describe them 144 00:09:49,550 --> 00:09:53,990 as hits in the context of tumor suppressor gene inactivation. 145 00:09:53,990 --> 00:09:56,120 Sometimes it's mutations. 146 00:09:56,120 --> 00:09:58,880 Sometimes it's mutations coupled with chromosome loss 147 00:09:58,880 --> 00:10:00,470 as the second hit. 148 00:10:00,470 --> 00:10:03,740 But regardless, two mutations are 149 00:10:03,740 --> 00:10:06,500 necessary to get rid of both copies of the tumor suppressor 150 00:10:06,500 --> 00:10:08,320 gene. 151 00:10:08,320 --> 00:10:12,100 And I also briefly introduced you to the fact 152 00:10:12,100 --> 00:10:20,420 that tumor suppressor genes are often-- not always-- but 153 00:10:20,420 --> 00:10:22,880 for the most part, familial cancer syndromes, where 154 00:10:22,880 --> 00:10:25,340 the individuals have a predisposition to developing 155 00:10:25,340 --> 00:10:29,300 a particular type of cancer are caused by inherited mutations 156 00:10:29,300 --> 00:10:30,530 in tumor suppressor genes. 157 00:10:40,130 --> 00:10:42,530 So one of the hits, one of the mutations, 158 00:10:42,530 --> 00:10:44,930 is inherited from one parent. 159 00:10:44,930 --> 00:10:48,140 Meaning that every cell in that person's body 160 00:10:48,140 --> 00:10:50,130 carries one of the mutations already. 161 00:11:03,930 --> 00:11:06,630 Meaning that only one hit, one mutation, 162 00:11:06,630 --> 00:11:08,280 is required somatically. 163 00:11:08,280 --> 00:11:13,170 That is in the individual's own cells in their body. 164 00:11:13,170 --> 00:11:14,916 And this is why these individuals 165 00:11:14,916 --> 00:11:16,290 are cancer prone, because they're 166 00:11:16,290 --> 00:11:19,200 one step away from lacking the tumor suppressor 167 00:11:19,200 --> 00:11:22,350 gene altogether, whereas in most people 168 00:11:22,350 --> 00:11:25,740 two mutational events are necessary, and it's rare-- 169 00:11:25,740 --> 00:11:27,780 not never, but rare-- 170 00:11:27,780 --> 00:11:30,300 to get those two mutations. 171 00:11:30,300 --> 00:11:37,450 And I showed you briefly this pedigree, which 172 00:11:37,450 --> 00:11:41,050 is a pedigree of familial retinoblastoma, 173 00:11:41,050 --> 00:11:44,710 where the individuals inherit a defective copy of the RB gene, 174 00:11:44,710 --> 00:11:46,870 and as such are predisposed to the development 175 00:11:46,870 --> 00:11:48,160 of this tumor of the eye. 176 00:11:48,160 --> 00:11:50,800 And in fact, they will develop the tumor typically 177 00:11:50,800 --> 00:11:56,020 in both the eyes, and typically multiple foci of tumor. 178 00:11:56,020 --> 00:11:58,810 So they inherit a defective copy of the gene from one parent 179 00:11:58,810 --> 00:12:04,880 and they go on to develop the disease at high frequency. 180 00:12:04,880 --> 00:12:08,730 When you look at this pedigree, remembering back 181 00:12:08,730 --> 00:12:28,604 to your lessons in disease genetics, 182 00:12:28,604 --> 00:12:30,520 this looks like an autosomal dominant disease. 183 00:12:33,500 --> 00:12:35,810 If you inherit the disease allele, 184 00:12:35,810 --> 00:12:38,570 you have a very high likelihood of developing the disease 185 00:12:38,570 --> 00:12:41,720 regardless of who your other parent was. 186 00:12:41,720 --> 00:12:44,710 It looks like an autosomal dominant disease 187 00:12:44,710 --> 00:12:48,170 with actually incomplete penetrance, as we can see here. 188 00:12:48,170 --> 00:12:50,660 And we'll talk more about this in a second. 189 00:12:50,660 --> 00:13:01,350 An autosomal dominate disease, but interestingly, we've 190 00:13:01,350 --> 00:13:07,980 been talking about the fact that the mutations are actually 191 00:13:07,980 --> 00:13:09,250 recessive. 192 00:13:09,250 --> 00:13:11,010 So this seems confusing. 193 00:13:11,010 --> 00:13:12,510 So who can explain it? 194 00:13:12,510 --> 00:13:16,770 How do we have a recessive mutation at the cellular level 195 00:13:16,770 --> 00:13:19,980 causing what appears to be an autosomal dominant disease? 196 00:13:19,980 --> 00:13:23,455 Who can answer that question? 197 00:13:23,455 --> 00:13:24,910 Yeah? 198 00:13:24,910 --> 00:13:28,305 AUDIENCE: Predisposition is the dominant. 199 00:13:28,305 --> 00:13:30,250 It only needs one mutation. 200 00:13:30,250 --> 00:13:31,180 PROFESSOR: Exactly. 201 00:13:31,180 --> 00:13:31,960 Exactly. 202 00:13:31,960 --> 00:13:34,150 You are predisposed. 203 00:13:34,150 --> 00:13:35,950 And there's a very high likelihood 204 00:13:35,950 --> 00:13:38,980 that in some or in fact, many of your cells, 205 00:13:38,980 --> 00:13:40,540 this second event will occur. 206 00:13:40,540 --> 00:13:42,610 It's almost guaranteed. 207 00:13:42,610 --> 00:13:44,590 And since it's almost guaranteed, 208 00:13:44,590 --> 00:13:46,930 if you inherit just one mutation, 209 00:13:46,930 --> 00:13:49,420 you will develop the disease, and therefore it 210 00:13:49,420 --> 00:13:52,090 appears to be at the organismal level-- 211 00:13:52,090 --> 00:13:55,750 autosomal dominant-- because your predisposition nearly 212 00:13:55,750 --> 00:13:59,170 always guarantees that you will develop the disease even 213 00:13:59,170 --> 00:14:05,050 though the mutations at the cellular level are recessive. 214 00:14:05,050 --> 00:14:09,070 And so with that in mind, as we consider a pedigree similar 215 00:14:09,070 --> 00:14:11,800 to the one I just showed you, where one parent is 216 00:14:11,800 --> 00:14:15,940 heterozygous for the mutation-- the loss of function mutation-- 217 00:14:15,940 --> 00:14:21,160 passes that onto the next generation and beyond, 218 00:14:21,160 --> 00:14:24,130 in this individual, as well as the other ones shown 219 00:14:24,130 --> 00:14:28,210 with the dark symbols where a tumor did develop, 220 00:14:28,210 --> 00:14:32,640 what is a necessary second event? 221 00:14:32,640 --> 00:14:34,340 The loss of the wild type of allele, 222 00:14:34,340 --> 00:14:38,240 either by a second mutation, or a chromosome loss event. 223 00:14:38,240 --> 00:14:40,469 And that happens at very high frequency. 224 00:14:40,469 --> 00:14:42,260 In the case of retinoblastoma, it typically 225 00:14:42,260 --> 00:14:46,870 happens in a dozen cells in the developing retina-- 226 00:14:46,870 --> 00:14:49,510 leading to an average of a dozen independent tumors 227 00:14:49,510 --> 00:14:51,460 in those kids. 228 00:14:51,460 --> 00:14:53,470 OK, but now let's think about this individual 229 00:14:53,470 --> 00:14:58,180 here who did inherit the defective allele because he 230 00:14:58,180 --> 00:15:01,480 actually passed it on to his three sons, but he 231 00:15:01,480 --> 00:15:03,970 himself did not develop retinoblastoma. 232 00:15:03,970 --> 00:15:05,030 How can we explain that? 233 00:15:07,580 --> 00:15:08,645 Why was he spared? 234 00:15:13,420 --> 00:15:15,670 Well, there are two general explanations. 235 00:15:15,670 --> 00:15:19,720 First, he was incredibly lucky. 236 00:15:19,720 --> 00:15:23,650 Although it's highly likely that some cell or cells 237 00:15:23,650 --> 00:15:25,420 in the developing retina will mutate 238 00:15:25,420 --> 00:15:27,910 the normal copy of the gene. 239 00:15:27,910 --> 00:15:30,200 In him, it just didn't happen. 240 00:15:30,200 --> 00:15:30,880 He got lucky. 241 00:15:30,880 --> 00:15:34,990 None of his cells mutated the normal copy of the gene. 242 00:15:34,990 --> 00:15:36,972 His eyes developed normally. 243 00:15:36,972 --> 00:15:38,680 And after that point, actually, the cells 244 00:15:38,680 --> 00:15:40,450 are much less sensitive to mutation, 245 00:15:40,450 --> 00:15:44,410 and therefore after about three or five years of age, 246 00:15:44,410 --> 00:15:46,540 you typically wouldn't develop the tumor. 247 00:15:46,540 --> 00:15:48,370 So he might be incredibly lucky. 248 00:15:48,370 --> 00:15:53,740 Or it might be that in him, because of some other inherited 249 00:15:53,740 --> 00:15:56,920 allele of some other gene, even if he 250 00:15:56,920 --> 00:15:59,980 were to lose the wild type alleled of RB gene 251 00:15:59,980 --> 00:16:02,800 it wouldn't matter, because he's got some other gene that's 252 00:16:02,800 --> 00:16:06,040 functioning maybe in the place of the RB gene, 253 00:16:06,040 --> 00:16:07,630 leading to him to be protected. 254 00:16:07,630 --> 00:16:09,430 And these two possibilities exist, 255 00:16:09,430 --> 00:16:13,560 and we have examples of how both can be important. 256 00:16:13,560 --> 00:16:15,240 OK, final question on this slide-- 257 00:16:15,240 --> 00:16:17,430 what would happen if an individual inherited 258 00:16:17,430 --> 00:16:19,770 a mutation from both parents and was therefore 259 00:16:19,770 --> 00:16:23,159 homozygous for a mutation in a tumor suppressor gene. 260 00:16:23,159 --> 00:16:24,450 What do you think would happen? 261 00:16:27,260 --> 00:16:29,440 The answer was they would be stillborn 262 00:16:29,440 --> 00:16:32,350 or they wouldn't make it out of embryogenesis. 263 00:16:32,350 --> 00:16:34,850 And that's usually the case. 264 00:16:34,850 --> 00:16:39,040 And we know that not so much from the study of people who 265 00:16:39,040 --> 00:16:41,800 are homozygous for these mutations, 266 00:16:41,800 --> 00:16:45,280 because it's actually quite rare to find people who are 267 00:16:45,280 --> 00:16:48,640 heterozygous who have children-- so the number of such examples 268 00:16:48,640 --> 00:16:50,140 is few-- 269 00:16:50,140 --> 00:16:51,655 but we know it from knock-out mice. 270 00:16:57,970 --> 00:16:59,590 All of these tumor suppressor genes 271 00:16:59,590 --> 00:17:04,390 exist within the mouse genome as well. 272 00:17:04,390 --> 00:17:07,089 And my group and others have made mice 273 00:17:07,089 --> 00:17:09,190 with mutations in these genes. 274 00:17:09,190 --> 00:17:13,119 And actually we know that, in fact, for many of the tumor 275 00:17:13,119 --> 00:17:16,030 suppressor genes that we care about, 276 00:17:16,030 --> 00:17:18,760 like the RB tumor suppressor gene, 277 00:17:18,760 --> 00:17:22,750 if one creates a homozygous mutant mouse, 278 00:17:22,750 --> 00:17:26,319 or the APC tumor suppressor gene, which 279 00:17:26,319 --> 00:17:29,770 is important in colon cancer prevention, 280 00:17:29,770 --> 00:17:34,330 or the BRCA1 tumor suppressor gene, 281 00:17:34,330 --> 00:17:38,020 which is important in breast and ovarian cancer prevention-- 282 00:17:38,020 --> 00:17:48,640 in all of these cases, the embryos don't survive. 283 00:17:48,640 --> 00:17:52,390 And they die at different points along the way of embryogenesis. 284 00:17:52,390 --> 00:17:55,780 And it's actually not because they develop lots of cancer 285 00:17:55,780 --> 00:17:56,680 as embryos. 286 00:17:56,680 --> 00:17:58,930 Although, you might have thought that was true. 287 00:17:58,930 --> 00:18:00,700 They die because these genes are actually 288 00:18:00,700 --> 00:18:03,040 important in normal development. 289 00:18:03,040 --> 00:18:05,950 They're not there just to protect against cancer. 290 00:18:05,950 --> 00:18:07,570 They're there because they play a role 291 00:18:07,570 --> 00:18:11,170 in regulating normal cell division processes, normal cell 292 00:18:11,170 --> 00:18:14,890 death processes, normal physiology, 293 00:18:14,890 --> 00:18:19,070 such that when they're missing, the embryo can't survive. 294 00:18:19,070 --> 00:18:21,064 There's actually one exception to this. 295 00:18:21,064 --> 00:18:22,480 Well, I shouldn't say it that way. 296 00:18:22,480 --> 00:18:23,979 There are a few exceptions to this-- 297 00:18:23,979 --> 00:18:25,870 but one notable exception to this. 298 00:18:25,870 --> 00:18:29,410 And that happens to be the P53 tumor suppressor gene 299 00:18:29,410 --> 00:18:31,240 that I've introduced you to. 300 00:18:31,240 --> 00:18:37,120 My group and others have made animals that are mutant for P53 301 00:18:37,120 --> 00:18:38,930 either heterozygous for the mutation. 302 00:18:45,800 --> 00:18:50,109 What would you expect the phenotype of these mice to be? 303 00:18:50,109 --> 00:18:52,400 Are they going to be totally normal mice, do you think? 304 00:19:02,050 --> 00:19:04,420 They are, in fact, cancer prone. 305 00:19:04,420 --> 00:19:08,020 They look like those people with inherited predisposition 306 00:19:08,020 --> 00:19:09,490 to cancer. 307 00:19:09,490 --> 00:19:13,060 They carry one mutant copy of a tumor suppressor gene. 308 00:19:13,060 --> 00:19:14,860 And they're one mutational event away 309 00:19:14,860 --> 00:19:17,470 from lacking the tumor suppressor gene altogether. 310 00:19:17,470 --> 00:19:20,590 And that happens at some frequency in their cells. 311 00:19:20,590 --> 00:19:24,460 And the mice will go on to develop cancer and die early 312 00:19:24,460 --> 00:19:26,200 for that reason. 313 00:19:26,200 --> 00:19:29,500 We cross these mice together with an expectation 314 00:19:29,500 --> 00:19:32,940 that again, they would not survive embryogenesis. 315 00:19:36,350 --> 00:19:39,290 But in fact to our surprise, you can 316 00:19:39,290 --> 00:19:42,632 make a fully P53 null mouse. 317 00:19:42,632 --> 00:19:44,840 And what do you think the phenotype of that mouse is? 318 00:19:48,350 --> 00:19:49,790 It's very cancer prone. 319 00:19:57,710 --> 00:19:59,750 Because this is a mouse, that in all 320 00:19:59,750 --> 00:20:02,510 of its cells, this very important tumor suppressor gene 321 00:20:02,510 --> 00:20:03,990 is lacking. 322 00:20:03,990 --> 00:20:07,920 Normal mice will live about 2 and 1/2 to three years. 323 00:20:07,920 --> 00:20:10,470 These mice will live about 1 and 1/2 years 324 00:20:10,470 --> 00:20:13,740 and die from cancer as a consequence. 325 00:20:13,740 --> 00:20:16,470 These mice will live about four to six months 326 00:20:16,470 --> 00:20:18,700 and die from cancer. 327 00:20:18,700 --> 00:20:22,140 So P53 is actually not important in normal development. 328 00:20:22,140 --> 00:20:24,510 It is a true tumor suppressor gene. 329 00:20:24,510 --> 00:20:27,090 It probably evolved to protect cells 330 00:20:27,090 --> 00:20:31,230 against the kind of damage that is inflicted on cells 331 00:20:31,230 --> 00:20:33,690 in an individual's lifetime. 332 00:20:33,690 --> 00:20:35,970 And if that damage is sufficiently great, 333 00:20:35,970 --> 00:20:38,910 the cells are eliminated or arrest permanently 334 00:20:38,910 --> 00:20:40,770 so they will not develop into cancer cells. 335 00:20:40,770 --> 00:20:45,250 It's a true tumor suppressor gene in that case. 336 00:20:45,250 --> 00:20:49,425 OK, so I've told you about oncogene and tumor suppressor 337 00:20:49,425 --> 00:20:49,925 genes. 338 00:20:53,400 --> 00:20:57,480 We are now entering an era over the last couple of years 339 00:20:57,480 --> 00:21:05,280 really, where many, many more cancer 340 00:21:05,280 --> 00:21:08,340 genes are being discovered through the application 341 00:21:08,340 --> 00:21:12,510 of genomic sequencing in the context of cancer. 342 00:21:12,510 --> 00:21:16,290 Cancer genomics is all the rage, including here at MIT, 343 00:21:16,290 --> 00:21:18,630 for example in the Broad Institute. 344 00:21:18,630 --> 00:21:20,100 And there are many papers appearing 345 00:21:20,100 --> 00:21:22,290 in the literature like these looking 346 00:21:22,290 --> 00:21:26,610 at the complexity of the genome of individual cancers, 347 00:21:26,610 --> 00:21:30,900 like this study out of the Broad on prostate cancer, 348 00:21:30,900 --> 00:21:34,200 and this study out of the Sanger Institute in England 349 00:21:34,200 --> 00:21:36,150 on small cell lung cancer. 350 00:21:36,150 --> 00:21:39,150 All the genes or the entire genomes 351 00:21:39,150 --> 00:21:42,390 of lots of different cancers are being sequenced and compared 352 00:21:42,390 --> 00:21:45,330 to the normal DNA of the same individual 353 00:21:45,330 --> 00:21:47,790 to catalog all of the mutations that 354 00:21:47,790 --> 00:21:49,970 are present within an individual tumor. 355 00:21:53,014 --> 00:21:54,430 And although there are differences 356 00:21:54,430 --> 00:22:05,440 depending on the cancer type, the average cancer genome 357 00:22:05,440 --> 00:22:14,520 actually has 100's and sometimes thousands of mutations. 358 00:22:19,960 --> 00:22:24,430 Small cell lung cancer, for example, has tens of thousands 359 00:22:24,430 --> 00:22:28,000 of mutations compared to normal cells of the lung. 360 00:22:28,000 --> 00:22:28,930 Why? 361 00:22:28,930 --> 00:22:31,420 Because they arise following years of exposure 362 00:22:31,420 --> 00:22:33,790 to cigarette smoke, which carries 363 00:22:33,790 --> 00:22:37,900 mutagens that bathe the DNA in mutation causing 364 00:22:37,900 --> 00:22:41,910 chemicals leading to mutations. 365 00:22:41,910 --> 00:22:45,440 Now, not all of the mutations that you find in a cancer cell 366 00:22:45,440 --> 00:22:49,220 are relevant to the cancer phenotype. 367 00:22:49,220 --> 00:22:50,870 In fact, we think that there's only 368 00:22:50,870 --> 00:22:53,750 amongst all those mutations that are found that there's 369 00:22:53,750 --> 00:23:06,340 only about 5 to 20 or so mutations in oncogenes or tumor 370 00:23:06,340 --> 00:23:08,250 suppressor genes. 371 00:23:08,250 --> 00:23:11,790 And we call these mutations driver mutations. 372 00:23:17,374 --> 00:23:19,040 Driver mutations, meaning, they actually 373 00:23:19,040 --> 00:23:21,980 are participating in the development of the tumor, 374 00:23:21,980 --> 00:23:24,726 causing some aspect of the cancer phenotype. 375 00:23:32,170 --> 00:23:35,030 And the remainder, we call passenger mutations. 376 00:23:41,400 --> 00:23:44,070 Silent mutations-- mutations that actually don't do anything 377 00:23:44,070 --> 00:23:45,540 to the cancer cell, but they just 378 00:23:45,540 --> 00:23:48,450 happened to occur at the same time, 379 00:23:48,450 --> 00:23:51,120 or in the lifetime of the cancer cell 380 00:23:51,120 --> 00:23:53,140 when another important mutation took place. 381 00:23:53,140 --> 00:23:56,190 So that clone of cells that develops 382 00:23:56,190 --> 00:23:58,950 carries those mutations too, but they're not actually 383 00:23:58,950 --> 00:24:00,990 contributing to the cancer phenotype. 384 00:24:00,990 --> 00:24:03,240 So among the hundreds and thousands of mutations, 385 00:24:03,240 --> 00:24:05,730 some of them really matter, and some of them 386 00:24:05,730 --> 00:24:08,670 are just going along for the ride. 387 00:24:08,670 --> 00:24:10,980 It makes the analysis of the cancer genome 388 00:24:10,980 --> 00:24:12,930 much more complicated, actually, because it's 389 00:24:12,930 --> 00:24:16,210 hard to tell what's a passenger, and what's a driver. 390 00:24:16,210 --> 00:24:19,770 But increasingly recognizing what are the important ones 391 00:24:19,770 --> 00:24:23,820 and focusing our attention on them. 392 00:24:23,820 --> 00:24:27,440 OK, that's all I'm going to tell you about cancer genetics. 393 00:24:27,440 --> 00:24:30,310 And I want to now turn my attention for the last 25 394 00:24:30,310 --> 00:24:32,060 minutes-- and I may run over a little bit, 395 00:24:32,060 --> 00:24:35,270 so I ask for your patience if I run over a little bit, 396 00:24:35,270 --> 00:24:37,160 because I do want to finish this-- 397 00:24:37,160 --> 00:24:40,190 to talk about cancer therapy. 398 00:24:40,190 --> 00:24:43,250 Before I make the switch to cancer therapy, 399 00:24:43,250 --> 00:24:47,480 I want to first introduce the concept of cancer prevention. 400 00:24:55,310 --> 00:24:57,790 A lot of us work on cancer genes and cancer genetics 401 00:24:57,790 --> 00:25:00,004 to understand how to treat cancer better. 402 00:25:00,004 --> 00:25:01,420 But in the future, hopefully we'll 403 00:25:01,420 --> 00:25:03,790 have many fewer cancers to treat, 404 00:25:03,790 --> 00:25:05,690 because we'll be able to prevent them. 405 00:25:05,690 --> 00:25:07,540 If people would stop smoking, we'd 406 00:25:07,540 --> 00:25:11,290 have 80% fewer lung cancers to treat. 407 00:25:11,290 --> 00:25:13,270 If you use sunblock and stay out of the sun, 408 00:25:13,270 --> 00:25:16,930 we'll have fewer skin cancers to treat and so forth. 409 00:25:16,930 --> 00:25:19,540 Better diet and excess exercise will prevent a lot 410 00:25:19,540 --> 00:25:21,094 of other types of cancers. 411 00:25:21,094 --> 00:25:22,510 So there are lifestyle things that 412 00:25:22,510 --> 00:25:25,960 can lower the number of cancers in the context of cancer 413 00:25:25,960 --> 00:25:27,520 prevention. 414 00:25:27,520 --> 00:25:32,380 There's also ways to prevent agents from producing cancer 415 00:25:32,380 --> 00:25:33,430 in your body. 416 00:25:33,430 --> 00:25:36,790 And the best example of that is Gardasil. 417 00:25:36,790 --> 00:25:40,360 Gardasil is an example of cancer prevention involving 418 00:25:40,360 --> 00:25:41,335 a particular virus-- 419 00:25:51,750 --> 00:25:54,630 human papillomavirus-- and specifically, 420 00:25:54,630 --> 00:25:58,450 human papillomaviruses, which are described as the high risk 421 00:25:58,450 --> 00:25:58,950 type. 422 00:26:03,330 --> 00:26:08,010 Human papillomaviruses or HPV of the high risk type 423 00:26:08,010 --> 00:26:10,500 can cause cervical cancer. 424 00:26:10,500 --> 00:26:13,830 They are the main reason that women develop cervical cancer. 425 00:26:13,830 --> 00:26:15,930 And they're responsible for other types of cancers 426 00:26:15,930 --> 00:26:17,230 as well, including in men. 427 00:26:20,810 --> 00:26:29,060 And what we know is that in a normal cell of the cervix, 428 00:26:29,060 --> 00:26:33,020 when infected by the human papilloma virus, 429 00:26:33,020 --> 00:26:41,040 will at some frequency, and after a period of time, 430 00:26:41,040 --> 00:26:42,850 develop into cervical cancer. 431 00:26:49,010 --> 00:26:52,190 This suggests that the virus-- 432 00:26:52,190 --> 00:26:55,660 some genes of the virus-- 433 00:26:55,660 --> 00:27:00,120 are changing the cells behavior in such a way 434 00:27:00,120 --> 00:27:01,500 that it develops into cancer. 435 00:27:01,500 --> 00:27:03,315 Yes? 436 00:27:03,315 --> 00:27:05,790 AUDIENCE: I don't know if you're talking 437 00:27:05,790 --> 00:27:07,275 about our class or something else, 438 00:27:07,275 --> 00:27:09,255 but it's very rude to talk. 439 00:27:09,255 --> 00:27:12,340 It makes so much noise during the lecture. 440 00:27:12,340 --> 00:27:13,215 PROFESSOR: Thank you. 441 00:27:16,680 --> 00:27:19,620 So something in the virus is causing the cells 442 00:27:19,620 --> 00:27:22,470 to divide abnormally into a tumor. 443 00:27:22,470 --> 00:27:25,140 And this has been studied at length. 444 00:27:25,140 --> 00:27:28,590 And we now know that there are two genes, which 445 00:27:28,590 --> 00:27:33,330 are responsible for causing cervical cells to become cancer 446 00:27:33,330 --> 00:27:34,560 cells-- 447 00:27:34,560 --> 00:27:38,610 two genes of the virus called E6 and E7. 448 00:27:38,610 --> 00:27:41,640 And it's been learned that these genes in fact 449 00:27:41,640 --> 00:27:45,810 encode proteins that inhibit cellular proteins that we're 450 00:27:45,810 --> 00:27:47,310 actually quite familiar with. 451 00:27:47,310 --> 00:27:51,180 And we now believe we understand why the virus causes cancer. 452 00:27:51,180 --> 00:27:55,150 E6 inhibits P53. 453 00:27:55,150 --> 00:27:59,200 And E7 inhibits RB. 454 00:27:59,200 --> 00:28:03,400 So the virus for its own reasons of viral replication, 455 00:28:03,400 --> 00:28:06,830 takes out these two tumor suppressor genes. 456 00:28:06,830 --> 00:28:09,907 And as such, the cells are lacking these two 457 00:28:09,907 --> 00:28:11,740 critical tumor suppressor genes, and they're 458 00:28:11,740 --> 00:28:16,720 well on their way to becoming uncontrolled cancer cells. 459 00:28:16,720 --> 00:28:22,350 OK, so that's how HPV high risk types cause cancer. 460 00:28:22,350 --> 00:28:32,020 And what was developed in the context of Gardasil is an HPV 461 00:28:32,020 --> 00:28:41,890 vaccine so that individuals cannot be infected productively 462 00:28:41,890 --> 00:28:50,450 with this class of viruses, specifically it's a component 463 00:28:50,450 --> 00:28:55,610 vaccine made of recombinant proteins that are present 464 00:28:55,610 --> 00:28:58,730 in the high risk types of HPV. 465 00:28:58,730 --> 00:29:04,240 As a component vaccine, this vaccine 466 00:29:04,240 --> 00:29:07,210 does not produce a replicating virus. 467 00:29:07,210 --> 00:29:09,580 It's just pieces of the virus. 468 00:29:09,580 --> 00:29:11,830 So there's no risk of a viral infection here. 469 00:29:17,990 --> 00:29:21,890 But an potent antibody response can 470 00:29:21,890 --> 00:29:25,460 be elicited, including neutralizing antibodies that 471 00:29:25,460 --> 00:29:27,320 will prevent an individual from being 472 00:29:27,320 --> 00:29:30,670 infected by the real thing at a future time. 473 00:29:30,670 --> 00:29:33,800 OK, so that's an example of cancer prevention, 474 00:29:33,800 --> 00:29:36,980 eliminating an ideological agent that is responsible. 475 00:29:36,980 --> 00:29:41,820 There aren't many examples of virus caused cancers in humans. 476 00:29:41,820 --> 00:29:44,160 So this is kind of a special case. 477 00:29:44,160 --> 00:29:48,470 But HBV-- hepatitis B virus induced liver cancer 478 00:29:48,470 --> 00:29:52,780 will be another one before too long. 479 00:29:52,780 --> 00:29:57,092 OK, so now let's talk about cancer therapy. 480 00:29:57,092 --> 00:29:58,800 I'm going to talk to you in a few minutes 481 00:29:58,800 --> 00:30:01,500 about some new cancer therapies that 482 00:30:01,500 --> 00:30:04,380 are based on our improved knowledge 483 00:30:04,380 --> 00:30:06,810 of the genes in cancer cells. 484 00:30:06,810 --> 00:30:11,430 I'm going to tell you more about anti HER-2 antibodies. 485 00:30:11,430 --> 00:30:13,710 I'm going to talk to you more about a small molecule 486 00:30:13,710 --> 00:30:15,690 inhibitor of this kinase. 487 00:30:15,690 --> 00:30:17,460 There are actually many theorems that 488 00:30:17,460 --> 00:30:22,705 are based on mutations that we know occur in cancer cells. 489 00:30:22,705 --> 00:30:24,330 There are processes that I've mentioned 490 00:30:24,330 --> 00:30:27,450 to you, like angiogenesis, the recruitment of new blood 491 00:30:27,450 --> 00:30:28,750 vessels. 492 00:30:28,750 --> 00:30:30,990 These two have led to new therapies for cancer 493 00:30:30,990 --> 00:30:35,390 to block that process and inhibit cancer development. 494 00:30:35,390 --> 00:30:38,180 In the case of tumor suppressor genes, 495 00:30:38,180 --> 00:30:41,570 individuals are trying to develop gene therapy 496 00:30:41,570 --> 00:30:43,260 to put the genes back. 497 00:30:43,260 --> 00:30:45,770 If the gene is lost in a cancer cell, 498 00:30:45,770 --> 00:30:48,710 perhaps you can restore its function by gene therapy, 499 00:30:48,710 --> 00:30:51,002 and normalize the growth of the cancer cells. 500 00:30:51,002 --> 00:30:52,460 And although I won't talk about it, 501 00:30:52,460 --> 00:30:56,590 there's a lot of promise for immunitherapy for cancer. 502 00:30:56,590 --> 00:30:58,930 Cancer cells acquire a lot of mutations. 503 00:30:58,930 --> 00:31:01,450 As such, they produce a lot of antigens. 504 00:31:01,450 --> 00:31:02,950 In theory, your immune system should 505 00:31:02,950 --> 00:31:07,390 recognize those as foreign and eliminate the cancer. 506 00:31:07,390 --> 00:31:11,787 But in general, the cancer wins, the immune system fails. 507 00:31:11,787 --> 00:31:13,870 And we think that there's ways the cancer actually 508 00:31:13,870 --> 00:31:16,870 inhibits the immune system from functioning properly. 509 00:31:16,870 --> 00:31:18,430 But that's being figured out now, 510 00:31:18,430 --> 00:31:22,310 so it's possible that we'll be able to develop new cancer 511 00:31:22,310 --> 00:31:25,850 therapeutics based on the immune system. 512 00:31:25,850 --> 00:31:30,830 All right, but before I get into the cool new stuff, 513 00:31:30,830 --> 00:31:33,680 let me tell you just a little bit about cancer therapy 514 00:31:33,680 --> 00:31:34,835 more generally-- 515 00:31:46,220 --> 00:31:48,740 what we would consider to be conventional cancer therapy. 516 00:31:54,560 --> 00:31:57,339 The most effective form of cancer therapy is surgery. 517 00:31:57,339 --> 00:31:59,630 If you can get to the tumor early before it has spread, 518 00:31:59,630 --> 00:32:01,775 you cut it out, the person is generally cured. 519 00:32:04,300 --> 00:32:07,630 Another very effective form of cancer therapy 520 00:32:07,630 --> 00:32:09,260 is radiation therapy. 521 00:32:09,260 --> 00:32:11,470 And this is good because you can focus the radiation 522 00:32:11,470 --> 00:32:13,360 beam directly on the cancer cells 523 00:32:13,360 --> 00:32:16,600 and eliminate them by causing a lot of damage to those cells. 524 00:32:20,960 --> 00:32:23,300 And the third is chemotherapy. 525 00:32:23,300 --> 00:32:24,740 And chemotherapy is used when you 526 00:32:24,740 --> 00:32:26,810 think that the cancer has spread, 527 00:32:26,810 --> 00:32:29,570 so radiation can't work because the cancer cells are somewhere 528 00:32:29,570 --> 00:32:30,470 else-- 529 00:32:30,470 --> 00:32:33,170 and you need a drug that can diffuse throughout the body 530 00:32:33,170 --> 00:32:34,940 and hopefully kill the cancer cells. 531 00:32:39,010 --> 00:32:43,990 Radiation and many chemotherapies 532 00:32:43,990 --> 00:32:45,670 act in the same general way. 533 00:32:50,380 --> 00:32:53,290 Adriamycin, which you will have heard of, 534 00:32:53,290 --> 00:32:56,050 cisplatin, which you will have heard of-- 535 00:32:56,050 --> 00:32:59,710 these are well used cancer therapeutics-- 536 00:32:59,710 --> 00:33:09,470 and many more function by inducing in the cancer cell DNA 537 00:33:09,470 --> 00:33:11,510 damage. 538 00:33:11,510 --> 00:33:13,370 And the damage can be sufficiently severe 539 00:33:13,370 --> 00:33:15,230 that the cell will die. 540 00:33:15,230 --> 00:33:19,320 And these therapies can be effective. 541 00:33:19,320 --> 00:33:22,560 There's another class of cancer drugs 542 00:33:22,560 --> 00:33:34,490 for which Taxol is the best known, 543 00:33:34,490 --> 00:33:36,930 which are described as mitosis inhibitors. 544 00:33:36,930 --> 00:33:39,770 These drugs actually bind to microtubules, block 545 00:33:39,770 --> 00:33:42,860 the formation of the microtubular spindle, 546 00:33:42,860 --> 00:33:46,400 and that way prevent cells from dividing. 547 00:33:46,400 --> 00:33:48,470 And since cancer cells divide a lot 548 00:33:48,470 --> 00:33:50,120 and you want to inhibit their division, 549 00:33:50,120 --> 00:33:52,482 these drugs are used and can be effective. 550 00:33:56,730 --> 00:33:59,580 In fact, they're used because they were tested and shown 551 00:33:59,580 --> 00:34:06,440 to be effective first in cell-based studies, where one 552 00:34:06,440 --> 00:34:13,730 looks at the growth or survival of cells in a Petri dish, 553 00:34:13,730 --> 00:34:16,010 scoring the number of cells or the percentage of cells 554 00:34:16,010 --> 00:34:18,440 that are alive at any given time, 555 00:34:18,440 --> 00:34:26,480 or in any given dose of drug when the concentration of drug 556 00:34:26,480 --> 00:34:28,790 is increasing in this experiment. 557 00:34:28,790 --> 00:34:39,699 What we find is that for certain normal cells, 558 00:34:39,699 --> 00:34:41,949 they will survive to a certain concentration of drug 559 00:34:41,949 --> 00:34:44,489 and then start to die off. 560 00:34:44,489 --> 00:34:54,659 And for certain cancer cells, the concentration 561 00:34:54,659 --> 00:34:56,850 required to kill them is lower. 562 00:35:01,932 --> 00:35:04,140 And this difference is called the therapeutic window. 563 00:35:09,450 --> 00:35:12,060 In theory, this looks good, because it suggests 564 00:35:12,060 --> 00:35:14,790 that the cancer cells are more sensitive to the drug 565 00:35:14,790 --> 00:35:16,230 than are normal cells. 566 00:35:16,230 --> 00:35:18,390 And that's why some cancer therapeutics 567 00:35:18,390 --> 00:35:20,712 work for some cancers. 568 00:35:20,712 --> 00:35:21,670 But there are problems. 569 00:35:32,310 --> 00:35:43,230 Some normal cells in your body, unlike these normal cells, 570 00:35:43,230 --> 00:35:45,870 are very sensitive to the drug at low concentrations-- 571 00:35:45,870 --> 00:35:49,300 the DNA damaging agents, for example. 572 00:35:49,300 --> 00:35:50,710 This results in side effects. 573 00:35:55,660 --> 00:35:58,930 And I suspect you are all familiar with the side 574 00:35:58,930 --> 00:36:01,060 effects of cancer chemotherapy. 575 00:36:01,060 --> 00:36:02,830 Your hair falls out. 576 00:36:02,830 --> 00:36:04,570 You get nauseous. 577 00:36:04,570 --> 00:36:06,070 You get anemic. 578 00:36:06,070 --> 00:36:08,950 This is because cells in your hair follicles, 579 00:36:08,950 --> 00:36:12,100 or your intestines, or your blood system 580 00:36:12,100 --> 00:36:15,430 are dying at low concentrations of the drug. 581 00:36:15,430 --> 00:36:17,980 They're actually dying by apoptosis. 582 00:36:17,980 --> 00:36:21,940 They're actually dying by P53 dependent apoptosis. 583 00:36:21,940 --> 00:36:25,720 So that's why cancer drugs cause many bad side effects, 584 00:36:25,720 --> 00:36:27,880 because some cells in your body are very sensitive 585 00:36:27,880 --> 00:36:31,000 and will kill themselves in response to low concentrations 586 00:36:31,000 --> 00:36:31,500 of the drug. 587 00:36:34,500 --> 00:36:46,570 The second problem is that some, in fact not a small percentage, 588 00:36:46,570 --> 00:36:49,490 are very resistant to the concentrations of the drug-- 589 00:36:49,490 --> 00:36:51,850 even high concentrations of the drug. 590 00:36:51,850 --> 00:37:05,950 And one reason for that is that many cancer cells 591 00:37:05,950 --> 00:37:08,350 are lacking P53. 592 00:37:08,350 --> 00:37:11,800 I told you that P53 is mutated in about 50% or more 593 00:37:11,800 --> 00:37:13,570 of human cancers. 594 00:37:13,570 --> 00:37:16,840 I also told you that P53 was required for cells to respond 595 00:37:16,840 --> 00:37:19,600 to DNA damage and die. 596 00:37:19,600 --> 00:37:22,030 And these cells lack that protein. 597 00:37:22,030 --> 00:37:24,550 And therefore, are very resistant to dying. 598 00:37:24,550 --> 00:37:26,770 So many therapeutics don't work, because 599 00:37:26,770 --> 00:37:29,570 this important machinery is lacking. 600 00:37:29,570 --> 00:37:32,290 So we have problems with standard therapies 601 00:37:32,290 --> 00:37:34,630 based on both kinds of issues. 602 00:37:34,630 --> 00:37:37,090 So the goal then, is to find drugs 603 00:37:37,090 --> 00:37:39,640 that don't cause these kinds of side effects 604 00:37:39,640 --> 00:37:43,570 and can work even in a P53 deficient cell, which leads us 605 00:37:43,570 --> 00:37:48,370 to developing new types of therapy. 606 00:37:48,370 --> 00:37:52,020 OK, so I want to introduce you specifically to two. 607 00:37:52,020 --> 00:37:55,650 And they are probably the best known and highly effective 608 00:37:55,650 --> 00:37:58,470 actually, great examples of molecularly targeted 609 00:37:58,470 --> 00:38:00,720 anti-cancer agents. 610 00:38:00,720 --> 00:38:05,140 The first is in the context of breast cancer. 611 00:38:05,140 --> 00:38:07,780 And the gene in question here is a gene called HER-2. 612 00:38:13,520 --> 00:38:18,010 In a normal breast cell, there are two copies 613 00:38:18,010 --> 00:38:23,950 of this HER-2 gene, as there are in virtually all of your cells. 614 00:38:23,950 --> 00:38:26,710 And those produce amounts of RNA that 615 00:38:26,710 --> 00:38:29,920 produce amounts of protein that lead 616 00:38:29,920 --> 00:38:32,450 to the decoration on the surface of these cells-- 617 00:38:32,450 --> 00:38:38,300 the certain number of receptor molecules 618 00:38:38,300 --> 00:38:41,870 called HER-2, which are a growth factor receptors. 619 00:38:41,870 --> 00:38:43,850 They bind to specific growth factors. 620 00:38:48,510 --> 00:38:51,080 And when they are engaged with their growth factors, 621 00:38:51,080 --> 00:38:53,150 they send a signal into the cell. 622 00:38:53,150 --> 00:38:56,341 And the product of that signal is for the cell to proliferate. 623 00:38:59,290 --> 00:39:02,740 And this is necessary in normal development and in other times. 624 00:39:02,740 --> 00:39:07,780 So this is normal regulation, normal signaling in response 625 00:39:07,780 --> 00:39:10,280 to a growth factor in the normal levels of a growth factor 626 00:39:10,280 --> 00:39:10,780 receptor. 627 00:39:21,060 --> 00:39:35,670 30% of breast cancers carry a mutation 628 00:39:35,670 --> 00:39:41,770 that results in amplification of the HER-2 gene. 629 00:39:41,770 --> 00:39:45,600 So we don't have two copies anymore, we've got 10, or 20, 630 00:39:45,600 --> 00:39:50,830 or 50, or 100 amplification. 631 00:39:50,830 --> 00:39:57,010 This is a mechanism by which all good genes get activated. 632 00:39:57,010 --> 00:40:01,600 Too many genes, too many proteins. 633 00:40:01,600 --> 00:40:04,510 This cell now has way too much of that growth factor 634 00:40:04,510 --> 00:40:06,850 receptor on its surface. 635 00:40:06,850 --> 00:40:09,910 And in the presence of the same concentration of the growth 636 00:40:09,910 --> 00:40:14,410 factor itself, we get a much stronger signal-- 637 00:40:22,420 --> 00:40:24,960 much higher levels of proliferation. 638 00:40:31,080 --> 00:40:33,510 This also affects the ability of the cells to survive. 639 00:40:33,510 --> 00:40:37,050 It keeps them alive at times when they shouldn't be. 640 00:40:37,050 --> 00:40:40,230 Too much proliferation, too much survival. 641 00:40:40,230 --> 00:40:43,590 Given this situation, a logical therapeutic 642 00:40:43,590 --> 00:40:46,980 would be something that blocks the function of this growth 643 00:40:46,980 --> 00:40:48,850 factor receptor. 644 00:40:48,850 --> 00:40:51,660 And what a company called Genentech discovered 645 00:40:51,660 --> 00:40:54,240 was that they could make an antibody. 646 00:40:54,240 --> 00:40:56,730 An anti-HER-2 antibody. 647 00:40:59,910 --> 00:41:06,660 And that led to a drug called Herceptin, 648 00:41:06,660 --> 00:41:10,150 which binds to the growth factor receptor 649 00:41:10,150 --> 00:41:12,640 and prevents it from functioning. 650 00:41:12,640 --> 00:41:17,580 And in women who have this alteration, and only in them, 651 00:41:17,580 --> 00:41:19,650 the drug is actually highly effective. 652 00:41:19,650 --> 00:41:21,660 In the metastatic setting, it will 653 00:41:21,660 --> 00:41:24,180 lead to multiple additional years of life. 654 00:41:24,180 --> 00:41:26,970 But it is actually not curative in that setting. 655 00:41:26,970 --> 00:41:29,850 Recently, individuals are being typed 656 00:41:29,850 --> 00:41:32,340 for this mutation at a much earlier stage in their disease 657 00:41:32,340 --> 00:41:33,510 course. 658 00:41:33,510 --> 00:41:35,640 And when women are given the drug then, 659 00:41:35,640 --> 00:41:37,950 it's leading to some cures. 660 00:41:37,950 --> 00:41:39,630 So this is a targeted agent which 661 00:41:39,630 --> 00:41:43,800 is highly effective in the context of a specific mutation. 662 00:41:43,800 --> 00:41:45,720 And actually only then-- other breast cancer 663 00:41:45,720 --> 00:41:48,814 patients given the same drug have no benefit whatsoever. 664 00:41:52,701 --> 00:41:53,950 So this is what it looks like. 665 00:41:53,950 --> 00:41:55,971 This is actually the drug package. 666 00:41:55,971 --> 00:41:57,720 And this is what I just described to you-- 667 00:41:57,720 --> 00:42:02,580 normal cells, cancer cells, Herceptin antibody binding to 668 00:42:02,580 --> 00:42:06,570 and blocking the function of this abnormal number of growth 669 00:42:06,570 --> 00:42:09,540 factor receptors. 670 00:42:09,540 --> 00:42:14,550 OK, let me now turn to the second classic example. 671 00:42:14,550 --> 00:42:17,350 And this comes in the context of chronic myelogenous 672 00:42:17,350 --> 00:42:23,250 leukemia, which is a leukemia-- a blood cell tumor. 673 00:42:23,250 --> 00:42:26,700 It's a particular type of blood cell-- the myeloid lineage 674 00:42:26,700 --> 00:42:29,470 type of white blood cell. 675 00:42:29,470 --> 00:42:32,500 You can diagnose this disease by looking at blood smears 676 00:42:32,500 --> 00:42:34,600 and you can see that this is the normal blood 677 00:42:34,600 --> 00:42:37,370 smear with a single of these myeloid cells. 678 00:42:37,370 --> 00:42:39,010 And here is a cancer situation where 679 00:42:39,010 --> 00:42:43,640 we've got too many of these white blood cells circulating. 680 00:42:43,640 --> 00:42:47,880 This is a disease that's been studied for a very long time. 681 00:42:47,880 --> 00:42:51,140 And it's been discovered that in the vast majority 682 00:42:51,140 --> 00:42:56,960 of this type of cancer, there is a specific chromosomal event-- 683 00:42:56,960 --> 00:43:02,600 a specific mutation caused by a particular translocation. 684 00:43:02,600 --> 00:43:08,220 And that translocation was actually 685 00:43:08,220 --> 00:43:11,676 identified a long time ago in the city of Philadelphia. 686 00:43:15,570 --> 00:43:18,750 And as such, it's called the Philadelphia chromosome. 687 00:43:18,750 --> 00:43:21,390 It's the product of a specific translocation-- 688 00:43:28,830 --> 00:43:33,600 chromosome 9, which has a gene on it 689 00:43:33,600 --> 00:43:38,550 called ABL, which encodes a protein that 690 00:43:38,550 --> 00:43:42,345 is a kinase involved in phosphoralating other proteins. 691 00:43:44,940 --> 00:43:50,570 And chromosome 22, which has another gene called BCR-- 692 00:43:55,630 --> 00:43:58,210 chromosome break events occur here. 693 00:43:58,210 --> 00:44:00,970 Chromosome break events occur here. 694 00:44:00,970 --> 00:44:07,750 And a translocation results, which 695 00:44:07,750 --> 00:44:09,580 produces a new chromosome-- 696 00:44:09,580 --> 00:44:20,730 the Philadelphia chromosome, which has the BCR gene and ABL 697 00:44:20,730 --> 00:44:23,820 gene inappropriately fused to each other. 698 00:44:28,720 --> 00:44:36,635 This produces a fusion gene, which encodes a fusion protein. 699 00:44:40,070 --> 00:44:43,210 And that fusion protein is referred to as BCR ABL. 700 00:44:54,640 --> 00:44:57,070 And it was discovered that the BCR ABL form 701 00:44:57,070 --> 00:44:59,143 had increased kinase activity. 702 00:45:05,560 --> 00:45:07,990 And this resulted in increased proliferation 703 00:45:07,990 --> 00:45:10,240 within the cells that carried that translocation. 704 00:45:13,940 --> 00:45:20,360 And so the question was, could one develop an inhibitor? 705 00:45:20,360 --> 00:45:24,900 An inhibitor that blocked the kinase? 706 00:45:24,900 --> 00:45:26,670 And this resulted in the development 707 00:45:26,670 --> 00:45:29,220 of a drug called Gleevec. 708 00:45:31,870 --> 00:45:34,775 Gleevec, which is highly, highly effective. 709 00:45:38,340 --> 00:45:43,110 This is the idea, here's the BCR ABL fusion protein. 710 00:45:43,110 --> 00:45:47,670 It binds to ATP, which it needs to transfer the phosphate group 711 00:45:47,670 --> 00:45:52,760 onto a substrate protein in this signaling cascade. 712 00:45:52,760 --> 00:45:55,910 The idea is that one could make a small molecule drug that 713 00:45:55,910 --> 00:46:00,110 could fit into the ATP binding site very specifically, 714 00:46:00,110 --> 00:46:02,900 and block access of ATP, therefore shutting off 715 00:46:02,900 --> 00:46:03,930 the kinase. 716 00:46:03,930 --> 00:46:05,930 And if that were possible, then the cancer cells 717 00:46:05,930 --> 00:46:08,030 would be deprived of this signal, 718 00:46:08,030 --> 00:46:10,910 and may stop proliferating, or even die. 719 00:46:10,910 --> 00:46:12,620 That was the idea. 720 00:46:12,620 --> 00:46:15,500 In fact, they were successful in making a small molecule drug. 721 00:46:15,500 --> 00:46:17,294 And that may surprise you, because you 722 00:46:17,294 --> 00:46:19,460 might think there are a lot of kinases in this cell. 723 00:46:19,460 --> 00:46:21,200 They all bind to ATP. 724 00:46:21,200 --> 00:46:24,980 How could you ever find one that was specific to this kinase? 725 00:46:24,980 --> 00:46:26,390 But in fact, it was possible. 726 00:46:26,390 --> 00:46:29,690 You can make kinase inhibitors, because not all 727 00:46:29,690 --> 00:46:32,759 the ATP binding pockets look the same. 728 00:46:32,759 --> 00:46:34,550 And you can therefore get some specificity. 729 00:46:38,140 --> 00:46:41,560 And when this drug was used in patients, 730 00:46:41,560 --> 00:46:43,908 it showed remarkable activity. 731 00:46:52,040 --> 00:46:56,350 If we looked at white blood cell number, 732 00:46:56,350 --> 00:46:58,720 normal individuals would have a certain low level. 733 00:47:01,960 --> 00:47:05,250 And in case of CML, the level would be high. 734 00:47:05,250 --> 00:47:08,970 And actually, it goes higher still 735 00:47:08,970 --> 00:47:14,430 as the disease progresses through a phase called 736 00:47:14,430 --> 00:47:17,930 blast crisis, where additional alterations take place 737 00:47:17,930 --> 00:47:21,610 and the cells begin to divide even more abnormally. 738 00:47:21,610 --> 00:47:25,590 In this context, however, if you give the drug 739 00:47:25,590 --> 00:47:31,390 Gleevec, in the vast majority of patients, 740 00:47:31,390 --> 00:47:33,820 the numbers drop precipitously. 741 00:47:33,820 --> 00:47:36,920 And the drug is extremely well tolerated-- has almost no side 742 00:47:36,920 --> 00:47:37,420 effects. 743 00:47:37,420 --> 00:47:40,780 The patients take the pill with their orange juice 744 00:47:40,780 --> 00:47:44,590 in the morning every day, keeping their cancer cells 745 00:47:44,590 --> 00:47:48,800 at bay, leading to what is called clinical remission. 746 00:47:55,180 --> 00:47:58,270 Clinical remission-- the disease has gone into remission. 747 00:47:58,270 --> 00:48:01,030 And it can stay in remission for a very long time. 748 00:48:01,030 --> 00:48:03,580 And it's sometimes curative. 749 00:48:03,580 --> 00:48:07,630 But sometimes the disease cells come back. 750 00:48:12,410 --> 00:48:15,660 And this is a phase we call relapse. 751 00:48:15,660 --> 00:48:18,720 And even though the drug is present throughout this disease 752 00:48:18,720 --> 00:48:22,740 course, the tumor cells are dividing again. 753 00:48:22,740 --> 00:48:25,960 Can anybody tell me why? 754 00:48:25,960 --> 00:48:26,460 Mutation. 755 00:48:29,190 --> 00:48:33,710 The cancer cells have acquired additional mutations, 756 00:48:33,710 --> 00:48:35,900 specifically within DCR ABL. 757 00:48:39,010 --> 00:48:50,300 If we imagine DCR ABL, it can bind to Gleevec, 758 00:48:50,300 --> 00:48:52,360 and be shut off. 759 00:48:52,360 --> 00:48:54,610 At some frequency, however, mutations 760 00:48:54,610 --> 00:49:01,430 can occur, which change the active site in such a way 761 00:49:01,430 --> 00:49:05,180 that Gleevec can no longer bind. 762 00:49:05,180 --> 00:49:07,460 And this is still an active kinase. 763 00:49:07,460 --> 00:49:10,040 So now the cells begin to divide again. 764 00:49:10,040 --> 00:49:14,810 So the question now is what can you do about it? 765 00:49:14,810 --> 00:49:18,070 And the answer is, you can make a new drug. 766 00:49:21,070 --> 00:49:23,410 And this has actually been done successfully. 767 00:49:23,410 --> 00:49:25,930 A new drug that can bind specifically 768 00:49:25,930 --> 00:49:29,765 to the mutant form of ABL kinase. 769 00:49:33,050 --> 00:49:36,020 And there's a drug called SPRYCEL, which is now also 770 00:49:36,020 --> 00:49:42,170 FDA approved for the treatment of drug resistant forms of CML. 771 00:49:42,170 --> 00:49:50,140 So before you run away, this is what I've just told you, 772 00:49:50,140 --> 00:49:51,940 here's ABL kinase. 773 00:49:51,940 --> 00:49:53,830 This is where the drug binds. 774 00:49:53,830 --> 00:49:55,550 This is the structure of the drug. 775 00:49:58,560 --> 00:50:00,720 But at some frequency, mutations occur 776 00:50:00,720 --> 00:50:02,310 within that ATP binding site. 777 00:50:02,310 --> 00:50:07,980 And different mutations will do this, as shown down here. 778 00:50:07,980 --> 00:50:11,742 And those mutations will block the access of the drug. 779 00:50:11,742 --> 00:50:13,200 And the good news is that one could 780 00:50:13,200 --> 00:50:16,350 make new drugs that will overcome 781 00:50:16,350 --> 00:50:17,800 that form of resistance. 782 00:50:17,800 --> 00:50:22,520 So this is a good news, bad news, good news story. 783 00:50:22,520 --> 00:50:24,440 We'll stop there.