Stand Up To Cancer’s (SU2C) mission is to raise funds to accelerate the pace of groundbreaking translational research that can get new therapies to patients quickly and save lives now.
SU2C brings together the best and the brightest researchers and mandates collaboration among the cancer community. By galvanizing the entertainment industry, SU2C has set out to generate awareness, educate the public on cancer prevention and help more people diagnosed with cancer become long-term survivors.
Here we stand, on the verge of unlocking the answers that will finally conquer cancer.
Cancer takes one person every minute. One life in a moment. They are our brothers, our sisters, our fathers and mothers, our husbands and wives, our best friends, our children, ourselves. Every day in America 1500 people die despite the fact that the means to save them are literally within our reach. To wait any longer for someone else to save our lives and the lives of those we love is unforgivable. We must act now.
For the first time in history, we can envision the possibility of stopping cancer in its tracks. Now more than ever, as government funding for cancer research is disappearing from the national agenda, every single one of us affected by cancer must stand up and be heard.
Working with the top experts in cancer research, Stand Up To Cancer is forging a new way to develop breakthroughs that will end cancer. We’re putting together the best and the brightest minds in cancer research, investing in their projects and taking the bureaucratic obstacles out of their way. SU2C’s interdisciplinary Dream Teams of scientists, clinicians, technicians and other experts, are hard at work on solutions to the unique problems that cancer presents. Learn More.
SU2C’s funding is administered by the American Association for Cancer Research, the largest scientific organization in the world focusing on every aspect of high-quality, innovative cancer research. Together with Stand Up To Cancer’s “Blue Ribbon” Scientific Advisory Council, comprised of world-class scientists across several disciplines and patient advocates, the most promising projects are identified, mentored, and funded.
We now understand the very biology that drives cancer. With knowledge gained from the mapping of the human genome, we can target the genes and pathways that are involved in turning normal cells into cancerous ones. We are on the brink of possessing a toolbox full of new, advanced therapies just waiting to be adapted to benefit patients. Right before us, so close we can almost touch them, are scientific breakthroughs in the prevention, detection, treatment – and even reversal – of this disease.
This is where the end of cancer begins: when we unite in one movement, unstoppable.
Dennis Slamon: From Newcastle to New Science
by Eli Dansky
Dennis Slamon: From Newcastle to New Science
Dr. Dennis Slamon
At 11:22 a.m., I’m speeding north on Westwood Blvd in a borrowed car trying to make my 11:25 a.m. appointment with Dr. Dennis Slamon. He’s the man behind breast cancer wonder drug Herceptin and a fellow described in various publications as a “zealot” possessing a “murderous resolve.” He is affording me the only free 40 minutes he has this month, squeezing my piddling interview between what I presume to be marathon sessions of lifesaving research. I have to get to UCLA parking lot number 9 by 11:25 to get to his office on time, and although I’ve nearly pounded the gas pedal into the floorboard, I’m not going to come close to making it.
Dennis Slamon is one of the miracle workers at the center of Stand Up To Cancer. His role in the development of Herceptin is widely known and celebrated in philanthropic circles, the cancer community, scientific journals, and what he refers to as “the lay press.” Robert Bazell’s book HER-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer, details Slamon’s often times frustrated but ultimately triumphant journey through the maze of institutional biomedical science out onto the crest of a new wave of targeted exploration and therapy in translational cancer research.
Bazell’s book, “told like a good television script,” according to the New York Times Book Review, is the basis for an upcoming Lifetime movie, with Harry Connick, Jr. playing the leading man: Dennis Slamon. So even if you haven’t heard the story yet, get basic cable and you’ll be able to tune in at some point in the near future to get the scoop. The gist of the story of Herceptin, and in part, Dennis Slamon (POSSIBLE SPOILER ALERT), is this:
Dennis Slamon is from New Castle, PA, just West of Pittsburgh-a region known more for it’s propensity to produce hall hall-of of-fame quarterbacks than world world-class oncologists. But Dennis Slamon wasn’t very good at football. And he drew what seemed to be the only biology teacher at his high school who wasn’t a member of the football team’s coaching staff.
Instead, he got a rookie. “This guy was just starting. He had a fire in his belly, was excited about the subject, and just turned me on to this whole idea of biology and biologic processes. And what it meant, and it’s sort of secrets and the questions of life itself.” By then Slamon already knew the power of medicine, learned as child when he watched as his parents’ faces would flood with relief each time the doctor set foot in the Slamon home on a house call.
So it was probably a good thing that he turned out not to have a golden arm. Nothing against Dan Marino or Joe Montana, but Slamon ended up becoming a doctor and a researcher; his unwavering belief in the power of hard, objective data helped him to join the ranks of those who understood breast cancer not as one single disease but as having identifiable subtypes, various pathways. This in turn led him to help identify a genetic alteration that was part of the pathogenesis of one of the more aggressive forms of breast cancer. His belief in looking at results without pre-conceived notions led him toward the theory that antibodies might reverse or mitigate the effect of the fateful alteration and derail the disease.
It very nearly didn’t happen. Skepticism ran deep, and Slamon and his closest colleagues worked hard to champion the power of the data that they produced. Eventually, relief came in the form of a cash grant from Revlon and the Entertainment Industry Foundation, with efforts spearheaded by Lilly Tartikoff and Lisa Paulsen.
By 1998, Herceptin broke through clinical trials to become one of the first gene-based therapies for cancer. It targeted the HER-2 alteration and helped to change the landscape of cancer research and treatment, transforming one of the most lethal forms of breast cancer into one of the most manageable. Future generations of women can be grateful that Dennis Slamon was a lousy football player, or he might never have jack-hammered his way from New Castle to new science and triumphed over the calcified cognoscenti regulating research.
It’s a good story, made even better by the fact that it’s not fiction.
Finally I discover an entryway onto the open roof of lot number 8. It’s crowded. My friend’s car is a compact and I fit into the only spot available within a half-mile. And then I’m sucked into some sort of déjà vu wormhole:
I’ve been on this roof before. In a car belonging to the very same friend. The last time was in the summer of 2004. My friend’s mother had been through several rounds of intense chemo and was in patient care for the excruciating experience of stem cell therapy in one of the buildings nearby. It was not immediately clear how much longer my friend’s mom would be alive. I would drive my friend in her car so that she could spend time with her mother and have a ride back. After a while, she’d get back in the car, and we would sit for a while more. We didn’t talk much. Maybe a hug. There wasn’t a great deal to say.
My friend’s mother was being treated by, among others, Dr. Dennis Slamon. I did not know Dr. Slamon or even know of him at the time. I simply drove my friend to lot number 8 and waited. Now, four years later, my friend’s mother is in good health and I’m back on this roof, stuck in this car again.
It’s a nice story. Stories do tend to be nice. They allow us to impose a certain degree of order on what seems like chaos.
But sometimes they are dishonest. Yes, I get to show a personal connection to this interview, but in truth I had been a third-rate, fourteenth-hand caregiver, a bench-warmer on an all-star moral support team. I was basically a chauffeur.
Beyond that, I’d met Dennis Slamon before this interview. I knew him only to be a sweet and patient man. Resolute, to be sure, but not a scary guy. If he was a jackhammer, he was a velvet jackhammer. And whatever fears his specter might’ve roused were softened by the fact that he books his own appointments and is congenitally late, in this case by about an hour.
Stories are nice, but sometimes it’s what happens after the end that is infinitely more complex, interesting, and important. Case in point: Slamon didn’t fade to black after Herceptin hit the market. That wasn’t the end of the story. And I finally got out of my friend’s car to go ask him what was next.
Eli Dansky: It seems like a hallmark of the relentlessness of good science is that you have to unlearn what the establishment believes.
Dennis Slamon: If you go with pre-conceived notions, you’re as likely to get burned as you are to be successful. Everybody has pre-conceived notions based on how they were trained and what they learned. But we knew we were on new ground [with Herceptin] and went in with no pre-conceived notions and just asked, “What genes, if any, would be altered? And if they are altered, do they play a role and how would you prove that?” Setting that up as a simple paradigm and following it never let us down.
ED: So how do we get there?
DS: If you sit down with physicians and share with them the pre-clinical data and the early clinical data and keep them informed, you’re able to move quickly. The objective now is to look at all the technology and the ideas we have, knowing that not all of them will work, certainly, even good ideas based in good science with good data. But you’re more likely to hit oil than in a rich field. What we promise everybody we’ve been collaborating with, and what we need to have collaborative teams working around, is a promise to everybody that we’ll be drilling in rich fields.
ED: How do you identify the rich oil fields? How do you identify the good grant proposals?
DS: There are two schools of thought here. One is, just fund the best science and the cream will rise to the top. And there are outstanding, accomplished scientists who believe that’s absolutely the way we should be proceeding. Then there’s a whole separate camp which expects that you’re going to do good science. But the fields are dictated by the realities of the diseases, so you want to drill where there is an absolute need and a potential for a good outcome. Now the way we’re going to find our research is, we’ll identify the problem and agree that we’re going to commonly work on the problem. We’re each going to be assigned a piece of the task, and we’re responsible for that piece of the task in a real-time way – generating data, reviewing data, evaluating and deciding the next steps.
ED: What are the characteristics you’ll identify for the people who are going to constitute that dream team? How do you identify the next Judah Folkman, or Dennis Slamon, for that matter?
DS: Success speaks well in and of itself, so it’s nice to start with people who have a track record. That doesn’t mean there aren’t people out there with incredible ideas who could make a huge impact if they’re brought into something like this. Identifying those people is a lot more difficult than identifying the people that have a track record. but we need to do both, and we need to do both well. The experts working in this area, in general, know all of the senior and junior people working on the problem. They’re involved in the field day in and day out. They attend all the meetings. And they have a network of contacts and colleagues who tell them what’s going on. So rather than information being 18 months or 24 months old, it may be 3 or 4 months old. That’s getting a little closer to real time. There are plenty of successful people out there, but the big challenge is putting together the necessary puzzle pieces of expertise so that you have a picture you can look at. But I think that’s eminently doable.
ED: What changes have happened for you professionally and personally since the development of Herceptin?
DS: You go from the outside to the inside pretty quickly if you’re fortunate enough to be involved in a success like Herceptin. So the fact that it worked so well in metastatic disease, and ultimately in early disease, means that a lot more people believe our ideas than when we started in 1986. The problem is, we needed the help back then. not now. The drug could’ve been and should’ve been available to patients seven years before it was, and if it weren’t for donor money, it would’ve been another five to seven years beyond that. We’re talking about not having Herceptin until maybe 2008 or 2010.
ED: In 2001, on the cover of New York Magazine in an article about you, there was a quote claiming that there would be a global conquering of cancer within the next five to ten years. It doesn’t sound like we’re going to conquer cancer in the next two years or so. What’s different now?
DS: A lot is different. First of all, I was very careful never to make a comment like that, and I was sort of shocked to see it. But that’s what makes a headline. There has been some real progress, but not the kind that the public has come to expect based on what people have told them. There are a couple of things that are important to know. One, there won’t be any silver bullet for cancer, because it isn’t one disease. Even within the same organ system, it’s multiple diseases, depending on what’s broken. That brings us back to the hard work, which is figuring out what’s broken and how to attack it. Whether we could do it in five years is saying a lot. Remember what has to happen. You have to find what’s broken at the molecular level and figure out how to approach that, prove that approaching it makes an impact. Then it has to go to clinical trials. In clinical trials, now you’re doing experimentation in human beings. But you have to execute those trials, and those take a long time to accrue. All we needed was 450 patients with HER-2-positive metastatic breast cancer. You’d think we could put that together in a couple of months, but it took us two years, in part because people didn’t think it would work. Then there’s the observation period where all the data mature. So you did your new therapeutic and you compared it to the best available standard therapeutics, and now you want to know, do the two curves diverge? The company, Genentech, predicted that the data would take four years to mature. I predicted that it would take two years. We were both wrong. In one year, the curve split apart. But still, add that twelve months on the two years it took to accrue and you’re talking about three years. That’s why we need teams that are equipped to do everything, with clinical people who understand how to design and execute clinical trials quickly; people who understand the right questions to ask in the laboratory; people who understand the clinical problems; and people who can recognize and critique the preclinical data. It has to work better than the way we’re doing it now.
ED: So part of it is accelerating the process?
DS: Considerably accelerating the process, yes. There’s often the ultimate reductionism of a question to its finest point in science, without someone backing up a little bit and saying, “How much more will learning about this pathway or the nth degree of this pathway give us?” That doesn’t happen a lot in the camp that believes the best science will float to the top. Ultimate reductionism does get funded, many times. Because you know a lot about this pathway, you write your next grant proposal based on the information you have, and you keep drilling down until you drill through the well and hit dirt again. Is that going to pay off more than going out and finding a new well? We know a lot more about combination therapies than we did five years ago and eons more than we did ten years ago. All of that’s exploitable now. It’s just having the right people thinking about it and being incentivized to think about it. The other problem with cancer research is that in many respects, the incentives are misaligned. If you’re an academic investigator you’re competing with other academic investigators for grant funding and for publications, so you don’t really collaborate. All science is based in some part on some collaborations, but it’s not built on collaboration itself, which is what we’re going to do with Stand Up to Cancer.
ED: You have a wife and two kids. You’re traveling all over the world, you’re curing cancer, caring for patients…how do you strike a balance?
DS: My wife and two kids would probably tell you not well, and there’d be a lot of truth to that. In the early days of the HER-2 story, I lived, slept, drank the science of that whole pathway. That’s the kind of effort we’re going to be looking for in Stand Up to Cancer. That doesn’t mean you can’t have somewhat of a normal life and do other things; you can and should. But we want people who are committed to fixing this problem. The public has been told for years that this effort’s going to make a difference or that effort’s going to make a difference. All of us involved in Stand Up to Cancer believe that this effort’s going to make a difference, but we’re willing to put some benchmarks on this. Will every one of our programs succeed? Of course not. But do we believe that some of them are going to succeed? Yes. And do we believe that the process will be accelerated considerably? Absolutely. So we want people who are committed, who are really going to make that effort, and we want this to be a big part of their lives. It’s not simply a day job.
ED: For you, the next horizon is combination therapy.
DS: It’s combination therapy, and it’s how do we take the lessons we learned from the HER-2 story and apply it to other cancers? Not that it’ll be the HER-2 chain or that it’ll be Herceptin, but it’ll be a separate gene or a separate pathway and another inhibitor of that gene or pathway. And to not make the mistakes we made in terms of the lag time of getting Herceptin to work, but actually reduce that considerably by having the right people at the table.
ED: How much did the Revlon part of development help? Is part of the slowdown in some of these areas a lack of a new infusion of funding?
DS: It’s a huge part of it, and the Revlon funding, as I’ve said in the past, made all the difference in the world. Had we had to depend on federal funding to do this, we’d never have been able to get it done. The process by which grants are submitted, reviewed, approved and funded is incredibly long, and it reduces ideas to lowest common denominator approaches. Approaches that are innovative frequently don’t get funded. They have to be vetted in a study section of a panel of twenty or twenty-five experts, all of whom have their own bias that they bring to the table, understandably. What they do is critique it: what’s wrong with this, as well as what’s right with it. Then they give you the critique back and probably 85% of the time say, “We don’t have funding for this.” So you rewrite it, take another three to six months, send it back, and then it takes another process of about twelve months to get it funded. Then you have to say what you’re going to do. The monies are earmarked in different silos, and to move money out of Silo A and into Silo B if the data tell you to is like an act of Congress. You have to say at the beginning of the grant what you plan on doing over five years, and you can make a good guess, but the technology and the data may change considerably. While they say they allow for that, the reality is, they don’t very easily.
ED: There are going to be certain critics who say the same thing about this. They’ll ask, how can people who are outside of science dictate goals and direct study? Isn’t this some sort of encroachment on the scientific process, to give lay people votes in determining what constitutes progress?
DS: Progress is an objective thing. This isn’t politics. Objective data is going to be the final arbiter of whether the approach worked. There are 4.77 billion dollars a year being spent by the National Cancer Institute on research being done in the traditional way. No one’s saying disassemble that whole system. What we’re saying is, here’s a different model. What right do people have who are outside science? Well, they’re funding the change. That gives them a lot of rights. And there are going to be objective parameters. There’s going to be an advisory group of people of unchallengeable expertise who are going to be looking at what the output is of this science. They’ll apply the quality assurance that the right science is getting done and that it’s consistent with what the funders—the people who are putting in their money or involved in raising money from the public—are looking to do. And they certainly want good science that is credible and meaningful. But they want science that’s likely to impact the disease, so they’re going to direct the funding in that direction. We won’t just fund good basic science and wait for the cream to float to the top. That isn’t the right approach today.
ED: So SU2C supports a different sort of accountability than the NCI?
DS: It’s a different sort of accountability in the sense that the money’s being put up front and reviewed on the back end in terms of progress.
ED: We keep talking about curing cancer, curing cancer. What does curing cancer really mean?
DS: If we turn cancer into a chronic disease that’s manageable, have we cured it? No, not any more than you “cure” hypertension. You treat hypertension, and if you successfully treat hypertension the patient may die, but they’re going to die of something other than hypertension or the diseases related to hypertension. Does that constitute a cure? It constitutes an appropriate control of the disease so that it isn’t what’s life-ending. This sounds like dancing around the question, but it’s not. Cancer is a real consequence of who and what we are biologically and what has to happen inside cells every time they divide. Can we make the perfect cell that will never make a mistake? Possibly, but we don’t have the technology right now. Even when we do it in the laboratory in the best experimental setting, mistakes get made in the copy of genetic material. If you think about the number of cell divisions that need to occur in a human being’s life, it’s astronomical. A mistake only has to be made in one of those cells in the right gene and you’re off to the races. So cancer is a consequence of being alive. Now the issue is, let’s make it not a life-ending disease.
ED: So that’s why the funding, the research, is still so important.
DS: Exactly. It’s critically important. And there are things that we’re going to learn from the research about how to prevent certain alterations. But to say that we’re going to have a preventive strategy that means you’ll never have cancer would be lying to the public.
ED: So what will be happening in five or ten years?
DS: Five or ten years? I’d be disappointed if we didn’t have really meaningful results in three years. There are diseases for which, today, the best available standard therapy is horrific in terms of outcomes. Pancreas cancer, ovarian cancer, lung cancer, some forms of prostate cancer, gastric cancer, some forms of colorectal cancer. We can do a lot better with those diseases than we currently do, and that’s just to name a handful. If we are successful, if we raise enough funds to launch a series of “dream teams” as part of the Stand Up to Cancer initiative, and each of the teams approaches this in a Manhattan-Project-like approach where you have the right people sitting at the table, thinking together, the right kind of teams will make an impact. And there will be incredible cross-fertilization between teams. There will be real communication and real interaction about findings from Team A and how they might apply to Team B. Now, it’s a new approach. I believe it’s a very logical approach. I believe it’s an approach that will work. The proof of the pudding is in the tasting. Let’s get it launched and see what happens in twenty-four and thirty-six months in terms of the outcome and the output of what these teams will be. And everyone’s going to be looking at it. It isn’t going to slip under the radar screen, because there will be enough people saying, “You said there was going to be something different. Where’s the beef?”
ED: So it’s not five to ten years to curing cancer, it’s five to ten years to having discernible impact.
DS: In five to ten years I think for sure we’re going to have a discernible impact. Otherwise we’ll have failed.
ED: So if and when this does work to a tangible degree, do you think that organizations like the NCI will take note? Do you think that this is a game changer? That people will understand that this as a model that should be applied elsewhere?
DS: Yes. I certainly think so, and I hope so. That doesn’t mean that the NCI approach is ever going to go away. Nor should it go away. The idea of funding the best science and hoping that the cream will float to the top is not a bad idea. But putting all your eggs in that basket is probably a bad idea. When we proposed Stand Up to Cancer and the approach we’re taking, not everybody was enthusiastic about it. There were many people from the orthodox scientific community who said you can’t use this approach, it’ll never pass the smell test, and my answer was, what passes the smell test is what works. And what the public wants, I believe, is what works. How we get there, as long as we do everything right scientifically, is less relevant to the public and more relative to the scientific bureaucracy. So I absolutely believe that this approach will work and that some federal money will get allocated to this kind of approach. Foundations and donor money are already being used this way, in large part, so they know something, obviously, that other people don’t. And I can only go back to my own experience, my own story. If we hadn’t had Revlon, the Entertainment Industry Foundation, Lilly Tartikoff and the Los Angeles community get behind us, I can assure you with a great deal of certainty that we’d never have been able to accomplish what we accomplished, and certainly not in the time we accomplished it. And that’s what we want to do in Stand Up to Cancer.
BREAST CANCER DREAM TEAM PROGRESS UPDATE
An Integrated Approach to Targeting Breast Cancer Molecular Subtypes and Their Resistance Phenotypes
Funding: $17.5 million
Leader: Dennis J. Slamon, M.D., Ph.D., University of California Los Angeles, Jonsson Comprehensive Cancer Center
Fast Facts on Breast Cancer:
There are nearly 3 million women living in the United States with a history of invasive breast cancer.
It is estimated that 226,870 new cases will be diagnosed in 2012 in the United States.
Because of improved treatments and detection, the overall 5-year relative survival rate for female breast cancer patients has increased from about 75% between 1975 to 1977 to 90% for 2001 through 2007.
During the past several years, researchers have come to understand that breast cancer is not a single disease but rather a spectrum of conditions that vary in their biology and response to treatment. Understanding breast cancer’s molecular diversity has been the driving force leading to the development of new treatments for this disease. Researchers are rapidly moving beyond the “one size fits all” approach into a new era in which breast cancer treatments will be tailored to the biology of the tumor. This project will address the most significant issues related to the three major subtypes of breast cancer — ER positive, HER2 positive, and triple negative (simultaneously ER negative, PR negative and HER2 negative) and will use that information to develop innovative, less toxic therapies with the potential to improve the treatment outcomes for women with this disease.
One of the primary obstacles to effective cancer treatment is the ability of cancer cells to become resistant to treatments that are initially effective. Over a period of time, cancer cells are able to develop ways of “outsmarting” the drugs and agents designed to kill them, a phenomenon known as drug resistance. This Dream Team will study the driving mechanisms that lead to drug resistance in the three major breast cancer subtypes. Understanding resistance opens the door to developing innovative therapeutic agents that overcome this critical problem.
Another area of interest is in the role that cancer stem cells play in resistance. Researchers now realize that the growth and spread of many cancers, including breast cancers, are influenced by the existence of these stem cells which are often highly resistant to otherwise effective treatments. The Team will study the ways in which this unique malignant cell population operates across the three major breast cancer subtypes, knowledge that could be important to the developing new treatments for breast as well as other major cancers.
One critical component of this study will be to bring together the vast amount of information that exists about breast cancer into an integrated data base that will form a “discovery platform”, or basis for identifying and validating new drug combinations and targets that can be pursued in clinical trials. The Team expects that these efforts will lead to significantly improved therapies for breast cancer, especially the most difficult to treat forms, within the three-year period.
6 month milestones
In the first six months, the Dream Team focused on implementing a variety of integrated approaches to identify novel targets and mechanisms that may lead to later stage clinical trials opportunities. These so-called “discovery” studies included the development of (1) techniques that can measure drug impacts on single cells; (2) xenografts model from human tissues; and (3) 2D and 3D assays to examine the interaction of tumor cells with their environment in response to drug treatment. In addition, they completed the construction of a library of “short hairpin RNAs” (shRNAs) that will be used to systematically inactivate genes in order to identify potential new targets for therapy. The Dream Team also established a state-of-the-art bioinformatics and data analysis platform aimed at maximizing multi-site communication and collaboration.
On the clinical side, the Dream Team made progress in the validation of new drug treatments to circumvent anti-hormone resistance in ER positive breast cancers. Potential candidates include VEGFR2 inhibitors, buthionine sulfoximine (BSO), c-SRC inhibitors, as well as PI3K inhibitors. They also showed that cells expressing the gene ZNF217 were more resistant to chemotherapy, suggesting that this gene could be good target for new therapies. For HER2 positive breast cancers, the Dream Team focused on the development and characterization of tumor cell lines model that demonstrate either acquired or de novo resistance to two different drugs: lapatinib or trastuzamab. Analyses of these preclinical data are ongoing, and potential targets will be selected for in vivo validation studies. The Dream Team also reported an interesting correlation between a deficiency in the product of the gene RAD51, and strong response to chemotherapy for triple negative breast cancers. Finally, the Dream Team developed a method to identify cancer stem cells (CSCs) in breast cancer cell lines. They reported data indicating that Herceptin may target those CSCs when used in combination with a chemotherapeutic agent.
12 month milestones
In this period, the Dream Team continued their preclinical studies to determine how resistance arises in each subtype of breast cancer, and the best drugs that can be employed to overcome this resistance. Some of the planned targets, such as c-SRC, failed to be confirmed as drug resistance mechanisms in ER positive breast cancers. They began planning clinical trials to test other potential targets, such as VEGFR2, or cdk-4/6. Positive results for HER2 positive breast cancers were reported as the Team identified the loss of PTEN, combined with mutations in the PI3K pathway, as a potential mechanism of resistance. The Dream Team also reported the results of clinical trials demonstrating that the drugs Lapatinib and Trastuzumab have a synergistic effect when used in combination.
The “discovery group” within the Dream Team assembled and classified several hundred breast cancer cell lines, and the bioinformatics Team began working to extract novel information from this large dataset. Progress on 3D models of breast cancer cells was also reported. There, the Team has made the interesting observation that those cells in the outer layer in 3D cultures seem to be protected from treatment with PI3K inhibitors. Their next step was to explore the molecular mechanism responsible for this phenomenon.
18 month milestones
At the half-way point, the Dream Team translated some of their preclinical studies into the clinic; multiple clinical trials were started for each of the different types of breast cancers, and more were still in the planning phase. The Dream Team also reported extensive preclinical evaluation of T-DM1, a HER2-targeted agent which appears to be effective against HER positive breast cancer cell lines, even when Trastuzumab and/or Lapatinib failed. The Dream Team reported on their continued effort to discover new targets and agents for triple negative breast cancers, particularly those targeting DNA repair pathways which tend to be crippled in many triple negative breast cancers. Of note, the product of the gene PTPN12 seems to act as a tumor suppressor by interfering with the activity of a number of receptor tyrosine kinases, and appears to be mutated in 5% of triple negative breast cancers and absent from as many as 60%. This finding suggests that Sunitinib (or Crizotinib) and Lapatinib might have beneficial activity against these tumors.
The Team also reported follow-up studies based on their observation that cells located in the outer layer of 3D cultures were activating a variety of survival signaling pathways leading to treatment resistance. They confirmed that this phenomenon was also evident for model breast cancer cells propagated in vivo, and for breast cancer tissue specimens in women treated with anti-breast cancer agents. These preclinical experiments have nominated combinations of targeted drugs and the BCL-2 antagonist ABT-737 for future clinical trials.
24 month milestones
At the two year mark, the Dream Team had made significant progress at integrating “omics” data from various sources. They launched the SU2C Cancer Genomics Browser that contains both SU2C-generated and other published data from hundreds of cell lines. Most of the data from other platforms, such as those generated by other SU2C Dream Teams, or non SU2C-affiliated laboratories, can be easily ported to the SU2C Cancer Genomics Browser and added to the collection.
The Team also continued to make progress in defining both prognostic and predictive genomic signatures. Notably, their preclinical work using cell lines and animal models led to the identification of genes potentially involved in the development of resistance to hormone therapy. These included MEK1/2, mTOR, B1-intergrin, FAK, c-Src, and PTEN. From these efforts, a new clinical trial was planned to test the effect of specific inhibitors of MEK1/2, mTOR, B1-intergrin, and FAK.
The studies on the effect of the microenvironment on drug sensitivity continued moving forward with linkages to the clinical research components of the Team. Specifically, the up-regulation of Bcl-2 in the microenvironment suggested that it might create an opportunity for combination therapy using a Bcl-2 antagonist. The Dream Team also reported plans to move forward with a PARP inhibitor that was shown to be 100-fold more potent than other agents currently in the clinic; a phase I trial was initiated. The Dream Team plans to take the drug into trials for ER positive and HER2 positive breast cancers.
30 month milestones
By the end of this period, the Dream Team has initiated or joined a significant portfolio of breast cancer clinical trials, clearly contributing to improving breast cancer outcomes. Of note are attempts to improve treatment of HER2 positive breast cancer using the new drug T-DM1. A neoadjuvant trial of the conjugate given in alone and in various combinations (including with Pertuzumab and no cytotoxic chemotherapy) should discern the magnitude of the treatment effect. Another promising study involves the new PARP inhibitor BMN-673 that appears to be so much more potent that the other existing PARP inhibitors.
The Dream Team reported a fascinating opportunity for triple negative breast cancers with PTPN12, which is lost in 65-70% of triple negative breast cancer cases, exhibits tumor suppressor actions when reintroduced into breast cancer cells devoid of the enzyme. The Team is now exploring the possibility of a clinical trial with sunitinib and crizotinib, two drugs that are FDA-approved and marketed by Pfizer; contacts with the oncology development group at Pfizer have been initiated.
Also, several key preclinical concepts generated by the Team are advancing to clinical assessment. For instance, the Team has continued its effort to tease apart mechanisms of adaptive resistance to targeted drugs exhibited by breast cancer cells in the context of 3D cultures. They identified the gene Bcl-2 as a critical component of treatment resistance. The Dream Team reported a number of clinical observations that provide a strong rationale for the use of Bcl-2 antagonists in combination with HER2 treatment.
The various screens using shRNA libraries developed by the Dream Team since the inception of the project appear to have the potential to discriminate adaptive versus selected resistance mechanisms. Several screens have been completed; others are in the pipeline. Finally, the combined cell line screening studies and enhanced bioinformatics efforts have begun to produce genomic signatures related to drug sensitivity and resistance as well as prognosis for different breast cancer types and are suggesting ways to link drugs to treatment of cancers with specific genomic signatures. The Team intends to disseminate data and analysis tools broadly to other SU2C-funded Dream Teams and eventually the broader scientific community.
36 month milestones
During this last period of the initial grant term, the Dream Team has continued to make significant progress in all studies initiated. They have completed some, and will pursue others through monies leveraged from other sources. The Team has continued to develop the work demonstrating the role of Bcl-2 in breast cancer cell survival, including the possible use of Bcl-2 inhibitors (e.g., ABT-737) in breast cancer treatment. They have also continued their efforts to develop the new PARP inhibitor (BMN-763) for possible use in breast cancer patients. Supplemental funding of $1.0 million was approved to allow a subset of the original Dream Team to translate these two promising avenues of research into the clinic.
In this period, the Team reports the development of a robust system to assess genomic aberrations and drug responses in cells grown on cell spot microarrays (CSMA). Numerous studies are now underway using this system. Analyses of the 32 completed genome-wide RNAi screens using the third generation shRNA library (74,304 shRNAs targeting > 19,000 genes) have also continued; data has been analyzed for 16 of the 32 so far. For the sequencing, the Team has transitioned to high capacity platforms and developed a new protocol that will allow completion of sequencing in the first half of 2013. The Team has continued to develop and improve computational methods to analyze and visualize the wealth of data generated by this and other SU2C-funded Dream Teams. These include: PARADIGM, PARADIGM- SHIFT, Differential Pathway Signature Correlation (DiPSC), and the SU2C Cancer Genome Browser.
The Haussler group is requesting further support from SU2C to support the UCSC Cancer Genomics Browser as a common resource to service all SU2C teams. The browser will be a platform for data sharing, and provides a coherent mechanism for teams to release data to the public. The browser will serve as a living data portal to view, access and retrieve past and current SU2C team data. As each team concludes their projects, the datasets generated under their awards could be made available at a common site that provides storage and retrieval, dynamic access and online exploration. If funded, The Haussler lab would work with all the teams to process and host their data sets.
42 month milestones
Following the end of their 3-year grant term, the Slamon, Brugge, and Ashworth laboratories have continued to work in two areas.
The first project is a collaboration between the Brugge and Slamon laboratories that expands upon previous work that demonstrated the role of Bcl-2 in breast cancer cell survival and suggested a possible use of Bcl-2 inhibitors (e.g., ABT-737) in breast cancer treatment. Their initial in vivo analyses suggest that ABT-737 does indeed sensitize a subset of the protected cells. However, the drug combination, ABT-737 plus an inhibitor of HER2 (lapatinib), also appeared to induce unknown toxic side effects on the mice. The Team is currently optimizing the treatment regimen to alleviate these issues. In further studies of xenografted tumor cell lines, the Team discovered that BCL2 expression is not upregulated in invasive lesions lacking contact with the basement membrane, which suggests a role for the microenvironment in the upregulation of BCL2. The group will continue these analyses, as well as the analysis of clinical samples from the Slamon-Hurvitz B07 clinical trial of HER2-targeted therapies -/+ chemotherapy (carboplatin + docetaxel). The latter seem to confirm that there is elevation of BCL2 in intraductal tumor cells in patients’ samples from this trial.
The second project focuses on triple negative breast cancer, and is a collaboration between the Ashworth and Slamon laboratories. These studies also build on preclinical work performed during the Dream Team’s three-year grant term. The group has continued their collaboration with Biomarin, the company that developed BMN-673, a new and extremely potent PARP inhibitor the drug, to determine if the increased potency exhibited by BMN673 would translate into an improved therapeutic window. The results are highly encouraging but still very preliminary. During this period, the Team has also continued their studies of the protein ARID1A, whose reduced expression is strongly associated with advanced clinical stage and poor prognosis. They have obtained evidence that dasatinib, and inhibitor of certain tyrosine kinases (e.g., BCR/Abl and Src), could be used to treat patients with tumors harboring a mutation in the ARID1A gene.
48 month milestones
The Brugge and Slamon laboratories have now completed their analyses of patient samples from the TRIO-B07 clinical trial. The evaluation of the results is ongoing, but seems to confirm that elevation of BCL2 in intraductal tumor cells correlates with poor response to treatment.
The Dream Team is still optimizing the dosage regimen for combinatorial therapies to alleviate toxic side effects observed in their mouse models.
The Ashworth and Slamon laboratories have continued their collaboration to determine if the increased potency exhibited by the PARP inhibitor, BMN673, would translate into an improved therapeutic window. They have now obtained strong evidence, in various mouse models, that BMN673 is highly potent in inhibiting tumor cells with mutation in genes like PTEN, BRCA1 or BRCA2. Using patient- derived tumor xenograft models, they established a treatment regimen that has subsequently been validated in human in a Phase 1 clinical trial.
Fast Facts on Prevention Tips:
Exercising four or more hours a week may lower breast cancer risk. The effect of exercise on reducing risks may be greatest in premenopausal women of normal or low weight. Please exercise safely.
Having one first-degree relative (mother or sister) with breast cancer doubles the risk of developing the disease. Please consult your healthcare provider to assess your risks and decide the best course of action.
Drinking alcohol has been shown to increase the risk of breast cancer. The risk rises with the amount of alcohol consumed.
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