Oncogenes: A Genetic Paradigm for Cancer

Part 1: Forging a Genetic Paradigm for Cancer

00:00:03.10 Hello. I am Mike Bishop from the University of California, San Francisco, and I am going to talk with you about cancer,
00:00:10.05 what we presently know about the disease and how we are trying to apply that knowledge.
00:00:14.18 Cancer is the most fearsome of human adversaries.
00:00:19.20 In the United States as many as one in three individuals will develop the disease and one in four will die of it.
00:00:26.05 It is soon to become the leading cause of death in this country and worldwide, more than 8 million individuals die of cancer every year.
00:00:34.29 We have not been doing well in our struggle against cancer until recently.
00:00:40.26 Consider this comparison. Between 1975 and 2005 mortality from cardiovascular disease decreased by 70%,
00:00:51.00 whereas that of cancer decreased by only 7.5%.
00:00:54.25 Numbers of this sort have inspired disappointment and even skepticism amongst the public and the press.
00:01:00.15 Witness this lead article in Newsweek in 2008.
00:01:03.09 Now we can rationalize our difficulties with cancer. Consider this comparison again.
00:01:10.02 Cardiovascular disease is essentially a single disease of a single organ system with a single cause.
00:01:16.21 Whereas cancer has multiple causes, numerous causes, and every organ system has its own forms of cancer.
00:01:25.07 There are at least a hundred discrete forms of human cancer.
00:01:30.04 But we have been able to cut through this complexity with a unifying simplification that we call the genetic paradigm of cancer.
00:01:37.15 And that is that all cancer arises through the malfunction of genes.
00:01:42.13 I am going to tell the story in three chapters.
00:01:48.05 In the first chapter, I will review the history of how we came to this insight.
00:01:53.09 In the second chapter I will talk about the challenges that it represents and the promise.
00:02:00.09 And in the third chapter I will delve more deeply into one application of this insight in therapeutics for cancer.
00:02:08.11 Five paths of investigation converged to give us the genetic paradigm for cancer.
00:02:17.15 The first of these paths was the most elemental.
00:02:21.06 And that is the fact that cancer is a heritable cellular phenotype.
00:02:25.18 Cancer cells breed true. One of the first persons to recognize this was a man named Rudolf Virchow, a German pathologist,
00:02:34.10 who in 1858 pointed out that the metastases of cancer resembled the primary tumors,
00:02:40.23 as if the metastases and the primary tumors might have a common origin.
00:02:48.11 It had previously been believed that what we call a metastases might be tumors of independent origin.
00:02:54.17 This insight also inspired Virchow to coin a well-known aphorism that "All cells come from cells"
00:03:05.11 to advertise the newly emerging theory of the cell.
00:03:09.27 Virchow would not have been in position to know how close he was to the truth.
00:03:20.07 We now know that most if not all cancers have their origin in a single cell.
00:03:26.16 All of the cells in a cancer have a lineage that can be traced back to one cell that went awry sometime in the past.
00:03:35.25 Now there are subtleties to this that we will explore a little later, but fundamentally, this is another testimony
00:03:42.18 to the extraordinary durability of the malignant phenotype once it has been established.
00:03:48.05 Let me dramatize that durability with a story that has been widely appreciated because of a best-selling book.
00:03:57.29 And that is the story of Henrietta Lacks. In 1951, Mrs. Lacks died of cervical cancer at Johns Hopkins University.
00:04:08.16 Cells from her cancer were put into test tubes and Petri dishes and have been propagated ever since.
00:04:16.06 It is estimated that they have been propagated to a quantity of at least 20 tons.
00:04:23.22 Or others put it this way, more HeLa cells, as they are called, now exist than all of the visible stars in the universe.
00:04:34.08 This of course is a stunning testimony to the stability of the malignant phenotype.
00:04:39.21 In conclusion, the durability of the malignant phenotype clearly suggests a genetic underpinning.
00:04:47.23 The second of our paths to the genetic paradigm of cancer involved the recognition that there are external causes of cancer,
00:04:57.06 and that many of these causes act by damaging DNA by causing mutations in our genes.
00:05:03.19 As long ago as 1761 Dr. John Hill, a physician in London, noticed an association between the use of snuff
00:05:11.27 and the occurrence of cancer of the tongue, jaw, throat.
00:05:16.28 We now call snuff by the disarming term "smokeless tobacco," but its consequences can be just as onerous as illustrated by this figure.
00:05:26.15 Soon thereafter, Percival Pott made a landmark observation.
00:05:32.10 He recognized that scrotal cancer was very common in chimney sweeps in London.
00:05:38.27 And he made a leap, an induction, and attributed this incidence of cancer to the soot
00:05:46.21 that was accumulating on the skin of the chimney sweeps.
00:05:50.29 With the emergence of the industrial revolution more and more external causes of cancer became apparent.
00:05:58.26 Mainly from large industrial exposures, or in the case of X-rays,
00:06:05.16 in the case of experimentalists who were working with X-rays in the early days after their discovery.
00:06:13.25 To give you a sense of the power of these observations, consider the chemical 2-naphthylamine,
00:06:21.17 which we now know can cause bladder cancer.
00:06:24.23 Individuals who work with this chemical and have exposure for at least five years are almost guaranteed of having bladder cancer.
00:06:38.00 Here is a list of some of the other examples, and the point of this list is to dramatize the great variety of cancers
00:06:49.02 that can emerge from external causes, from exposure to industrial chemicals and physical agents.
00:06:56.28 But could this be replicated in experiment?
00:07:02.23 Could it be proven that these external agents were causing the cancer?
00:07:07.27 In 1915, Katsusaburo Yamagiwa reported that he could induce skin cancer in rabbit ears by the repeated application of coal tar.
00:07:20.00 This was a riveting discovery. It was the first direct demonstration that a chemical could elicit cancer.
00:07:29.08 Yamagiwa was ecstatic over his discovery, so much so that he wrote a commemorative haiku in his own beautiful calligraphy.
00:07:40.01 Roughly translated the haiku reads, "Cancer was produced. Proudly I walk a few steps."
00:07:47.21 By 1938 a great variety of external agents, mainly from industrial sources had been identified as causes of cancer.
00:07:58.06 and the thought that there are external causes of cancer was well established.
00:08:04.04 Now how do these agents work? Well, the first clue came from the work of one of America's great scientists, H. J. Muller,
00:08:14.09 who working with fruit flies discovered that X-rays caused mutations in the genes of the fruit fly.
00:08:20.15 Some years later, American scientist Bruce Ames discovered using a very clever bacterial test that many carcinogens are mutagenic.
00:08:34.06 Not all, but many.
00:08:38.03 The third of our convergent paths to the genetic paradigm of cancer involved the study of abnormal chromosomes in cancer cells.
00:08:47.26 In 1903, Walter Sutton was a PhD student working at Columbia University. Sutton was working with grasshoppers.
00:09:00.06 And from his studies he was the first to reach the solid conclusion that chromosomes are carriers of heredity.
00:09:09.10 He published that work, but never published another paper. Instead he became a surgeon and died prematurely at the age of 39.
00:09:18.22 In 1914, the German biologist Theodor Boveri while studying worms and sea urchins had a vision.
00:09:31.02 And in a famous monograph published an argument that the abnormalities of chromosomes might account for cancer.
00:09:40.04 He anticipated the current form of the genetic paradigm with a remarkable prescience, but there was no evidence for his vision until 1959
00:09:53.03 when two scientists in Philadelphia, Peter Nowell and David Hungerford, the latter of whom was still a graduate student,
00:10:00.19 discovered a miniature chromosome, an abnormal chromosome that was unique to the cells of chronic myeloid leukemia.
00:10:08.20 The chromosome was dubbed the Philadelphia chromosome in honor of the city where it was discovered.
00:10:15.06 Now the nature of this chromosome was not known until 1972 when Janet Rowley, working at the University of Chicago,
00:10:22.25 demonstrated that the Philadelphia chromosome results from a reciprocal translocation between two chromosomes, chromosomes 9 and 22.
00:10:33.06 Here is an image of what Janet Rowley had discovered.
00:10:39.09 The two chromosomes essentially swapped pieces.
00:10:42.03 In the end a piece of chromosome 22 is now on chromosome 9, and a piece of chromosome 9 is now on chromosome 22.
00:10:53.18 That is the Philadelphia chromosome.
00:10:56.23 We now know that abnormalities of chromosomes are common in human cancer,
00:11:03.24 and sometimes there is sheer chaos among the chromosomes.
00:11:08.05 Consider this example of colon cancer.
00:11:11.14 Here are the normal human chromosomes arrayed and colored so you can distinguish one from another.
00:11:17.15 And here are the chromosomes from the colon cancer.
00:11:20.21 In some instances there are three instead of two. In some instances there you see what Rowley had found before.
00:11:30.07 Chromosomes have swapped pieces.
00:11:31.18 Here is a piece of a red chromosome on a blue gray chromosome.
00:11:35.21 This kind of chaos suggests that havoc has been wreaked with the genes in the cancer cell.
00:11:43.25 Now what might be the genetic consequences of both mutagenesis by external agents
00:11:51.25 and the chromosomal mayhem that we find in cancer cells?
00:11:56.02 The answer to this question came from the discovery that certain cancer genes carried in viruses
00:12:02.27 are actually derived from normal cells, from cellular genes that we call proto-oncogenes.
00:12:08.28 This story began in 1909 when Peyton Rous at the Rockefeller Institute discovered a virus
00:12:16.05 that causes sarcomas in chickens, Rous Sarcoma Virus.
00:12:20.02 It was a complete mystery as to how this virus caused cancer until 1970 when Steven Martin at the University of California, Berkeley,
00:12:32.04 isolated a mutant of Rous Sarcoma Virus that demonstrated temperature sensitive transformation.
00:12:41.11 In other words the virus could create a cancer cell at one temperature, but not at another.
00:12:47.07 Here is an illustration of what Steven Martin had discovered.
00:12:51.22 These are normal chicken fibroblasts growing in culture, and here's what those fibroblasts look like near 24 hours
00:13:01.00 after having been infected with Rous Sarcoma Virus.
00:13:04.16 What Martin discovered was that if he infected the cells at 35 degrees with this mutant,
00:13:13.02 the cells transformed, but as soon as the cells were shifted to a higher temperature,
00:13:18.10 they reverted to the normal state.
00:13:22.02 You could cycle the cells back and forth between the transformed and the normal state just by shifting the temperature.
00:13:28.08 To geneticists, this meant that there was at least one gene that was clearly responsible for eliciting the neoplastic transformation.
00:13:36.24 We came to call these genes oncogenes and the gene in Rous Sarcoma Virus was dubbed src because it elicits sarcomas.
00:13:46.09 In due course we learned that Rous Sarcoma Virus has four genes, only four genes, arrayed along its RNA genome as illustrated here.
00:13:57.02 Three of these genes are responsible for viral reproduction.
00:14:01.23 The fourth, the src gene, is responsible for cancer but only the induction of cancer.
00:14:09.22 It is not required for replication of the virus.
00:14:11.26 The seeming irrelevance of src to the welfare of the Rous Sarcoma Virus inspired our research group in San Francisco
00:14:21.14 to ask whether this gene might actually be acquired from a normal cell.
00:14:26.19 That it is an accident of nature. That proved to be the case. At some time in the past during the course of replication,
00:14:36.14 the virus that became Rous Sarcoma Virus acquired a cellular gene and inserted it into its own genome creating the viral oncogene src.
00:14:49.09 At first it seemed that Src might be a mere curiosity.
00:14:55.25 But many other retroviral oncogenes were identified, and in almost every instance these too were found to be acquired from the normal cell.
00:15:04.28 The cellular genes that gave rise to the viral oncogenes became known as proto-oncogenes.
00:15:12.08 This led to a larger hypothesis. If a change in a proto-oncogene can create a viral oncogene,
00:15:23.20 why could not the same sort of thing occur within the cell without the intervention of the virus?
00:15:29.20 Why couldn't proto-oncogenes become the progenitors of cellular oncogenes?
00:15:39.29 That thought was made a reality by the discovery that proto-oncogenes are affected by genetic abnormalities in human cancer.
00:15:50.22 Three forms of abnormalities were involved in this discovery. The first was something known as gene amplification.
00:15:58.11 A focus on a chromosome, the DNA at that locus,
00:16:04.02 replicates many times over, sometimes giving rise to little chromosomes that are thrown off and called double minute chromosomes,
00:16:17.12 which then can re-insert into a chromosome and create what is called a homogeneously staining region.
00:16:22.17 This was first observed with a proto-oncogene known as MYC in human cancer cells.
00:16:28.22 The consequence is gross overproduction of the gene product.
00:16:33.15 The second abnormality involved translocation of the sort first described for the Philadelphia chromosome.
00:16:40.15 Translocations of the MYC gene were the first to be seen, and these translocations alter the control of the expression of MYC
00:16:52.04 and again create a gross overproduction of the gene product.
00:16:56.28 Third, single point mutations were discovered in another proto-oncogene known as RAS in human tumor cells.
00:17:07.27 This point mutation converted the protein from a controlled state to an uncontrolled state.
00:17:17.03 The protein activity could now run rampant.
00:17:20.24 We now know of several hundred proto-oncogenes that have been implicated in human cancer.
00:17:27.23 Several hundred genes of the normal cell that if altered in one way or another can contribute to the genesis of cancer.
00:17:37.17 Now, the malady here is exaggerated activity, which we can equate to a jammed accelerator.
00:17:47.22 Formally speaking, it is a gain of function, and it is genetically dominant.
00:17:53.21 You need have this happen to only one of the two copies in the cell for the difficulty to arise.
00:18:01.19 Our fifth path to the genetic paradigm of cancer involved the study of congenital cancer
00:18:10.20 and incidentally uncovered an entirely new form of cancer gene.
00:18:16.13 This work departs from the fact that about 5% of human cancer is strongly hereditary.
00:18:22.23 And it began with a study of a childhood tumor known as retinoblastoma, and here is an example.
00:18:32.26 In some instances, retinoblastoma is inherited in a very strong manner,
00:18:38.02 as illustrated in this family tree, where every red box or circle indicates a case of childhood retinoblastoma.
00:18:46.01 The first hint to what was going on here was the discovery of a defective chromosome
00:18:52.24 in familial retinoblastoma, inherited retinoblastoma.
00:18:56.18 It involved chromosome 13, and it was discovered that in some cases of retinoblastoma, there was a focal deletion.
00:19:08.00 A piece of this chromosome was missing. This band here had disappeared in the chromosome of the family.
00:19:18.26 It was immediately apparent that this deletion segregated with the disease in families.
00:19:22.29 And in due course through the use of molecular biology, a single gene was identified as the culprit.
00:19:31.08 A gene that was known as the retinoblastoma gene, or RB1.
00:19:35.20 And it was the loss of this gene that was causing the trouble.
00:19:39.24 Here is how we understand the inheritance of retinoblastoma.
00:19:45.12 One of the two chromosomes in the family is carrying this deficiency.
00:19:54.10 And some time during the early life of the child, the corresponding normal copy in the other chromosome
00:20:01.20 is also damaged for one reason or another. Now the cell is totally deficient in this gene, and that gives rise to the cancer.
00:20:11.28 A retinoblastoma also occurs as a spontaneous tumor.
00:20:16.04 And in that instance, there is no inherited abnormality.
00:20:21.04 Both copies of the gene are damaged during early life, giving rise to the cancer.
00:20:33.28 And both of these are rare events, so as a consequence, for two of them to occur in the same lineage of cells,
00:20:40.18 it makes this a very rare tumor and one in perhaps 30,000 people.
00:20:46.23 So this is a new form of cancer gene, a genetic deficiency that we now know is present in both congenital and sporadic cancer.
00:20:59.15 And the affected genes are known as tumor suppressors because in their absence cancer is favored.
00:21:06.17 Typically both copies of the genes are defective in a tumor, and that is how we usually spot them.
00:21:13.08 And the deficiency is genetically recessive because both copies must be affected.
00:21:20.19 Here are a few prominent examples. These examples were... almost all of them were discovered first by the study of inherited cancer.
00:21:33.09 But with the latter day techniques of genomics, we can now identify tumor suppressor genes
00:21:40.04 without any assistance from congenital cancer or heritable cancer.
00:21:45.26 Now the malady here is loss of a gene or its activity,
00:21:50.22 which we could equate to a faulty brake as opposed to the jammed accelerator of proto-oncogenes.
00:21:57.11 So the geneticist calls this a loss of function, and it is genetically recessive.
00:22:03.25 So we have identified two major culprits in cancer cells, proto-oncogenes, which suffer gain of function in tumor cells,
00:22:16.24 and tumor suppressor genes which suffer loss of function in cancer cells.
00:22:22.25 And these two collaborate in ways that we don't fully understand just yet to produce the final malignant state.
00:22:28.26 A variety of events can create the genetic malfunctions in cancer, and these all can affect either a proto-oncogene or tumor suppressor gene.
00:22:38.06 They include: gain or loss of entire chromosome;
00:22:41.27 focal amplification or deletion within a chromosome, as I illustrated for you with the retinoblastoma gene;
00:22:47.14 chromosomal translocations, as I illustrated for you with both the Philadelphia chromosome and the case of the proto-oncogene MYC;
00:22:56.18 a direct mutation in the gene product, which activates the gene product in the case of a proto-oncogene,
00:23:02.04 but inactivates it in the case of a tumor suppressor gene; or defective control of expression, either up or down.
00:23:09.06 Up for a proto-oncogene, down for a tumor suppressor gene.
00:23:13.15 And all of these have been observed in human cancer.
00:23:17.27 Now how can we authenticate the powerful circumstantial evidence that these genes are involved in cancer?
00:23:26.20 And there are four general approaches. First, what I call guilt by association.
00:23:31.28 If you find the Philadelphia chromosome in every case of chronic myeloid leukemia,
00:23:37.08 which is essentially the case, surely it has something to do with the disease.
00:23:41.02 We can also install replicas of the damaged proto-oncogene or tumor suppressor gene in mice,
00:23:50.18 and this often leads to the production of tumors, and it often leads to production
00:23:58.15 of the same kind of tumor in which the lesion was originally identified in human cancers.
00:24:05.12 And finally, in very recent years, it has been possible to demonstrate that targeting
00:24:11.16 at least a few of these abnormalities with therapeutics gives rise to a therapeutic response.
00:24:17.09 Something I will talk about in greater detail in my second and third chapters.
00:24:24.00 Now how many of these adverse events are required to produce a malignant cell?
00:24:28.18 Epidemiologists were among the first to approach this problem.
00:24:32.00 And by simply charting the incidence of a particular tumor against age,
00:24:38.18 they reached the conclusion that multiple events were required, and by mathematical analysis of the data,
00:24:45.25 they could assign a rough approximation of the number of events required to give rise to certain cancers.
00:24:52.15 For example, childhood leukemia, only a few events were required which was probably the reason that these diseases occur in children.
00:25:00.15 Lung cancer, 6 or more, and prostate, which we commonly associate
00:25:05.02 with the late middle age and elderly, may involve 20 or more discrete events.
00:25:11.19 If we look at this in a biological sense, we see evolution in miniature.
00:25:23.29 An initial event occurs in a single cell, causing that cell to replicate.
00:25:31.04 And then an event occurs in one member of that population, which changes the cell yet again.
00:25:38.29 This happens multiple times, giving rise finally, to a tumorigenic clone.
00:25:46.18 We call this tumor progression, and at the genetic level, the molecular level, we believe, and in fact we have been able to show
00:25:58.29 that what is happening over the course of time is the accrual of independent genetic events.
00:26:04.29 So that by the end there is a combination of these events that give rise to the malignant cell.
00:26:12.17 Recently it has become apparent that sometimes a cataclysmic event can occur that shatters an entire chromosome,
00:26:23.23 and the pieces are then stitched back together in a random order.
00:26:31.06 This is a... and this single event can create more than one cancer gene along the array of the chromosome.
00:26:38.03 We do not know how often this occurs but it obviously would be an accelerating event in tumor progression.
00:26:45.03 So we have reached our genetic paradigm for cancer, and it has these components.
00:26:54.06 There are many causes of cancer, but they all work by damaging genes or otherwise disturbing the function of the genes.
00:27:04.08 Both gain and loss of gene function are involved, cooperate in some way in the production of the tumor.
00:27:11.23 Multiple genes are involved, from as few as one or two to as many as twenty or more depending on the cancer and the age that it arises.
00:27:20.26 There is a stepwise evolution of malignancy,
00:27:24.09 probably resolving from the selection of favorable properties of the evolving malignant cell.
00:27:31.04 And there is this cooperation among gain and loss of function.
00:27:36.14 In 1978, Susan Sontag published a book entitled "Illness as Metaphor."
00:27:45.05 In that book she described cancer as "overlaid with mystification", "a triumphant mutation", an "inescapable fatality".
00:27:54.12 The emergence of the genetic paradigm for cancer has got the mystification in retreat,
00:28:01.09 exposed the triumphant mutation, and rendered that inescapable fatality vulnerable.
00:28:08.18 This is a triumph of modern science that offers great hope for the future management of cancer,
00:28:16.26 and it is that hope that I will turn to in the second chapter of my story.
00:28:22.17 Thank you for listening.

Part 2: The Cancer Genome: Challenge and Promise

00:00:01.27 Hello. I am Mike Bishop from the University of California, San Francisco,
00:00:06.18 and I want to continue with the second chapter in my story about cancer.
00:00:12.21 At the end of the first chapter we had reached the sound conclusion that all cancer arises from the malfunction of genes.
00:00:20.19 And we had identified two culprits, genes we know as proto-oncogenes, which suffer gain of function in cancer cells,
00:00:29.13 that essentially become jammed accelerators,
00:00:33.03 and tumor suppressor genes, which suffer loss of function, as if they were a failed brake.
00:00:39.18 And these combine to give rise to the malignant phenotype.
00:00:43.04 Now in order to apply this insight, we need to have a complete inventory of cancer genes.
00:00:50.19 A complete catalog for each form of human cancer,
00:00:54.19 and then with that catalog we need to distinguish what we call the drivers, genetic damage that is contributing to the malignancy,
00:01:04.25 from passengers, collateral damage if you will.
00:01:07.21 There are rules established for doing this, but it still seems a daunting task.
00:01:15.21 But it is less daunting than it used to be because of dramatic advances in DNA sequencing as illustrated by this plot.
00:01:27.01 The cost has come down many orders and orders of magnitude.
00:01:30.13 It is now possible to sequence all of the protein coding regions of the human genome (we call that the complete exome sequence)
00:01:37.28 for about 1500 dollars. That is the cost of an MRI exam in a hospital.
00:01:45.23 And there has been a similar dramatic increase in the speed of sequencing to the point where first-rate sequencing facilities
00:01:54.04 can now sequence the complete human genome in a week or so.
00:01:56.29 In order to achieve the inventory with this dramatically improved technology,
00:02:03.27 an International Cancer Genome Consortium has been formed, and its objectives are ambitious.
00:02:10.11 Five hundred genomes, full genome sequences, for each of 50 tumor types. 25,000 full genome cancer sequences.
00:02:21.27 What is the state of play? Well, as of the time I am recording this, there have been several hundred complete genomes sequences
00:02:31.15 for human cancer recorded, and the number is increasing by the day very rapidly.
00:02:37.04 And there have been at least 2000 complete exome sequences reported.
00:02:43.04 So it is still early days, but we can draw some provisional conclusions.
00:02:48.26 First of all, there are clearly numerous mutations in most human cancers.
00:02:52.24 The numbers can be as high as 100,000 or more, although some cancer have many fewer.
00:02:58.19 But among all of those mutations, there are a few that create anywhere from 5 to 20 drivers per tumor.
00:03:05.23 There are many more passengers, and all told, there are at least 400 different drivers that have been identified to date.
00:03:13.22 400 different genes which either suffer gain or loss of function in the production of tumors.
00:03:22.14 And experimental work with mice suggests that the repertoire of drivers could exceed 2000.
00:03:28.24 10% or so of the entire human genome.
00:03:33.09 Two important principles are emerging from this provisional data.
00:03:38.22 First of all, there are distinctive but not entirely unique genetic fingerprints for each type of cancer.
00:03:46.17 There is overlap from one type of cancer to another in the lesions,
00:03:51.18 but there are also distinguishing features.
00:03:55.06 And secondly, these numerous drivers, 400 or more, represent a far more limited number of cellular circuits.
00:04:05.13 This is a fact that will become important when we consider the feasibility of using this knowledge in therapeutics.
00:04:14.02 Let me illustrate this principle of circuitry with the example of pancreatic cancer.
00:04:22.04 Genome sequencing has revealed that there are twelve functions or circuits affected in cancer of the pancreas.
00:04:35.24 But when sequences from two different cell lines derived from two different pancreatic cancers
00:04:42.19 were compared, it was discovered that these twelve circuits were affected by mutations in different genes between the two cell lines.
00:04:56.23 There was only one example, the Ras gene, which was mutated in the two cell lines,
00:05:04.14 representing the K-Ras signaling pathway that is inevitably affected in pancreatic cancers.
00:05:10.18 In other words, if you are thinking about therapy, you will not necessarily think about
00:05:16.10 the mutations in individual cancers such as these two here,
00:05:20.09 but rather the pathways that the mutations share.
00:05:24.28 Now as this information accumulates we are beginning to see how it will be useful
00:05:34.14 in almost every aspect of the study of cancer and the clinical management of the disease.
00:05:41.03 It is going to help us identify causes and urgent need, genetic risk. It will help us improve early detection.
00:05:53.01 It is already transforming the classification of cancer, revealing new sub-types in lymphomas and breast cancers and others.
00:06:00.17 It is going to help in the prognosis, the prediction of outcome.
00:06:04.08 It is already inspiring new therapeutics, as I will explore in detail in my third chapter.
00:06:14.04 It is going to allow us at least to attempt a personalization therapy, the individualization of therapy.
00:06:20.15 With the rapid evaluation of individual responses, we may be able to evaluate
00:06:26.11 whether the tumor is responding in a matter of days rather than months.
00:06:30.17 And it is going to simplify and economize clinical trials.
00:06:37.14 I am going to examine a number of these by way of illustration.
00:06:43.09 First of all, what causes cancer?
00:06:46.09 This is a crucial question because we need to know the answer before we can devise prevention.
00:06:54.18 And it represents one of the most, well certainly what is to my eye, one of the most difficult forms of cancer research.
00:07:02.03 Now for some few major cancers, we know with some certainty at least one cause.
00:07:12.21 Cancer of the cervix is caused by infection with a virus, human papilloma virus.
00:07:16.21 Cancer of the liver is caused by infection with either of two viruses, hepatitis B or hepatitis C virus,
00:07:25.11 and/or by toxins such as those found in contaminated foods.
00:07:31.06 Cancer of the lung, much of it is caused by cigarette smoke.
00:07:36.21 Cancer of the skin you heard me say is caused by sunlight, the ultraviolet light in the sunlight.
00:07:44.10 And most cancer of the stomach is caused by a bacterial infection,
00:07:48.19 but many of our other major cancers remain without an established major cause.
00:07:54.26 And they are big killers, breast, prostate, colon, ovary, pancreas, brain.
00:08:00.27 We have nothing but hunches about what might cause these cancers.
00:08:07.06 Now the tools for discovery here are of two sorts.
00:08:12.09 One is guilt by association, also known as epidemiology.
00:08:17.07 And the other is represented by our newfound genomic tools, and they allow us to do two things.
00:08:25.23 They allow us to detect the presence of previously unrecognized microbes, either viral or bacterial.
00:08:33.18 And they can also reveal lesions in DNA that hint at the nature of the cause of the lesion.
00:08:40.23 I'll illustrate each of these briefly.
00:08:42.21 Perhaps the best example of and particularly successful example of guilt by association involves cancer of the liver.
00:08:50.21 This map has been known for many years. It displays the incidence of chronic hepatitis B virus infection around the world.
00:09:03.07 Quite some years ago medical scientists looked at this map and realized that it could be
00:09:09.13 superimposed on the distribution of liver cancer.
00:09:13.12 This led to more sophisticated epidemiological studies that clearly established that infection with hepatitis B virus,
00:09:23.02 chronic infection in particular, was at least one of the causes of liver cancer.
00:09:28.13 We now have an even more profound proof of that because we have a vaccine against hepatitis B virus,
00:09:37.16 which is being widely used and is clearly having an impact on the incidence of cancer
00:09:42.08 in those areas where the disease has been particularly common.
00:09:45.25 Now what do these genomic tools do for us?
00:09:50.23 Well, first of all, they can help us detect previously unrecognized viruses.
00:09:55.26 There are three examples and they represent a progression from an unsophisticated molecular technique to full genome sequencing.
00:10:07.12 The first of these was a discovery that all cervical cancers contain a previously unrecognized strain of human papilloma virus.
00:10:16.28 This virus was detected with very simple techniques of molecular hybridization.
00:10:23.02 Then the Kaposi Sarcoma Virus was identified by a somewhat more sophisticated technique of molecular hybridization.
00:10:35.06 And the most recent and very rare example is so-called Merkel Cell Carcinoma Virus.
00:10:41.00 This was literally detected by full genome sequencing.
00:10:47.09 Then there is the idea that we can deduce, or at least get a hint about the cause of a cancer
00:10:53.26 by the nature of the chemical damage in DNA.
00:10:57.01 And the premier example is skin cancer,
00:10:59.25 which we were already reasonably certain is due mainly to ultraviolet light in the sunlight.
00:11:06.20 But in the skin tumors, a tumor suppressor gene known as TP53
00:11:13.12 characteristically has a particular change in which just two nucleotides,
00:11:21.03 a pair of C's is converted to a pair of T's.
00:11:25.12 This is a hallmark of damage from ultraviolet light.
00:11:30.00 This is a stunning affirmation of our belief that sunlight has a crucial role in the genesis of skin cancer.
00:11:39.15 There are other examples. The genetic damage of lung cancer reflects the nature of the chemicals in cigarette smoke.
00:11:49.11 The genetic damage in liver cancer can reflect the nature of the toxins that might have been involved in the genesis of the cancer.
00:11:58.04 And finally in the tragic cases where secondary cancers arise as a result of vigorous chemotherapy,
00:12:05.06 the DNA damage there is diagnostic of the chemicals that were used in the therapy.
00:12:11.06 The principal point of learning the cause of cancer of course is to devise preventions, and alas we have only a few of those.
00:12:18.25 We can prevent most lung cancer by avoiding tobacco smoke.
00:12:25.01 We can certainly reduce the incidence of skin cancer by avoiding excessive exposure to sunlight.
00:12:30.06 We have a vaccine for hepatitis B virus, which is reducing the incidence of liver cancer,
00:12:36.14 and we now have a vaccine for human papilloma virus which when widely applied will certainly reduce the incidence of cervical cancer
00:12:46.20 particularly in those developing nations where it is particularly common and a common cause of death among women.
00:12:56.03 When you think of the genome and cancer, it is inevitable that you wonder about the possibility
00:13:06.01 of predicting individual risk of cancer.
00:13:08.20 And there are three basic origins of risk. There is the environment, sunlight for example.
00:13:16.07 There is behavior, cigarette smoking for example, and there is inheritance.
00:13:23.01 And with the advent of genome sequencing, with the advent of modern genomics, genes have come front and center.
00:13:32.11 There are two kinds of genetic risk for cancer. There is a strong risk due to single gene changes
00:13:41.06 that is responsible for perhaps five to ten percent of all cancer,
00:13:46.08 and the example of retinoblastoma I gave you is one, and we will talk about a few others momentarily.
00:13:53.00 Then there are multiple genes, each of which may be making a weak contribution to risk,
00:14:00.29 possibly for all cancers, but these are being identified at a considerable pace. There are many of them.
00:14:11.02 The question remains as to whether this will ever be useful information
00:14:15.18 because the risk contributed to any single change is relatively small.
00:14:21.14 Suffice it to say, it is a work in progress.
00:14:23.27 But we do have a few strong cancer genes that are responsible for inherited cancer and for which we will do genetic testing
00:14:35.18 if it is indicated, and it includes the retinoblastoma gene, the two BRCA breast cancer and ovarian cancer genes,
00:14:44.10 and a gene called APC, a deficiency of which is responsible for polyps and cancer of the colon.
00:14:51.01 Let me illustrate the APC problem. This is a normal colon, and this is a colon taken from a patient
00:15:03.14 who has inherited a deficiency in the APC tumor suppressor gene.
00:15:08.05 It is a sheet of polyps, and some of these polyps will inevitably progress to cancer.
00:15:16.28 It is clear that testing families that have this problem for the presence of the APC deficiency
00:15:25.26 is a valuable approach that can help in the prevention of disease in individual members of the family.
00:15:34.12 Unfortunately that prevention usually involves a complete resection of the colon.
00:15:39.23 Early detection is known to be a valuable in improving the outcome of cancer therapy.
00:15:54.00 And genomics is allowing us to improve early detection. Now the established techniques are only four in nature, in number.
00:16:04.19 The renowned Pap test which was extraordinarily effective in reducing the incidence of cervical cancer.
00:16:12.20 It may someday be replaced by the testing for the presence of the causative agent-the DNA of the human papilloma virus.
00:16:20.11 Then there is colonoscopy, which is an effective means of early detection, but also obviously a burdensome technique.
00:16:28.22 Mammography for breast cancer about which there is some controversy is presently swirling.
00:16:34.23 And the PSA test for prostate cancer, which is deeply mired in controversy and under thorough reconsideration.
00:16:43.11 This is hardly where we would like to be with early detection, and it is possible, for example, we don't have
00:16:53.03 validated tests for any of these major killers: lung cancer, ovary, pancreas, or liver.
00:16:59.14 There is no test available to detect these tumors early in their genesis.
00:17:06.24 We may get a help from what can be called molecular cytology.
00:17:11.03 The human body sheds cells into all of its orifices, into the colon, into breast fluid, into the secretions from the cervix and uterus,
00:17:24.05 from the bladder or the kidney, both coming out into the urine, and in the sputum of the lungs.
00:17:31.25 And these cells can be analyzed for the presence of telltale genetic lesions.
00:17:40.08 Lesions that would hint at a future cancer or the presence of an existing cancer.
00:17:45.19 But I want to illustrate this with a story of Hubert Humphrey, an American statesman who died in 1978
00:17:52.17 from bladder cancer. He first knew he had a problem in 1967 when he had a problem with his bladder
00:18:02.16 that his physicians deemed "not malignant". In 1973 they decided, yes, he might have a mild form of bladder cancer,
00:18:10.03 and they used local therapy. In 1976 they realized that they were dealing with a highly malignant disease.
00:18:16.28 Radical surgery was performed. It was too late. Mr. Humphrey died in 1978 from bladder cancer.
00:18:24.14 Some years ago scientists went back and looked at the specimens from Hubert Humphrey
00:18:32.24 that had been preserved and discovered that from the very outset
00:18:37.00 the tumor suppressor gene, TP53, was mutant.
00:18:41.10 In other words, molecular cytology done at this point in Hubert Humphrey's course
00:18:46.18 would have alerted the physicians that they were dealing with a truly dangerous circumstance,
00:18:52.25 and they could have taken aggressive action at that point, eleven years before Hubert Humphrey's ultimate death.
00:19:02.05 This is a dramatic illustration of what molecular cytology might offer us,
00:19:05.11 and there are vigorous efforts underway to make it a reality.
00:19:08.14 How about prognosis? Both patient and physician want urgently to know what they can expect
00:19:16.14 from the disease itself and from the therapeutic that they might receive.
00:19:22.05 The first example of how gene analysis might help with prognosis remains one of the most powerful.
00:19:32.25 It emerged in the early 80s, not too long after the discovery or at least the solidification of the reality of genetic damage in cancer.
00:19:43.18 It involves a gene known as MYCN, which was originally discovered by virtue of the fact that it is amplified.
00:19:52.05 It is overgrown, sometimes a hundred or a thousand fold in neuroblastomas, a tumor of children.
00:20:00.02 A large national study was conducted. The first purpose was simply to ask whether guilt by association applied here,
00:20:11.10 whether that amplification was common enough in neuroblastoma to be part of the mechanism of tumorigenesis.
00:20:18.14 But a very useful outcome occurred when it was realized that the presence or absence
00:20:26.05 of the amplification of this gene was a profound prognostic indicator.
00:20:33.20 And that is dramatized in this plot. Children whose tumors do not contain an amplification of MYCN
00:20:41.17 have a superb outcome after therapy.
00:20:45.06 Children whose tumors have MYCN amplified are going to be refractory to conventional therapies.
00:20:52.24 This test is now used in all major centers where neuroblastoma is handled.
00:20:59.09 And it remains the most powerful predictor based on genes for the moment.
00:21:05.00 But we have more sophisticated techniques and they are going to change the game.
00:21:13.14 This will be recognized by many of you as what we call a gene array analysis.
00:21:21.15 Simply put, it is now possible to test for the expression of every gene in the human genome.
00:21:32.17 And in this array the red squares indicate a gene that is active,
00:21:37.05 and the green squares indicate a gene that is at normal level or even not active.
00:21:44.02 And this can be used to survey or to compare gene expression in cancer cells with gene expression in normal cells.
00:21:53.03 And let me give you one example, which is actually commercially available, and it is known as "Mammaprint".
00:21:59.15 This is a set of seventy genes which comprises a fingerprint, and if that fingerprint is present
00:22:12.14 the likelihood of a poor outcome is increased.
00:22:20.05 Now this is not perfect. The prognostic accuracy is only about 50%.
00:22:28.04 And the "Mammaprint" is found in about 61% of breast cancers.
00:22:32.29 There is another signature known as the MSP Complex. That signature alone has about a 60% prognostic accuracy,
00:22:42.09 but it only occurs in 14% of human breast cancer.
00:22:48.02 If you put the two together, you get a remarkable improvement in accuracy, 82%,
00:22:54.05 but now the number of patients, the number of tumors, that is the fraction of tumors containing the combined signature is down to 9%.
00:23:03.09 So that is a discouraging limitation on the most effective prediction,
00:23:08.10 but it is also a dramatic reflection of how much more complex breast cancer may be than we had previously realized.
00:23:17.23 In other words that 9% represents a distinct biological and genomic subset of the disease that has not previously been recognized.
00:23:26.10 Which brings us to therapy which is always uppermost or usually uppermost in the public mind.
00:23:36.14 In using genetic lesions in cancer to guide our development of therapies,
00:23:45.20 we are designing an intervention in the elaborate circuitry that controls the lives of our cells,
00:23:52.00 and this is a simplification of that circuitry. The real thing is hundreds, thousands, perhaps tens of thousands of fold more complex.
00:24:00.19 And represented by the red dots are nodes in this circuitry where either a proto-oncogene or a tumor suppressor gene resides.
00:24:09.18 And we would like to target our therapeutics to those nodes that are malfunctioning in the cancer cell.
00:24:20.17 The two obvious ways to do this are either to inhibit a gain of function of a proto-oncogene,
00:24:31.04 or to replace the loss of function of a tumor suppressor gene.
00:24:34.07 Inhibiting gain of function is something we know how to do, and you'll hear a lot more about that from me in my third chapter.
00:24:40.26 It is, as I like to say, a growth industry. Replacement of function is not presently practicable.
00:24:48.12 We simply have no means by way to do that at the moment or in my view for the foreseeable future.
00:24:55.24 And then there is a third, newly emerging technique called, I call it, attacking from the flank,
00:25:01.20 in which neither the cancer gene itself nor its protein product is the direct target for therapy.
00:25:07.24 But the cancer gene or its protein product is never the less being exploited in the therapy,
00:25:13.09 and this will be a major subject of my third chapter.
00:25:16.25 What do we target then? Well, we target proteins, not genes.
00:25:26.15 We target proteins with both pharmaceuticals, small molecules, and biologicals, large molecules like antibodies.
00:25:33.27 We do this now in many instances and we will be doing it more in the future.
00:25:39.13 We don't target genes because the molecular surgery on tumor DNA, or for that matter, normal DNA, is not yet practicable.
00:25:48.08 Just we have no way of doing that.
00:25:50.27 Now the poster child for targeted therapy of cancer is a drug with the trade name Gleevec or the formal name imatinib.
00:26:03.22 And it has been developed and is extraordinarily effective against patients with
00:26:09.14 chronic myeloid leukemia containing the Philadelphia chromosome.
00:26:13.06 This is the translocation I told you about in my first lecture.
00:26:19.18 Now what this translocation does is create a sort of mongrel protein with portions from two different proteins being used.
00:26:27.24 The action of this protein is enzymatic in nature.
00:26:33.25 In the fusion, the mongrel version of the protein, this enzymatic activity is incessantly and excessively on.
00:26:41.02 It cannot be controlled, and that is one of drivers, perhaps the principal driver in the production of this tumor.
00:26:51.10 Some years ago a group of scientists, both academic and commercial,
00:26:56.18 teamed up to develop this chemical known as Gleevec.
00:27:01.03 And they developed it by screening for chemicals that could kill or arrest the growth of leukemia cells in the laboratory.
00:27:13.09 The efficacy in patients proved to be dramatic, and this is a story that is told in great detail by Brian Druker in his iBioSeminar,
00:27:22.23 and I refer you to that if you want to learn more about it.
00:27:25.27 So here are the early returns for what we call targeted therapy.
00:27:33.29 That is to say, therapy that actually has a specific gene product as its target.
00:27:40.08 The disease of acute promyeloblastic leukemia which was once incurable can now be cured.
00:27:46.03 And I will tell you about that in my third chapter.
00:27:48.29 Breast cancer, survival can be extended by several means.
00:27:54.08 The best known being Herceptin, a targeted therapy.
00:27:58.03 Chronic myeloid leukemia. I just told you about Gleevec.
00:28:00.27 This prolongs survival to the point that we are now causing this a chronic disease.
00:28:07.06 The term chronic myeloid leukemia is a bit of misnomer because this disease is ultimately lethal as well.
00:28:12.24 Now it can... if patients are treated early on, they have an outstanding prognosis.
00:28:21.20 And again, Brian Druker's iBioSeminar discusses that in detail.
00:28:26.17 And we have drugs that give us a brief remission in lung cancer
00:28:31.21 and a brief remission in melanoma. Both of these are targeted therapies and they simply point the way to a much more promising future.
00:28:40.20 I will discuss all of this in more detail in my third chapter.
00:28:44.22 Recently cancer scientists have realized that they have a different kind of target they may have to worry about.
00:28:52.19 A distinctive cellular target.
00:28:54.27 This target is known either as a cancer stem cell or a tumor initiating cell.
00:29:01.06 It appears that within the massive population of tumor cells, there is a small subset which is responsible for maintaining the larger mass.
00:29:16.08 This subset functions rather like a normal stem cell in that it is constantly regenerating itself,
00:29:24.16 but also spinning off what you could call a differentiated tumor cell.
00:29:30.27 Now these are the cells that we normally treat.
00:29:34.25 These are the cells whose response we normally measure in our therapy.
00:29:38.25 These are new actors in the game. There is controversy about how universal they are.
00:29:46.12 They have certainly been shown to be... their existence has certainly been well affirmed
00:29:52.22 in certain leukemias and there is strong evidence for them in some solid tumors as well.
00:29:58.06 Suffice it to say, this too is a work in progress, but the question arises:
00:30:04.02 "Do these cells differ from the mass of tumor cells in their therapeutic susceptibilities?"
00:30:11.10 One reason they might is that they are known to proliferate very slowly.
00:30:16.09 And the classical chemotherapeutics exploit the rapid proliferation of cancer cells.
00:30:24.01 So this would make these cells relatively resistant to the classical chemotherapeutics.
00:30:29.19 It is possible that they have a distinctive circuitry of the sort I talked about before,
00:30:36.05 which is in no way targeted by a drug that we develop for the circuitry
00:30:41.02 in the mature tumor cells that have been spun off from the stem cell.
00:30:45.29 Thirdly, these tumors.... these stem cells or tumor initiating cells often carry intrinsic drug resistance.
00:30:54.23 And the reason for that is speculative but makes sense.
00:30:59.16 And that is that if these cells were actually derived originally from normal stem cells,
00:31:07.22 normal stem cells are vital to the maintenance of our adult tissues,
00:31:12.19 and it would be only reasonable to think that they have over the eons evolved intrinsic resistance to environmental toxins of any sort,
00:31:25.06 naturally occurring or more recently of human origin.
00:31:29.19 So let's talk about resistance to cancer therapy for a moment.
00:31:34.24 It takes three forms: pumps that extrude chemicals from the cell,
00:31:43.09 mutations in the targets that we are treating, and peculiarities of the signaling circuitry.
00:31:53.22 Now we have known about these pumps for quite some time.
00:31:57.10 They are transporters that use energy to efflux various chemicals and a huge array of chemicals from the cell.
00:32:07.17 And unfortunately, they often efflux the agents that we use for treating cancer,
00:32:15.09 and this is the classical underpinning of much of the drug resistance against conventional therapeutics.
00:32:23.25 Then there's the problem of mutation in the target gene.
00:32:28.25 Now this I have illustrated here with BCR-ABL, the mongrel protein of chronic myeloid leukemia, that is normally targeted by Gleevec.
00:32:38.12 And this gene develops mutations under the pressure of Gleevec treatment that render the protein resistant to Gleevec
00:32:51.19 and require the development of additional drugs which has been done, successfully, and promises more for the future.
00:33:00.06 But arrayed along this cartoon are various points where mutations have been found that make the protein resistant.
00:33:08.22 This is the drug binding to the protein, so some of the mutations simply impede the binding directly.
00:33:16.03 Other of the mutations change the conformation of the protein in a way that makes it resistant to the therapy.
00:33:21.29 This is a common occurrence for various forms of therapy for various cancers.
00:33:28.09 And it is one that we will have to cope with, even with the new elegance of targeted therapy.
00:33:36.11 Then there's the peculiarities of the circuitry.
00:33:42.01 Now imagine a tumor that has a switch here on the surface that is a hyperactive proto-oncogene.
00:33:54.27 Gain of function. And you want to target that.
00:34:00.08 But if there is also a mutation in one of the downstream signaling elements such as the Ras gene,
00:34:04.28 targeting this will be of no avail because the Ras gene will still be running full tilt, and driving the cancer.
00:34:12.25 This has been found in human cancer as a form of resistance to drug therapy, and I'll say more about that momentarily.
00:34:20.05 And then here is another example of how the circuitry can undermine our therapeutics.
00:34:26.23 This involves the target for Herceptin, the breast cancer gene.
00:34:30.00 Herceptin is an antibody that binds to this surface switch, this gain of function, and shuts it down.
00:34:41.23 But, there are other surface receptors that play on the same downstream signaling.
00:34:47.23 And if any of them are also hyperactive in the cancer cell, shutting down HER-2 alone does not suffice
00:34:55.03 to shut down the signaling that is driving the tumor and gives rise to Herceptin resistance.
00:35:01.01 Trastuzumab-this is the fancy term, the chemical term, the formal term for Herceptin.
00:35:07.04 Clearly if we have the complete genome sequence and the full knowledge of the circuitry in a cancer cell,
00:35:16.10 we can predict either this form of resistance or this form of resistance.
00:35:21.16 So genomics is going to be an assist to us for dealing with this problem.
00:35:26.01 Clinical trials are notorious for a number of difficulties.
00:35:37.01 They need to be very large. Enrolling enough patients is a problem.
00:35:42.06 It takes a long time to get the results. Genomics may offer a solution to that.
00:35:48.04 First of all, as we learn what the drivers are,
00:35:52.13 and as we develop therapeutics for those drivers, we'll be able to define the trial population.
00:35:59.18 We will be able to restrict the population to people with the target.
00:36:03.12 This will make it possible to greatly reduce the size of the cohort,
00:36:10.21 which will reduce the cost, and it will also probably allow us to develop what are known as biomarkers.
00:36:18.00 Molecular or chemical changes that would permit us to evaluate
00:36:22.03 within a matter of days whether there is a response to the therapeutic.
00:36:26.29 And if we can get that kind of feedback, we can then make these trials adaptive.
00:36:33.06 We can change in midstream and use the same cohort to explore a revision of the therapeutic.
00:36:40.04 How many cures do we need for cancer?
00:36:45.03 Well, there is public hope for a panacea, a one hit, a stop cure all.
00:36:51.11 It is not going to be in all likelihood.
00:36:53.29 I have told you that there are varied genetic fingerprints from one tumor to another.
00:37:00.06 Hence there will be no single therapeutic regimen that will deal with all cancers.
00:37:04.11 There will be no single cure for cancer. We will have to for maximum efficacy we will have to personalize the therapy.
00:37:13.05 How do we do this? Well first of all, you have to profile the genome and gene expression in the tumor in question.
00:37:22.10 Identify the potential therapeutic targets.
00:37:27.06 And we may also have to deal with the problem that there are distinctive targets in cancer stem cells.
00:37:33.12 This is essentially an unknown for the moment, but under intense scrutiny.
00:37:41.27 From the genomic data, we'll be able to know whether there is a suitable drug metabolism.
00:37:51.14 Some of the drugs we use, such as tamoxifen for breast cancer,
00:37:53.22 have to undergo a chemical conversion in the cell before they are effective.
00:37:58.23 Genomic data will tell us whether that machinery is present.
00:38:04.02 It will also be able to identify nascent drug resistance of the sort I described in the circuitry, for example.
00:38:11.14 And all of this will allow us to tailor the therapy appropriately and in all likelihood, it will always have to be combination therapy.
00:38:23.16 And I will approach that also in my third chapter.
00:38:27.04 But let me dramatize this with a beginning. And that involves the treatment of non-small cell lung cancer,
00:38:34.14 a horrendous ailment and almost inevitably lethal.
00:38:42.14 It was some years ago discovered that there was a switch, a proto-oncogene protein product,
00:38:52.11 on the surface of lung cancer that is hyperactive. A gain of function. The so called EGF receptor.
00:38:58.18 Drugs to attack this receptor were developed. Their trade names are Iressa and Tarceva.
00:39:09.08 And these are chemical inhibitors of that switch.
00:39:11.15 In the first clinical trials of these inhibitors, there was no prolongation of life.
00:39:16.01 They appeared to have failed. However, in occasional patients, there were remarkable responses.
00:39:23.03 This image shows one patient, whose whole entire left lung is just full of cancer.
00:39:32.26 Six weeks after initiation of treatment with Iressa, the tumor had regressed dramatically.
00:39:40.16 It eventually recurred, but this was a very promising response.
00:39:45.00 But it was limited to only a few. Eventually we learned that it is limited to about 10% of all non-small cell carcinomas of the lung.
00:39:54.10 And that we can identify those patients because they have telltale mutations in that switch.
00:40:01.12 Telltale genetic changes in the gene that encodes the EGF receptor switch,
00:40:07.06 and those changes indicate a susceptibility, so this is a way that we can screen
00:40:11.01 all of these patients and find those that are going to respond to this drug.
00:40:15.04 So, in miniature, we are personalizing the treatment of lung cancer, at least with this drug.
00:40:24.13 We have to screen for the susceptible mutations.
00:40:28.27 We have to screen RAS because it is downstream, if you recall, of the EGF receptor,
00:40:36.19 and if it's mutant, there is no point in turning this off because that won't work.
00:40:39.11 In fact, the drug labeling now advises not to use this drug if there is a mutation in RAS.
00:40:49.14 So you then use these data to make your therapeutic decisions. This is in miniature personalized therapy in the making.
00:40:57.27 Now what about this immense genetic diversity that I've talked about before. Many malfunctioning genes.
00:41:08.02 Well some are relatively common and shared among different tumors,
00:41:10.06 such as overexpression of MYC, such as mutation in RAS. And as I emphasized or illustrated with the pancreas cancer,
00:41:21.20 there is a limited number of signaling pathways that are affected by mutations in a larger number of genes.
00:41:27.18 And we can focus on the signaling pathways in our thinking, and thereby reduce the complexity of the problem.
00:41:34.27 In other words, we will be able to expand the utility of individual therapeutics beyond what we might have expected
00:41:41.05 when we first recognized that there are many malfunctions in genes in cancer cells.
00:41:46.12 In 2010, Nature magazine polled 1,500 cancer scientists. Actually, medical scientists in general.
00:42:01.27 And they asked the question, "How soon do you expect personalized medicine
00:42:06.19 based on human genetic information to become commonplace?".
00:42:10.03 And if you accept those.. if you sort of include those who said, "It's already here",
00:42:15.17 with those that said within 5-10 years or 10-20 years,
00:42:19.18 you get a large majority of these medical scientists who think that personalized medicine is going to become common place.
00:42:26.20 There is one set of profound pessimists: those who say, "not in my lifetime".
00:42:31.00 and I strongly suspect that those are people in my age group.
00:42:34.26 On March 7th, 1986 the Nobel Laureate Renato Dulbecco published an essay in Science magazine.
00:42:44.05 It was one of the first formal calls to sequence the human genome, and he used cancer to justify his argument.
00:42:52.06 And in his conclusion, he said in essence that attention to DNA may, and this is a quote, "close the chapter" on cancer.
00:43:02.29 Well, we haven't closed the chapter yet, but I hope that what I have told you so far
00:43:08.26 has convinced you that we are turning the pages very rapidly.
00:43:13.00 Thank you for listening.

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.

Videos in this Talk

Part 1: Forging a Genetic Paradigm for Cancer
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad
Part 2: The Cancer Genome: Challenge and Promise
Audience:
- Researcher
- Educators of Adv. Undergrad / Grad
Part 3: The Cancer Genome and Therapeutics
Audience:
- Researcher
- Educators of Adv. Undergrad / Grad

Speaker: J. Michael Bishop

Total Duration: 1:53:02

Recorded: June 2011

Educator Resources for this Talk

All Talks in Human Disease

Talk Overview

Bishop begins his lecture with a historical review of the experiments that resulted in the realization that cancer has a genetic basis. He explains that mutations can cause normal cellular genes known as proto-oncogenes to become oncogenes, analogous to jammed accelerators causing uncontrolled cell division. Alternatively, mutations in tumor suppressor genes are analogous to a failed brake system. An accumulation of both types of mutation leads to the development of cancer.

In part 2 of his lecture, Bishop describes how the sequencing of cancer genomes will advance the study and management of cancer on various fronts, including the discovery of causes, the improvement of early detection, the prediction of outcome and the development of new therapeutics. He stresses the promise of designing therapeutics that can be targeted to those patients most likely to benefit from these drugs.

Bishop expands on this theme in part 3 where he describes experiments to find drugs that exploit vulnerabilities created by cancer genes, utilizing a genetic strategy known as “synthetic lethality.”

Speaker Bio

J. Michael Bishop

Dr. Bishop received his undergraduate degree from Gettysburg College and his M.D. from Harvard Medical School. Harvard provided Bishop with his first research experience and introduced him to the study of animal viruses. Bishop completed his clinical training at Massachusetts General Hospital and pursued a research fellowship at the National Institutes of Health. In 1968,… Continue Reading