Oncogenes: A Genetic Paradigm for Cancer
Transcript of Part 3: The Cancer Genome and Therapeutics
00:00:03.05 Hello. I am Mike Bishop from the University of California, San Francisco. 00:00:06.28 And I am now going to tell the third and final chapter of my story about cancer. 00:00:12.24 And this chapter begins with the German medical scientist Paul Ehrlich, 00:00:17.20 who towards the end of the 19th century became interested in using chemical dyes to stain human tissue. 00:00:27.26 He serendipitously discovered that some of these dyes preferentially stained microbes like bacteria and parasites, as opposed to human tissue. 00:00:40.22 And this inspired a vision of what he called "magic bullets". 00:00:46.01 If chemical dyes could preferentially stain a bacteria as opposed to a human cell, 00:00:53.03 perhaps drugs could be developed that would preferentially kill bacteria, as opposed to human cells. 00:01:00.06 He initiated what was probably the first drug screen in the history of medical science. 00:01:05.06 His first major discovery was a drug that was effective against trypanosomiasis. 00:01:13.18 But he became an international celebrity with his 606th drug that proved to be an effective therapy for syphilis. 00:01:23.01 He called it Salvarsan, as in salvation. 00:01:28.02 Most people do not know that Paul Ehrlich was not finished at that point because his ultimate objective was cancer cells. 00:01:40.06 He had a vision of a magic bullet that would kill cancer cells rather than normal cells. 00:01:49.01 Between 1904 and 1909, he put many hundreds of chemicals onto normal and cancer cells 00:01:57.18 in the laboratory without ever finding his magic bullet. 00:02:01.27 He received the Nobel Prize actually for another discovery, independent of his work with dyes and therapeutics, 00:02:11.19 but he died a disillusioned man telling his wife on his death bed that his life had been wasted. 00:02:19.23 This apparently was traced to his failure to find a magic bullet for cancer. 00:02:24.24 A century or more later, we now are on the verge of having Paul Ehrlich's magic bullets for cancer. 00:02:33.17 And it is based on the genetic paradigm of cancer that I have discussed in the first two chapters of my story. 00:02:41.09 The fundamental tenet is that all cancer arises from the malfunction of genes. 00:02:46.05 This tenet suggests that we can create magic bullets. 00:02:51.12 The targets would be cancer genes and their protein products. These would create distinctive therapeutic targets, 00:02:59.04 distinctive to the cancer cell as opposed to the normal cell. 00:03:02.18 In other words, we would hope to kill the outlaw cell without harming the innocent bystander. 00:03:12.29 There are two culprits involved: malfunctioning proto-oncogenes which suffer gain of function, 00:03:23.14 and malfunctioning tumor suppressor genes that suffer loss of function, and as I have explained in my first two chapters, 00:03:30.12 these combine to give rise to the malignant phenotype. 00:03:33.23 How would we approach targeting these ailments? 00:03:39.10 Well, we would inhibit a gain of function. We would want to replace a loss of function. 00:03:46.13 We know how to inhibit gain of function and it's an active exercise with some early successes. 00:03:56.00 But we do not yet know how to replace a loss of function. 00:03:59.18 There is a third newly emerging and still relatively experimental approach in which neither the cancer gene or its protein product is a direct target. 00:04:09.28 Instead, we attack from the flank. 00:04:11.18 I am going to use experimental data to illustrate inhibition of gain of function and two examples of attacking from the flank. 00:04:22.22 One directed to a refractory gain of function, and a second addressed to loss of function. 00:04:29.22 My first example is actually the only truly curative targeted therapy yet developed. 00:04:38.00 And it is to treat a disease known as Acute Promyelocytic Leukemia, and the leukemic cells are illustrated in this picture. 00:04:46.05 This was a serendipitous targeting, but now that we understand it, it is exquisitely specific. 00:04:55.29 This was an untreatable disease, an incurable disease, until 1986 when Chinese scientists in Shanghai discovered that a relative of vitamin A, 00:05:09.21 all-trans retinoic acid, could induce remissions, not cures, but remissions of this disease. 00:05:17.02 Then they combined all-trans retinoic acid (ATRA) with conventional poisons, conventional chemotherapy, 00:05:25.27 and developed a cure for about 80% of the patients. 00:05:30.10 This became standard procedure around the world and that was where things stood for quite some time. 00:05:36.11 Meanwhile, it was a mystery as to why the all-trans retinoic acid was working until about a decade or more later after its discovery. 00:05:50.03 The leukemic cell of acute promyelocytic leukemia contains a chromosomal translocation. 00:05:57.10 And this translocation fuses major portions of two genes: 00:06:01.07 one the gene that encodes a major receptor for retinoic acid, so called retinoic acid receptor alpha, 00:06:08.06 and the second a heretofore unknown gene known as promyelocytic leukemia gene now, PML. 00:06:17.00 This fusion protein is apparently a driver in the development and maintenance of the leukemia, 00:06:25.10 and the therapy with retinoic acid was presumably due to binding to the retinoic acid receptor portion of this mongrel protein. 00:06:34.17 Now what about the 20% failure rate? It was of two sorts. Some people never responded. 00:06:42.00 Some people relapsed after the conventional therapy and died. 00:06:46.12 And no one did much about this for quite some time, but meanwhile out in the provinces of China a solution was in the making. 00:06:58.04 A group of physicians and oncologists in Harbin province 00:07:04.18 were exploring the use of traditional Chinese medicines, and one of them is known as Ai-Lin 1. 00:07:11.08 And in 1992 they reported in a Chinese journal that this folk medicine elicited remissions of acute promyelocytic leukemia. 00:07:20.27 That report inspired the scientists in Shanghai who had developed retinoic acid therapy to take a look. 00:07:30.09 First of all, they became convinced that this was actually happening, that this folk medicine was eliciting remissions. 00:07:36.19 And then they decided to identify the active ingredient. 00:07:39.21 Ai-Lin 1 is composed of ground toad bladder, a rock that is rich in mercury, and a rock that is rich in arsenic. 00:07:48.29 The Chinese scientists decided to ignore the toad bladder. It was too complicated. 00:07:54.17 Mercury is a deadly poison. Arsenic when used in reasonable doses was already a therapeutic for some infections and for some leukemia, 00:08:04.26 so they thought, "Let's check out the arsenic." 00:08:09.23 The active ingredient of Ai-Lin 1 in the treatment of acute promyelocytic leukemia proved to be arsenic trioxide. 00:08:16.13 In 1997 a persuasive clinical trial was published by the scientists in Shanghai 00:08:26.00 demonstrating that arsenic trioxide elicits remissions following relapse from conventional therapy. 00:08:35.05 This was the way the drug was tested and used for quite some years. 00:08:39.09 Not as a primary therapy, but as a last resort after the conventional therapy had failed. 00:08:45.19 Meanwhile Diane Brown and Scott Kogan in my laboratory had developed a mouse model for acute promyelocytic leukemia. 00:08:54.07 They had linked the mongrel gene PML-RAR alpha taken from a human leukemia cell 00:09:04.25 to a control element called MRP8 which targets the expression of the mongrel protein 00:09:14.10 to the promyelocyte, the cell in which the leukemia allegedly originates. 00:09:22.11 To our great satisfaction, these mice developed acute promyelocytic leukemia. 00:09:31.07 In fact we could see a pre-leukemic state in their bone marrow long before the disease itself occurred. 00:09:37.19 They also developed benign epidermal polyps, but that was of no consequence to our work. 00:09:41.11 About the time that we had this model up and running, we learned from Hugues de The in France 00:09:48.13 of the Chinese experiments with all-trans retinoic acid... arsenic trioxide. 00:09:52.23 So we resolved to collaborate with de The and his colleagues, particularly Lallemand-Breitenbach, 00:10:00.23 and test the utility of arsenic trioxide in our mice as a single therapy and as a combination with all-trans retinoic acid. 00:10:12.13 The results were stunning. This is the survival of the untreated mice. 00:10:20.08 They all die quickly and almost synchronously. 00:10:24.01 There is a modest extension of lifespan here the dotted line is treated with all-trans retinoic acid alone. 00:10:33.11 Treatment with arsenic trioxide also extended lifespan modestly, but when we used the two together, the mice were cured. 00:10:44.10 In fact they live normal lifespans, and all evidence of leukemic cells or translocation disappeared 00:10:52.16 from their bloodstream or their bone marrow. 00:10:55.23 This inspired us to make two proposals. First of all, combination of all-trans retinoic acid and arsenic trioxide might alone be curative. 00:11:09.21 We might be able to eliminate the highly toxic chemotherapy part of the standard therapy, 00:11:18.10 anf secondly why wait for a failure? 00:11:21.05 Why not use this combination as frontline therapy? 00:11:24.09 It took ten years, as the development and analysis of clinical trials usually do, 00:11:30.20 but eventually the Chinese in Shanghai again came through 00:11:34.28 demonstrating that combination therapy with all-trans retinoic acid and arsenic trioxide 00:11:42.18 as frontline therapy, as first treatment, led to a 95% five-year survival. 00:11:50.17 That was of 2009, most of these patients are truly cured by now. 00:12:00.07 Now they were still using the combination with chemotherapy as well, 00:12:07.05 but in more recent years it has become apparent that many patients will respond to the combination of all-trans retinoic acid and arsenic trioxide 00:12:18.09 without the other chemotherapeutics just as our mice did. 00:12:22.29 And it is now possible to classify patients as to those who don't need the additional toxic chemotherapy and those who do. 00:12:32.17 Now why this efficacy? Well there are three explanations. One of them is a touch hypothetical, and that is 00:12:48.07 there may be only a single driver in this leukemia, 00:12:51.07 which would make this, that is to say, an exceptionally vulnerable pathogenesis. 00:12:56.19 We do know that the leukemia stem cell, this is one of the tumors in which stem cells have been authoritatively demonstrated. 00:13:07.23 I spoke on this in chapter two of my talk. 00:13:10.08 We know that this therapy kills the stem cell, not just the full-blown leukemic cell. 00:13:16.12 And we now know that it also represents a bimodal attack on a single target. 00:13:22.29 Now what do I mean by that? 00:13:24.19 Well, here is a cartoon taken from Hugues de The's writings showing the mongrel protein bound to DNA. 00:13:34.00 That is not the point. The point is that the all-trans retinoic acid attacks the retinoic acid receptor part of the protein. 00:13:42.29 The arsenic, it's now been shown, attacks the PML part of the protein. 00:13:49.13 The mechanisms of action are entirely different. 00:13:54.29 The likelihood that any single cellular lineage will develop resistance to both of these in the same molecule is infinitesimally small. 00:14:03.14 Hence the remarkable efficacy, and the failure of resistance to emerge and the consequent ability to cure. 00:14:13.03 So we've learned some lessons from this experience. First, our ability to predict the outcome of therapy as it might occur in humans, 00:14:29.01 and did occur in humans presaged a new era for preclinical models. 00:14:33.22 The classical mouse model for testing cancer therapies was essentially discredited by the time we began this work. 00:14:43.14 But many scientists have now been working to develop the kind of model that I described, which is based on the genetic lesion found in a human tumor. 00:14:54.15 And it is my belief that this type of model will set a new standard for preclinical testing of cancer therapy, and I am not alone in that. 00:15:04.00 Secondly, it is important to attack the tumor initiating cell, 00:15:09.21 which means that we are going to have to devise ways to identify that and distinguish it 00:15:15.20 from the bulk population of the tumor and evaluate its therapeutic response. 00:15:20.10 And third, we are not going to escape the need for combination therapy. 00:15:26.01 It is, if nothing else, the way to avoid the emergence of resistance, 00:15:31.07 and the combination of the bimodal attack on the mongrel protein in acute promyelocytic leukemia is a dramatic example of that. 00:15:39.15 Which brings me to the use of flank attack. 00:15:46.14 This is an approach that exploits a phenomenon known as synthetic lethality. 00:15:57.17 It represents a cooperation between therapeutic agent and the oncoprotein, the tumor driver. 00:16:03.19 Synthetic lethality has been known for many years. It was first discovered in bacteria and yeast. 00:16:10.10 And it is a simple phenomenon, but not always fully understood. 00:16:15.25 Two strains of a microbe with two different gene mutations, A and B, each of these separately are viable, 00:16:25.02 but when combined together they are lethal. 00:16:29.03 Now in our thinking about this, my colleagues and I and others simply substituted the cancer gene as mutation A, 00:16:39.05 and the therapeutic as mutation B. Both of these might well... certainly the cancer gene is consistent with viability. 00:16:48.17 And the therapeutic might be consistent with viability as well, but put the two together and perhaps we can get a synthetic lethal interaction. 00:16:55.00 We resolved to test this with the proto-oncogene MYC. 00:16:58.27 This encodes a highly pleiotypic transcription factor. 00:17:03.11 Some reports allege that it is involved in the control of as much as half of the human genome. 00:17:11.04 10,000 human genes. 00:17:13.14 The physiological expression of MYC is involved in a number of normal functions: 00:17:20.14 cell proliferation; cell growth, increase in size; differentiation. 00:17:24.17 And if the gene is overexpressed, it can lead to suicide, apoptosis, destabilize the genome 00:17:36.12 leading to chromosomal abnormalities and other genomic maladies. 00:17:41.13 If you install MYC in a transgenic animal and drive its expression to a particular lineage 00:17:48.10 as we did with the mongrel protein of acute promyelocytic leukemia, 00:17:51.18 it can be tumorigenic in various organ systems. 00:17:56.09 And most importantly, overexpression of MYC is among the most common ailments in human cancer, 00:18:04.27 and it is found in a wide variety of human cancers including some very important, such as breast cancer. 00:18:12.18 Now, so this sounds like a good target for therapy. 00:18:18.02 The problem is that it has got two liabilities. 00:18:20.18 First of all, MYC is essential for normal cells. 00:18:24.27 And we might well wreak havoc by inhibiting it directly. 00:18:29.04 And secondly, as a transcription factor, it is not a popular target for pharmaceutical chemists. 00:18:38.00 This may change soon. 00:18:39.27 There certainly is a lot of work being done on it. 00:18:43.06 But at the time that we were thinking about it, it was certainly considered, quote, "undruggable." 00:18:48.18 So why not attack from the flank? 00:18:51.17 I am going to show you two examples of how we have done this. 00:18:55.21 The first example involves inhibition of the G2 to M transition in the cell cycle. And the second example involves cytokinesis. 00:19:03.21 The first is the work of Andrei Goga with some help from Aaron Tward and David Morgan and myself. 00:19:11.07 And it derived from Andrei's interest in using inhibitors of cell cycle kinases. 00:19:18.23 The two that he had in mind were CDK2 and CDK1. 00:19:23.21 We set CDK2 aside because there were reports of failures with this. CDK1, however, had never been addressed. 00:19:38.07 Andrei utilized an inhibitor that had been developed in Peter Schultz's lab called Purvalanol. 00:19:45.09 This drug inhibits CDK1 preferentially, although not exclusively. 00:19:50.27 And it creates as these data will show, I am not going into detail, it creates a block at the G2-M transition. 00:19:59.13 If you create that block in a normal cell, it is reversible. 00:20:03.14 Take the drug away after a day or two and the cells recover and grow. 00:20:07.20 What Andrei discovered was that any cell, be it an otherwise normal cell or a human tumor cell, that was overexpressing MYC 00:20:17.18 would die when he used Purvalanol to inhibit CDK1. 00:20:22.17 This is a partial example of his results. So there's no killing of human fibroblasts, epithelial cells, rat cells, 00:20:30.29 rat cells expressing an oncogene, the RAS oncogene, and no killing of this cell line. 00:20:41.24 But, any cell line that he tested that was overexpressing MYC died promptly. 00:20:49.11 This led them to do some preclinical tests in mouse models. The first model is a liver tumor which arises from 00:20:59.25 targeting the expression of MYC to the hepatocyte. 00:21:03.06 This model had been developed in my lab, and Andrei used it to do a preclinical test. 00:21:12.06 And this was a more sophisticated model than the one I mentioned before. 00:21:16.15 We used a now familiar trick of placing the expression of the transgene under the control of doxycycline. 00:21:23.07 So in this instance doxycycline keeps the transgene off, 00:21:27.00 so Andrei was able to keep the animals, keep the transgene turned off until they were weaned, 00:21:36.01 and then turn it on. And if he treated the animals with a placebo, if you will, the livers looked like this after a few weeks. 00:21:47.06 But if he treated the animals during the same time period, the livers looked like this. 00:21:53.05 These animals are not cured but they have obviously undergone a dramatic resistance or regression of the tumor, 00:22:03.02 which eventually recurs and we have not explored the reason for that. 00:22:08.00 We also tested a B-cell lymphoma elicited by overexpression of MYC, and again, this time he was able to examine survival. 00:22:18.17 Notice that these data were collected after a single brief treatment of Purvalanol. 00:22:23.07 And he got a significant extension of lifespan just by inhibiting CDK1, not by addressing MYC directly. 00:22:31.27 So, we have here a classical synthetic lethal interaction between a therapeutic drug and an anomalous expression of a cancer gene. 00:22:45.18 The pre-clinical results certainly suggest potential therapeutic efficacy, and indeed, 00:22:50.19 Andrei is now as an independent member of the faculty at UCSF in the process of mounting a clinical trial to test this idea. 00:23:03.18 And it is also, we would suggest, that overexpression of MYC is going to prove 00:23:09.14 to be a biomarker for sensitivity to treatment of any kind of tumor by inhibition of CDK1. 00:23:15.06 Time will tell. 00:23:17.10 The other example of attacking MYC from flank involves a chromosomal passenger protein complex, and this is the work of Dun Yang. 00:23:25.09 The chromosomal passenger protein complex has three major components. 00:23:31.24 There is at least one and perhaps more, others, but the one that we care about is called the Aurora B kinase. 00:23:39.23 Now this complex is involved in a number of stages in cell division. 00:23:47.16 And one that is important to us is cytokinesis. 00:23:52.00 Dun used a drug called VX680, which was developed by Merck and is readily available. 00:24:05.11 This drug inhibits Aurora kinases, not only B, but others. It blocks cytokinesis, and it disables the spindle checkpoint, 00:24:18.12 the cellular response to mishaps in chromosomal segregation. 00:24:22.22 It has a reversible effect on normal cells. A crucial feature to developing any synthetic lethal therapeutic. 00:24:34.23 Dun first tested human cells. These RPE cells are epithelial cells, normal human epithelial cells. 00:24:45.16 Either as controls or as cells that he manipulated to overexpress MYC. 00:24:54.25 And he discovered that the normal cells did not die, and if he withdrew the drug here at the white arrow, 00:25:09.22 the normal cells recouped and grew and they had doubled in time within a few days. 00:25:14.12 The cells that were overexpressing MYC died. 00:25:21.06 The remarkable finding was that you could withdraw the drug after say three days, 00:25:28.06 as was done here, and the cells overexpressing MYC continued to die to extinction. 00:25:34.14 So we had what we called an early phase death and a later phase death. 00:25:40.00 The death by memory as opposed to the death by direct exposure, immediate exposure to the drug. 00:25:46.07 Now the early phase death is due to apoptosis. 00:25:49.16 Here we, Dun, monitored apoptosis, and this is rise to about a third, a little less than a third of the population of cells. 00:25:59.08 And then the apoptosis disappears. That leaves the delayed death that I defined in the previous diagram unexplained. 00:26:07.29 When Dun examined these cells closely he discovered that by electron microscopy, 00:26:14.12 they were rife with autophagy or "autophagy", take your choice. 00:26:20.03 He validated this with all the standard tests for autophagy. 00:26:28.04 I won't go into them in detail, but cogniscenti if any are watching or listening would recognize these. 00:26:34.17 They're all satisfied. These criteria are all satisfied by the cells in question. 00:26:42.19 So we came to the conclusion that more than likely the delayed death was due to the autophagy. 00:26:48.17 Dun authenticated that by inhibiting ATG genes. 00:26:55.26 The machinery for autophagy is encoded by a battery of genes known as ATG, and Dun used three different tricks. 00:27:04.10 I'll just refer to the two most persuasive. 00:27:10.05 He used interfering RNA to block the activity of either the fifth or the seventh ATG gene 00:27:18.04 or cells that were genetically deficient in the atg5 gene. 00:27:25.17 Blocking any of these genes in this manner spared the cells from the delayed death. 00:27:32.02 So we would argue that the autophagy is integrally involved in the killing. 00:27:36.17 So, incidentally we then here have a bimodal form of killing reminiscent of the bimodal form of therapeutic that I talked about before. 00:27:48.16 Dun did a preclinical test in three different models. First, a B cell lymphoma driven by a MYC transgene. 00:28:00.22 And the results represent about a threefold extension in lifespan. 00:28:06.04 He tested a T-cell lymphoma driven by a transgenic MYC. Again, a substantial increase in lifespan. 00:28:13.28 Finally he tested that very aggressive liver tumor that Andrei Goga had also used 00:28:21.02 and got a significant extension of lifespan with a brief intermittent therapy. 00:28:28.21 He also has looked at a battery of human cancer cell lines, 75 all totaled, representing quite a variety of human tumors. 00:28:40.07 And most of them respond as they should; if MYC is overexpressed, they die, and if it is not, they do not die. 00:28:52.12 There are exceptions, but let me show you two sets of data of successes. 00:28:57.22 Brain tumors and lung cancer cells. And the take home message from these data is that in either instance, 00:29:07.18 if the tumor cells were expressing MYC, they died. That's the black bars. 00:29:12.00 And if they were not expressing MYC, they survived the treatment with the inhibitor, with VX680. 00:29:19.20 Synthetic lethality combining VX680 with overexpression of MYC. 00:29:26.05 So we have here a synthetic lethal interaction that has potential therapeutic value. 00:29:34.27 We have a biomarker once again for sensitivity to this class of drug. VX680 is no longer in use, 00:29:41.11 and there are second and third generation drugs that are superior for a variety of reasons. 00:29:45.06 We simply use VX680 for a matter of convenience. This bimodal killing may impede the development of drug resistance, 00:29:54.09 just as the bimodal attack by therapeutics impedes it in the case of acute promyelocytic leukemia. 00:30:00.09 And the fact that normal cells can recover raises the idea that pulse therapy 00:30:07.20 may be a particularly innocuous approach to using this form of synthetic lethality and treating cancers. 00:30:18.12 And in fact Dun used pulse therapy in those pre-clinical trials in mouse models that I showed you. 00:30:24.24 All told now between our work and work in the literature, 00:30:28.19 there are five known perturbations of the cell that give a synthetic lethal interaction with overexpression of MYC. 00:30:38.09 They are listed here. I won't go into any more detail. The three from our lab include the inhibition of CDK1 00:30:47.11 and the inhibition of cytokinesis that I told you about, and work that we have not yet published on glutamine deprivation. 00:30:53.16 Other labs have reported that if you stimulate particular receptors on the surface of the cell, 00:31:01.23 you get a synthetic lethal interaction although this is very toxic. 00:31:05.24 And there has been a report of a synthetic lethal interaction between the inhibition of CDK2 and overexpression of MYC's cousin, MYC-N, 00:31:14.01 that you heard about when I was talking about prognostic markers with cancer genes. 00:31:20.21 Now this works with other genes. And the first example to come to light involved the mutant RAS gene. 00:31:33.19 This is from Mariano Barbacid and his colleagues in Spain. 00:31:37.19 Now this is important because RAS is another, to this day, undruggable but very widespread cancer gene. 00:31:45.23 So just as MYC had its disadvantages as a therapeutic direct target, so does RAS. 00:31:51.01 But Barbacid and his colleagues have found that indeed you can get a synthetic lethal interaction 00:31:57.00 between mutant K-RAS, one of the forms of the RAS family, 00:32:03.18 and inhibition of another kinase, CDK4. 00:32:08.29 Well, this is another gain of function lesion, another therapeutic combining in a synthetic lethal interaction in non-small cell lung cancer, 00:32:22.04 again a very refractory cancer for which any new therapeutic would be welcome. 00:32:29.17 Now you can broaden the reach of synthetic lethal therapeutics 00:32:38.05 to just screening the entire genome, and this has been done by a number of laboratories. 00:32:42.18 And what's involved here is that you simply take a target gene, like RAS, so you take cells expressing a mutant version of RAS, 00:32:51.29 and then you use a genome wide screen with interfering RNA. 00:32:57.01 You systematically knockdown expression of every gene, and this sort of screen is now quite common. 00:33:04.17 And you identify those genes which when inhibited have a synthetic lethal interaction with mutant RAS. 00:33:12.14 These would be potential therapeutic targets for flanking attack on RAS. 00:33:18.19 The first report of this identified something over 70, over 70, potential targets 00:33:27.23 that might have a druggable synthetic lethal interaction with RAS. 00:33:35.04 Another great virtue of, or at least potential virtue, of synthetic lethality 00:33:39.26 is attacking loss of function because we have no other recourse at the moment. 00:33:43.18 And I am going to illustrate that with the breast cancer genes, BRCA1 and 2. 00:33:52.28 These genes were discovered by studying families in which breast cancer was inherited in a very strong manner. 00:34:01.25 And this is a pedigree of a family and all of the circles, the red circles, are women with breast cancer. 00:34:11.02 The square is a male carrier. 00:34:13.26 So you can see the strong inheritance of this tumor, of this cancer, due to deficiency in a tumor suppressor gene, 00:34:22.19 In this instance it is BRCA1. 00:34:25.14 Now what do we know about these genes? 00:34:29.23 Well, they are essential for DNA repair. As a result a deficiency in these genes leads to an increase in spontaneous DNA damage, 00:34:41.18 unrepaired damage of the sort that is occurring in all of our cells throughout our lives. 00:34:46.27 This inherited deficiency and the subsequent increase in DNA damage creates a high risk of breast, ovarian, and prostrate cancer. 00:34:56.18 In July of 2009 this report in the New England Journal of Medicine electrified the oncology community. 00:35:08.06 An inhibitor of an enzyme known as poly(ADP-Ribose) polymerase showed remarkable efficacy against tumors carrying BRCA mutations. 00:35:21.07 We know how this works. It is a synthetic lethal interaction. 00:35:27.03 In normal cells, the BRCA genes are part of one form of DNA repair, so called homologous recombination. 00:35:38.14 And the PARP enzyme is involved in another form of DNA repair known as base excision repair. 00:35:44.05 In the tumors that are deficient in BRCA1, the tumor cell still survives. 00:35:54.28 But if you then bring in a drug that inhibits the other, another major form of repair, that is just too much for the cell to bear. 00:36:03.18 That combination leads to death of a cancer cell. 00:36:06.27 So, these are our principles of targeted therapy as we understand them now. 00:36:14.10 Therapeutic inhibitors for gain of function. Synthetic lethality for either gain or loss of function. 00:36:20.06 And combination therapy almost always essential. 00:36:24.19 What about combination therapy? Well, we can imagine three different forms, at least. 00:36:29.03 First of all you might attack two different signaling pathways. 00:36:34.00 An example that I've given here is the MEK kinase and the PI3 kinase that will be familiar to those of you who know something about signaling. 00:36:42.11 These are parallel pathways, and so you are ganging up on the tumor cell by inhibiting two of its supporting elements. 00:36:51.18 But you could also attack sequential targets in the same pathway. 00:36:56.14 For example in the RAS signaling pathway downstream of it is a RAF kinase and then the MEK kinase. 00:37:02.07 And by attacking two in the same pathway, you might also reduce the likelihood of resistance emerging 00:37:11.23 because for the same statistical arguments that have been used for the bimodal therapy before. 00:37:19.12 And then of course there is the bimodal attack, which is a reality with PML-RAR for acute promyelocytic leukemia, 00:37:28.09 which is under consideration for the Philadelphia chromosome, BCR-ABL, 00:37:33.07 as a way to avoid the inevitable resistance to Gleevec that emerges eventually. 00:37:40.25 And in those various forms of synthetic lethality for MYC, you could imagine combination therapy by utilizing several of those together. 00:37:51.07 So here is a sampler, looking at it from the standpoint now of the therapeutic. 00:38:00.10 Combination of all-trans retinoic acid and arsenic trioxide is curative for acute promyelocytic leukemia. 00:38:07.04 Herceptin for breast cancer extends lifespan, sometimes extraordinarily so. 00:38:15.16 Gleevec offers a remarkable extension of lifespan for chronic myeloid leukemia 00:38:22.25 and some rare tumors such as gastrointestinal stromal tumor or GIST. 00:38:27.12 I told you about two drugs that attack a switch on the surface of lung cancer cells that give a remission in select cases that can be identified by genomics. 00:38:41.05 A recently described drug that is effective at least short term against melanoma, which has received immense press coverage 00:38:54.29 because this is a deadly disease in its advanced stages, 00:38:58.08 and this drug gives remissions in the advanced stage of the disease. 00:39:03.25 And the PARP inhibitors, which should be useful at the least against breast, ovarian, and prostate cancer, 00:39:11.22 that have got a deficiency in one or the other of the BRCA genes. 00:39:16.23 You will notice that only the PARP inhibitors so far represent a therapy that's actually been 00:39:25.17 utilized in the clinic and proven to have effect against loss of function. 00:39:30.24 The rest of these are all therapeutics for gain of function. 00:39:33.24 Now there is much more out there. 00:39:36.13 For example, this is a compilation of the targets and the drugs presently... so these are the targets 00:39:48.22 in lung cancer, and the drugs that have been developed to attack them that are currently at one stage of study or another. 00:39:56.20 And beyond this is much more. At last count there were well over two hundred clinical trials 00:40:04.17 of various targeted therapeutics underway in the United States alone. 00:40:10.10 So we have much to look forward to in all likelihood. 00:40:14.09 So, we have made Paul Ehrlich's vision a reality. 00:40:22.17 Whether it will work as well as he hoped and we hope remains to be seen, 00:40:29.01 but there is certainly reason for hope, and both the public and even the press have got that message. 00:40:38.17 Thank you very much for listening.
