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On the Trail of a Gene Mutation

  Dr. Joanne B. Weidhaas
 

Dr. Joanne B. Weidhaas, Vice Chair,
Division of Molecular and Cellular Oncology, Department of Radiation Oncology
Photos: Ann Johansson

After Joanne B. Weidhaas, MD, PhD, co-discovered a relatively common but functional gene variant, she began a quest to understand what the mutation does, whom it affects and how to best control it.

Cancer, radiation oncology, genetics and affordable healthcare are all areas of interest for Joanne B. Weidhaas, MD, PhD, who joined the David Geffen School of Medicine at UCLA last year as vice chair of the Division of Molecular and Cellular Oncology in the Department of Radiation Oncology. Dr. Weidhaas is a physician-scientist, the co-founder of a biotech company and founder of a nonprofit research organization. Much of her work centers on a gene mutation known as the KRAS-variant, which she co-discovered in 2006 and which is found in as many as 25 percent of people in America with cancer and among roughly 1-in-20 people within the general population. It is implicated in several types of cancers and alters patients’ responses to treatment. U Magazine contributor Shari Roan spoke with Dr. Weidhaas about her journey as a doctor, researcher and businesswoman and her views on the use of genetic testing for cancer prevention and treatment.

How significant a role do genes play in cancer?
Dr. Joanne B. Weidhaas: They are huge. During my residency, I realized pretty quickly that much more cancer was inherited from your family than we’ve been able to account for. Unfortunately, the focus of genetics has really been on what’s broken in your tumor in order to try to target it for treatment. But we know now that in many, many cases, there is a lot that we can learn from your own “personal” genetics, both to help figure out who is at risk for cancer, as well as to define the best treatments for an individual’s cancer.

Why is the KRAS-variant mutation so important?
Dr. Weidhaas: This is one of the first known relatively common genetic differences between people that is functional, and it could help us identify a group of people who have higher cancer risk and have a unique response to cancer treatment. The only other genetic differences that predict cancer risk and that can be targeted by specific drugs are BRCA mutations, which are incredibly rare, occurring in about one-in-400 people. We also have found that there really is an opportunity for minimizing cancer risk for individuals with the KRAS-variant, as lifestyle actually affects this type of mutation. This could be important for a large group of people, as up to 6 percent of the entire population has this genetic difference, and 25 percent of cancer patients have it.

How did the discovery of the KRAS gene mutation come about?
Dr. Weidhaas: This only came about through a fabulous collaboration bringing together fundamental new science and a deep understanding of cancer. My collaborator at Yale, Dr. Frank Slack, had been part of the team that discovered microRNAs, specifically let-7, and had been studying how let-7 interacted with KRAS, a really important cancer gene. I had been studying KRAS for many years, and we joined forces to understand how miscommunication between let-7 and KRAS could lead to cancer. I literally found — with help from a pathologist — a number of tumor samples, from lung-cancer patients, stored in one of the Yale tissue-bank freezers, and our group then did a “hypothesis-driven investigation” of the areas where let-7 and KRAS communicate. This was not big data, but instead two people with different areas of expertise really putting their heads together to answer an important question. This is how we found the KRAS-variant and learned that this mutation interrupts the communication between the let-7 microRNA family and KRAS, leading to many changes for the people who have it.

What was so unique about the KRAS-variant mutation in lung-cancer patients?
Dr. Weidhaas: We found that about 20 percent of lung-cancer patients have the KRAS-variant, and in the first study, we saw that many of them would later go on to get a second cancer. We also saw that women who had the variant were much more likely to get lung cancer compared to men with the variant. This was the beginning of our mission to really uncover how individuals with the KRAS-variant, especially women, were different.

In what other types of cancers do you tend to see patients with the KRAS-variant mutation?
Dr. Weidhaas: We see the KRAS-variant most commonly in women with cancer — so breast-, ovarian- and lung-cancer patients. But we do see both women and men with cancer of all types with the KRAS-variant.

You recently identified a link between hormone-replacement therapy and breast cancer in patients with the KRAS-variant. What is the significance of that finding?
Dr. Weidhaas: We have a paper that was recently published suggesting that stopping estrogen abruptly appears to increase breast cancer risk in women with the KRAS-variant. This was really an exciting finding for me because I have seen how much we, as doctors, have changed our opinion on estrogen management over the past 15 years. First, it was great for everyone, then it was bad for everyone, and now we know it is good for some, but no one knows whom. Identifying women with the KRAS-variant as a group of women where estrogen management really matters confirms how important it is to respect estrogen and what an incredibly powerful chemical it is. We have a lot of ongoing work on this subject.

How has the focus on the development of the KRAS-variant differed from the focus on other gene mutations related to cancer?
Dr. Weidhaas: We really tried to approach the KRAS-variant keeping the patient in mind. We’ve done studies to understand how the KRAS-variant works. We’ve approached it as scientists and doctors and not as pure business people. We’ve collaborated with people around the world to find meaningful answers. We made a conscious decision early on to make every effort to define all the different ways the KRAS-variant could have an impact on human health, and because of that, through research, we know an incredible amount about the biology of the KRAS-variant. We are still doing research and trying to stir up discussions within the prevention and cancer fields to help define the best and safest management for individuals with the KRAS-variant. We’re not trying to force an answer to that question.

You founded a company for KRAS-variantmutation testing and then went to business school at Stanford. What led you to go to business school?
Dr. Weidhaas: We founded MiraDx because we knew that the KRAS-variant would be important in human health. But as a physician-scientist, I definitely didn’t have a business background. With the support of my wonderful husband, we uprooted our family from the East Coast to come to Stanford Business School to help me define the best path forward to build a company that was sustainable but, most important, patient-centric. From that experience, we also started a nonprofit to continue our research mission and find answers. The nonprofit, MiraKind, is the heart of what we’re doing. It’s a research institute that allows individuals to directly participate in studies to define answers that can directly affect them.

Among healthy people, who should be screened for the KRAS mutation?
Dr. Weidhaas: I really believe that, ultimately, the test is useful information for all women. However, we need to be very careful with how the information is communicated and at what point in a woman’s life it is considered most useful.

Among cancer patients, who should get KRAS testing?
Dr. Weidhaas: We have clear data that certain medicines work well and others not at all for cancer patients with the KRAS-variant. This is a program that we continue to develop to come up with creative ways to bring the findings to people.

Do we need better guidelines on genetic testing for cancer risk in general?
Dr. Weidhaas: My view is prevention always is best. While a cancer drug can work great, nothing is better than avoiding cancer altogether, so knowing that someone is genetically at increased risk is important. The problem is that our healthcare system is not set up that way; insurance doesn’t really pay for prevention. So that is our challenge. In the future, we should do genetic testing to figure out who really should be screened for cancer, because we can’t screen everyone, and we shouldn’t, but we do need to screen those at higher risk.

You want to make targeted genetic testing affordable, correct?
Dr. Weidhaas: I think the future of genetic testing, particularly for people without disease, is for people to take ownership of this personal information and be willing to pay a reasonable price for it, without depending on insurance coverage. Simply put, this information is much more important to you than it will ever be to your insurance carrier. For those who cannot afford it, we hope that foundations like MiraKind will provide the testing on a discounted or free basis.

What is the future of genetic testing, including whole-genome testing, to determine both cancer risk and response to treatment?
Dr. Weidhaas: It’s getting less expensive to do whole-genome sequencing, and that is a positive thing. That said, there has been an enormous amount of money spent on new technologies, and not a whole lot has come out of it. The best new technology without incorporating an understanding of biology is not, in my opinion, likely to lead to big advances in human health. I think we need to focus testing on what’s meaningful and not just get more information because we can.

Now that you are at UCLA, what is the focus of your research?
Dr. Weidhaas: One of the reasons I came to UCLA is to develop a personalized-genomics program for radiation therapy, which I refer to as radiogenomics. We have had some success in personalized medicine using targeted chemotherapy, but we have not done this for radiation therapy. We need to start to personalize it — there is a pressing need to do so. UCLA is optimally set up to do this because here we have terrific clinical data that are being collected in an ongoing way, and it was very easy to start getting genetic samples to merge with this. It’s an exciting undertaking, and it has great support from the department and from the participating patients.

“Estrogen Withdrawal, Increased Breast Cancer Risk and the KRAS-variant,” Cell Cycle, May 11, 2015

Earlier in his life, John C. Mazziotta, MD (RES ’81, FEL ’83), PhD, thought about becoming an architect. With a keen eye for form and function, he would apply his skills to the construction of great buildings. Instead, he chose medicine. Now, after more than 30 years at UCLA — where he has been chair of the Department of Neurology, an associate vice chancellor and executive vice dean, and founding director of the Ahmanson-Lovelace Brain Mapping Center — that style of visual thinking will serve him well in his new roles as vice chancellor for UCLA Health Sciences, dean of the David Geffen School of Medicine at UCLA and CEO of UCLA Health. “There are many parallels between architecture and construction and what we do in medicine and the building of a large medical enterprise,” he says. “And, on a purely administrative level, it doesn’t hurt to have some interest in the subject when you are managing millions of square feet of space and renovating a giant building. Having some interest and experience about how these things work is helpful.” Dr. Mazziotta spoke with U Magazine editor David Greenwald about his new roles and his aspirations for the future of the medical school and health system.

As vice chancellor, dean and CEO, you bridge the worlds of the health system and the medical school. How does each of these worlds inform the other?

Dr. John C. Mazziotta: We have one health organization with two big pieces to it: the health system — the hospitals, the clinics, the doctors and nurses and support staff — and the David Geffen School of Medicine at UCLA. The overarching goal of our medical enterprise is its academic purpose — to excel in research and education. To achieve that, we have to be excellent in all areas. We have to be good at the business of medicine — which has become very complicated over the years — in order to have the opportunities for our students, residents and fellows to have a place to train and to have the financial resources to support research and education. We have a responsibility to the citizens of California and Los Angeles, and to society in general, to produce great scientists and doctors and to develop new and effective treatments and, ultimately, cures for disorders of the human condition. Having one person over these arenas helps to ensure the correct balance and laser focus on our academic mission.

What are the opportunities that this presents?

Dr. Mazziotta: When there is a significant change in leadership, involving more than one individual, as is the case now, there is the opportunity to actually review the governance structure of the organization. It is like starting with a clean slate and makes it possible to ask questions such as, “What are the functions we actually need?” and “How do we change the structure to become more effective, efficient and responsive?” It has been, perhaps, 20 years since the overall structure of this organization has been examined, so this is a great opportunity for us to do just that. Chancellor Gene Block has assembled a task force to do exactly that, to look at the governance of the health sciences — not just medicine, but all of the health-science schools — as well as the health system. Change is healthy. It is good to have a chance to engage in self-examination and to think about whether or not we have the ideal approach to the governance structure. It is an exciting opportunity. When Thomas Watson Jr. was the CEO of IBM, he said, in the early 1960s, “I believe that if an organization is to meet the challenges of a changing world, it must be prepared to change everything about itself, except its beliefs.” Like the business-machine and early computer industry of Watson’s time, today’s healthcare environment is undergoing dramatic change, and we need to be prepared to adapt without changing the beliefs that are embedded in our core academic missions.

As you assume your new roles, what are your priorities?

Dr. Mazziotta: I’ve traveled all around the world in my career. What do you think is the first thing people mention when they identify someone as being from UCLA? Basketball. That is the one thing you will find that UCLA is known for pretty much anywhere in the world. So that makes me think we can work toward establishing a John Wooden-like dynasty of excellence in health science. In the future, people will say “basketball and medicine.” I believe that is possible. We should strive to be the best in the world at the things we choose to do. We can’t be the best in the world at everything, but, when we pick a subset of those things, we should pick the ones in which we can be the very best. When I first became chair in neurology, the faculty said, “We want to be the best in research.” So we constructed a strategic plan, and we executed the plan down to the most minute detail, and in a short period of time, we were No. 1 in the United States in research funding, and we maintained that distinction for nine consecutive years. Five years ago, the faculty wanted to enhance philanthropy. So we developed an approach and implemented it. Last year, neurology raised more philanthropic dollars than any other department on campus.

The strategy worked well for the department. How would that be applied to achieve similar results on a broader scale?

Dr. Mazziotta: We have a strategic plan for the health system and the medical school, and we will continue to implement the plan, particularly in this time of change. We have great teams in place. Our previous leadership left their legacy in the people who served with them. Our people are ready and, without question, able to execute on these plans to enhance our momentum. That is in the short term. For the long term, we want to be the best in the world in specific areas. For the health system, that means being the role model nationally for enabling an academic medical center to truly deliver patient-centered and integrated care to heal humankind one patient at a time. Instead of being compartmentalized into the “department of the eyeball” and the “department of the nervous system,” where the patient must go from one center to another to receive care, we want to create a system where whatever is needed for the patient surrounds him or her in a cost-effective way. No one has done this in academic medicine. The first one to do it will be the role model for the rest of the country, perhaps for the rest of the world. I want UCLA to be that role model. For the school of medicine, we have identified six research themes in which we want to particularly invest and excel. These areas are non-departmental; they are thematic: cancer; immunology; cardiovascular medicine; neuroscience; metabolism; and degeneration, regeneration and repair. In education, through the enormous generosity of David Geffen and the David Geffen Medical Scholarships, we attract the brightest medical-student applicants, and they can attend UCLA without financial burdens. Dr. Clarence H. Braddock, our vice dean for education and chief medical-education officer, will continue to restructure our pre- and post-graduate medical training. Our new Bioscience Graduate Program ensures optimal education for biomedical scientists. With this clear focus, we will be the future of medicine.

What are some examples of how we already excel in the research areas you have identified?

Dr. Mazziotta: There are many, but let’s highlight one: cancer. Within this past year, three new cancer therapies developed at UCLA have been approved by the U.S. Food and Drug Administration. These therapies are the results of years of investigation led by UCLA researchers, and they offer new alternatives for patients with such cancers as melanoma, non-small-cell lung cancer and estrogen-receptor-positive breast cancer. (See “Turning the Tables,” page 26.) I will highlight one other. In the area of cardiovascular research, our scientists have developed an entirely novel therapeutic approach to fighting vascular plaques — a synthetic protein that is designed to mimic HDL, or “good cholesterol.” This therapy was brought to clinical trial, which resulted a licensing agreement. These are just a couple of examples of the incredible work that is being done at UCLA, the kind of work we want to support and advance even further.

  John C. Mazziotta, MD, PhD takes the helm of UCLA’s medical enterprise  
  Photo: Ian White
We are speaking in your office in the Center for the Health Sciences building, what used to be the old UCLA Medical Center, before the hospital moved to Ronald Reagan UCLA Medical Center. This building has been undergoing a significant transformation. What is happening here?

Dr. Mazziotta: This has been the single-largest renovation project in the history of the University of California, to transform this building into a space for high-intensity-research laboratories. The building has been seismically retrofitted, and now it is being reassembled into clean, open spaces with all-new infrastructure. That phase is scheduled to be completed this June. The final phase will be outfitting the labs, which will be customized to serve different purposes — there will be a floor devoted to each of the six research themes that I previously mentioned. That phase will take another six-to-nine months. Other areas will be used to facilitate different kinds of partnerships — public-private partnerships. We will partner with established organizations and businesses in the private sector to do joint research projects, possibly startup companies. As a university, we’re not a bottom-line organization that focuses only on the money that can be made from these opportunities. Rather, we will pursue intellectual property that can lead to societal benefit, even if it isn’t necessarily a financial winner. That’s going to be a very exciting activity.

What have been the most pivotal moments in your life and career leading up to where you are now?

Dr. Mazziotta: I will go back to my childhood, growing up outside of New York City. My father was an individual who was a pretty structured guy. And whenever I would want something, for example, “Dad, I need a car,” his response was to say, “If you want it bad enough, you’ll figure out how to get it.” So, I would come up with a proposal for how to accomplish what I wanted. He would look at it and say, “You’re getting there. You’ll figure it out.” I would have to be creative, knowing that I had a certain amount of money, and maybe I could borrow some from him and perhaps earn extra money doing more jobs. And he would just say, “You’ll figure it out.” That taught me perseverance and to try to think in a variety of different ways to solve a problem. Rather than to just say I want something and get it, I had to come at it from five or six different directions. Eventually, I knew, some combination of those different approaches would be successful. There’s a proverb that I like: “In the struggle between the river and the rock, the river always wins, not through strength, but through perseverance.” That was a good lesson for me to learn. I believe every problem has a solution.

 

 





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