Research Q&A: Dr. Tim Bullock

BullockIn the latest blog post, we chatted with the University of Virginia’s Tim Bullock, Ph.D., a tumor immunologist in the Pathology Department and MRA-funded investigator. Read on to learn what he has to say about melanoma research and prevention efforts.

Can you explain a bit about your research?

I received an Academic Industry Award from MRA, which was a fantastic segue from the more basic/translational tumor immunology we were well-versed in to getting me more exposed to (and appreciative of) the challenges and opportunities that are presented in clinical tumor immunology. It really helped establish our lab in truly translational research.

The grant led us to begin to understand what goes wrong with T cells in patients with melanoma. We’re conducting research now to look at the transcriptional basis of what’s wrong with tumor infiltrating T cells, looking at the genes that control T cell function, and what signals from the tumor microenvironment influence the expression of these genes. We’re trying to understand if we can identify critical differences in genes in T cells that are failing to control tumors compared to those that either control tumors or infections, so that once we understand them, they could either be biomarkers for effective anti PD-1 therapies or provide opportunities to complement anti-PD1 therapy.

We take a collaborative approach with investigators at UVA, so I value working with clinicians and researchers from a variety of backgrounds. We work in teams to look at how targeted therapies and more traditional chemotherapies affect newer immunotherapies to understand the cumulative effects of these treatments. The hope is that this will help us identifying rational combinations of tumor-targeting therapies that will work well with immunotherapies.

Can you explain how your research is helping making a difference for patients?

Our most recent funding, as an Established Investigator, uses a fairly novel technology called focused ultrasound. It’s a way of delivering acoustic energy, as opposed to the more traditional radiation, into tumors, with the intent of causing damage to the tumor that the immune system can respond to. It’s in early stages yet, so we need to understand how innate and adaptive immunity, and the tumor, respond to this type of “insult.” This is focusing specifically on melanoma brain metastases as there is such an unmet need in this patient population. We’re trying to answer important questions, like:

  • Can we use it to treat brain metastases (similarly to how it’s being used to treat Essential Tremors and patients with Parkinson’s Disease)?
  • How does the brain’s immune components respond?
  • Can we integrate this technology with immunotherapy?

There are a lot of unanswered questions, but our goal is to get it to patients as soon as possible. We’re integrating our work with biomedical engineers and have funded this collaboratively because many people see the potential for focused ultrasound. If efficacy is the same as radiation, this technology could provide a new approach meet the challenge of these poorly served patients.

How has MRA funding helped your work?

Each stage of my career, MRA has been there. The Young Investigator Award helped get my lab up and running. And the continued support through Academic-Industry Partnership and Established Investigator awards have helped sustain my work.

The funding has been important, but I also value the collaborative network that MRA has fostered. The Scientific Retreat is a relaxed setting to chat about real challenges and new opportunities.

MRA has a real enthusiasm for thinking outside the envelope. MRA provides the building blocks and foundation to get important research moving forward. MRA is notorious for that and it’s certainly had an impact on my career.

What do you hope to see more of in the future of melanoma research?

The future is understanding how to integrate these amazing therapies we have now. We’re trying to understand each patient’s disease to select the appropriate combination of therapies to treat them.  We can almost come up with a “prescription” for each patient. We’re also talking about real-time monitoring of tumors to identify mechanisms of adaptive resistance. This could allow us to develop counter responses by figuring out how to react in near real time.

This is absolutely personalized, precision medicine, and I think melanoma researchers and the MRA are going to lead it.

Can you share a little about yourself? What do you outside of the lab?

One of the things I enjoy most is coaching soccer. Right now I’m coaching U14 girls soccer.

 

 

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Cancer’s Week in the Spotlight

Cancer has been in the news a lot this week. We learned that two pop-culture artists – David Bowie and Alan Rickman – lost their battles with cancer. It’s a stark contrast to the news we heard last month about President Jimmy Carter, who has had a positive treatment response to his melanoma, according to news reports.

As MRA’s founder, Debra Black, and President and CEO-Elect, Robin Davisson, penned in USA Today recently, the number of new treatments available for patients like Mr. Carter has grown rapidly in the last few years. And therapies that have been pioneered in melanoma are showing benefit for many other types of cancer. But there is no time for complacency.

While we don’t know details about the cancers that took the lives of Bowie and Rickman, their deaths underscore the breadth and devastation of this disease. They also highlight the need to focus our resources and collective efforts to address cancer.

But even factoring in optimistic expectations, experts agree that we are nowhere near curing or conquering this disease for all patients. The ongoing need for research is still extremely compelling. – Debra Black and Robin Davisson, in USA Today

On Tuesday, in the State of the Union address, President Obama announced a new initiative to coordinate national efforts to fight cancer. Vice President Biden, who lost his son to cancer last year, will spearhead the effort, Moonshot Initiative to Cure Cancer, which he explains on Medium.

While the goals are lofty and there won’t be one cure-all for cancer, many organizations have come out in support of this effort, including the National Comprehensive Cancer Network. As President Obama said in his State of the Union Speech: “For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all.”

 

Researcher Q&A: Dr. Vashisht Yennu Nanda

Vashisht Yennu Nanda, Ph.D., is an Assistant Professor in the Department of Melanoma Medical Oncology at MD Anderson Cancer Center. Dr. Yennu Nanda is the recipient of an MRA Young Investigator Award and shared a bit about his research for the blog.

How did you get interested in melanoma and your field of research?

It was during my postdoctoral fellowship period, when I found that melanomas were very sensitive to compounds that activate the p53 tumor suppressor by various mechanisms. I was also captivated by the many unknowns in the unique pigmentation-associated pathways that can promote the transformation of normal melanocytes into this aggressive cancer.

YennuNanda, VExplain your research and how it can make a difference for patients.

Over the past decade, treatment of melanoma patients with small-molecule inhibitors that exquisitely target specific oncogenic proteins in melanoma cells have produced groundbreaking responses in most of these patients. However, the responses are not long-lasting and most melanomas eventually become resistant to these inhibitors.

Our research is aimed at figuring out the mechanisms of resistance, and most importantly, developing strategies to counteract them.

What is one thing about melanoma research that surprised you when you first started?

As a grad student and postdoctoral fellow, I worked with many types of cancers, including melanomas, and I was always surprised by the molecular distinctiveness of melanomas compared to all other cancers. Our recent cancer metabolism study results have reinforced this sentiment, as we have found that melanomas are also metabolically distinct compared to other cancers.

How has MRA funding helped your work?

Our research is at a critical juncture of molecularly identifying targeted therapy-resistant melanomas that would best respond to a novel mitochondrial inhibitor, IACS-10759, and systematically evaluating this response. My Young Investigator Award from MRA is supporting this endeavor, which has the potential to make a difference for melanoma patients in the near future.

What do you hope to see more of in the future of melanoma research?

Although giant strides have been made in targeted therapy and immunotherapy of melanoma, resistance is still an issue, and a large number of patients do not respond to immunotherapies. I think the field will benefit from a stronger emphasis on bold fundamental research to understand the molecular changes that occur inside melanocytes and in their immediate vicinity that force these cells to become melanomas in the first place.

Also needed is a strong emphasis on understanding molecular changes in melanomas and their microenvironment during the various stages of metastatic growth, therapeutic response and resistance. Development of novel humanized animal models and a greater patient involvement will be imperative to the success of such research.

What do you do when you’re not conducting research?

Spending time with family and swimming are the two primary activities outside of my research life.

 

Melanoma and the Problem of Drug Resistance

In 2002, researchers discovered a link between mutated BRAF genes and nearly half of all melanoma tumors. Since then, BRAF inhibitors—drugs that target mutated BRAF—have become a leading go-to weapon in the battle against melanoma. Their job is to cut off signals sent by altered BRAF that promote the rapid growth and division of cancer cells.

BRAF Inhibitors and Drug Resistance

Studies show that BRAF inhibitors shrink melanoma tumors faster and better than chemotherapy. Unfortunately, the treatment’s success is short lived. It only takes about six months for cancer cells to figure out how to use alternate pathways to grow and divide once again.

Eventually, melanoma tumors become resistant to the drug’s effects, rendering the treatment essentially useless. This is similar to how skin, ear and respiratory infections can build up resistance to certain overused antibiotics.

Another problem with BRAF inhibitors is that 20 percent of users go on to develop a different type of skin cancer called squamous cell carcinomas. Although this form of skin cancer isn’t as serious as melanoma, they still require removal and treatment.

Combination Treatments for Melanoma: BRAF and MEK Inhibitors

Studies show that combining BRAF inhibitors with another targeted drug, MEK inhibitors, leads to better results.

You might be most familiar with the success of combination therapies to treat AIDS. Over the past two decades, the introduction of a triple cocktail—a combination of three gene-inhibiting drugs—has changed AIDS from being a deadly disease to making it more of a chronic, manageable condition. One goal with melanoma research is to come up with a combination drug therapy that works as well on melanoma.

How are Researchers Combating Drug Resistance?

The Melanoma Research Alliance is helping to fund many of these research projects in the hopes of finding better treatment options with improved outcomes.

  • Several ongoing clinical trials are exploring new drugs and drug combinations.
  • Other studies are looking into whether taking medications intermittently instead of daily might lower the risk of drug resistance.
  • Laboratory tests and clinical trials explore whether drug treatment should continue once cancer progresses to a certain point. Some studies suggest there may be benefits of continuing drug therapy, while other findings suggest otherwise.

Another innovative therapy now available for melanoma is immunotherapy. With this treatment, medications called immune checkpoint inhibitors stimulate the immune system to recognize and destroy cancer cells more effectively.

Studies are currently looking at the effectiveness of combining immunotherapy with other treatments, such as targeted therapies. Researchers also are exploring whether it’s best to start immunotherapy early in the treatment process or after the disease progresses.

Read more about research funded by the Melanoma Research Alliance.Some of this information was presented as part of our 7th Annual Scientific Retreat, which was held in February 2015. You can read about MRA’s Scientific Retreat.

Immunotherapy for Melanoma: Where We Are

As was reported last week, Former President Jimmy Carter has melanoma that has spread to other organs, and part of his treatment will include an immunotherapy drug. Immunotherapy is a term used to describe treatments that harness the body’s immune system to fight cancer cells. Several of these are approved by the FDA for treating melanoma, including the one Mr. Carter is getting, and newer ones are in the pipeline.

How Does Immunotherapy Work?

Using your immune system to fend off cancer sounds natural and appealing, right?  After all, the immune system helps to combat other diseases like infections, so why not cancer, too? Doctors have been trying for decades to take advantage of the ability of immune cells to distinguish between healthy normal tissue and diseased cancer tissue. Unfortunately, only recently has this worked well in cancer.

It turns out that in patients with melanoma, component cells of the immune system have been fooled into ignoring the melanoma. How does this happen? Certain molecules act as “checkpoints” to prevent attacks on healthy cells and turn off a potentially over-eager immune response to minimize autoimmune disease (when the body attacks and destroys healthy body tissues by mistake). Melanoma cells take advantage of this regulatory step and turn on checkpoint signals that let them avoid being detected by the immune system. It’s like Harry Potter and his cloak of invisibility or Klingon Warships with the same…pick your metaphor. The melanoma cells subvert checkpoint signaling to essentially become invisible and avoid being killed by the immune system.

A truly profound change in recent years is the advent of certain immunotherapy drugs that target and block these checkpoints, which increases your body’s immune response. Without the checkpoint signal, the immune cells can do their job of recognizing the tumor as foreign. In this way, immunotherapy drugs activate the immune system to invade tumors and attack melanoma cells.

Patients receive checkpoint inhibitor immunotherapy drugs intravenously (into a blood vein). They are systemic, which means that the treatments travel through the bloodstream to reach all parts of the body. Cancer physicians use systemic immunotherapy to treat metastatic cancer, which is cancer that has spread from its original location to other areas of the body.

What Immunotherapy Drugs are Used for Melanoma?

Since 2011, the U.S. Food and Drug Administration (FDA) has approved three immunotherapy drugs:

  • Yervoy® (Ipilimumab),an anti-CTLA-4 antibody, approved in 2011
  • Keytruda® (Pembrolizumab), an anti-PD-1 antibody, approved in 2014
  • Opdivo® (Nivolumab), an anti-PD-1 antibody, approved in 2014

The anti-PD-1 immunotherapy drugs in particular are showing promise for other types of cancer, too. In fact, earlier this year, the FDA approved nivolumab to treat a certain type of lung cancer.

What’s Next for Immunotherapy Drugs?

The approvals of these immunotherapy treatments have come at an amazing pace and along with targeted therapies the melanoma treatment landscape is dramatically improved compared to just 5 years ago. Unfortunately, the current treatments don’t yet offer a universal cure. The gains are significant and unprecedented – make no mistake.  But some tumors are resistant to treatment and new approaches must be developed to overcome the limitations.

Now, researchers are trying to understand how to tailor the treatments to maximize results for more patients. And history teaches us that using active drugs in unique combinations often works well in cancer. So, some of what we’re trying to understand now include questions like:

  • What are the optimal combinations that balance good activity and good tolerability
  • What is the best order to give these therapies to patients
  • How long should patients be treated for the best results
  • Which patients will most likely benefit from certain drugs or combinations

The European Commission recently approved nivolumab and pembrolizumab for treatment of patients with advanced metastatic melanoma, including in the first-line treatment of the disease. In the US, the FDA is considering this same indication for each drug, as well as the combination of nivolumab and ipilimumab. FDA decisions are expected by the end of 2015.

With anti-PD-1 drugs first approved just last year, these expanded uses clearly demonstrate the remarkable pace of advances for melanoma patients around the world and the hope for even better outcomes for patients in the months and years to come.

What We Can Learn from President Carter’s Melanoma Diagnosis and Treatment

By Louise M. Perkins, Ph.D.

Chief Science Officer

President Jimmy Carter revealed to the world his diagnosis with melanoma with both the grace and bravery that we may all aspire to in the face of such news. His melanoma presentation was a bit unusual and naturally confusing. He was initially diagnosed with a tumor in his liver and then on closer exploration it was found to have spread to the brain. Once the tumor in his liver was removed and analyzed, his doctors could tell that it was a melanoma. Understanding what type of cancer he has is important, as it is helping to direct his treatment. It is fairly typical for melanoma to progress to the brain, as has been reported in President Carter’s case.

Image courtesy of cancer.gov

            Image courtesy of cancer.gov

So, how can a cancer that usually starts in the skin suddenly pop up in someone’s brain and liver?  Well, first of all, this is really rare. Some estimates say only 2% to 6% of melanomas are identified without ever finding the original (primary) tumor. Where do these odd melanomas come from?

Let’s back up a second. Melanomas are pigment-producing cells called melanocytes that have become cancerous.

Melanocytes are not only present on what we think of as skin, but also found in mucosal surfaces like the inside of the nose or mouth, under nails, as well as in eyes and ears – and even some organs.

So, in the case of President Carter, there are a couple possibilities:

  1. He may have had a skin melanoma that had a couple bad cells that split off and hid while his immune system effectively dealt with the primary tumor and he was none the worse. For whatever reason the stray cells then got out of control, leading to his current disease.
  2. Alternatively, something similar may have happened with the melanoma being relatively benign at a rare site in his body, but a few “bad guy” cells broke away and seeded in the brain and liver and then grew more aggressively.

We may never know.

The good news is that Mr. Carter is able to take advantage of the benefits of research that has led to sweeping advances in melanoma. Beginning in 2011, care for patients with advanced melanoma changed profoundly and the FDA has approved eight new treatments since then. Of relevance to President Carter’s specific treatment plan, MRA has funded research on melanoma brain metastases as well as on the combination of anti-PD-1 treatment and radiation therapy, similar to what has been offered him by his doctors.

MRA’s critical and timely infusion of funding has contributed to the sweeping changes in melanoma care with a significant part of our portfolio invested in research on just the types of treatments that will hopefully help President Carter and tens of thousands of other cancer patients in the future. My thoughts and prayers are with him and the many others engaged in their fight against melanoma.

You can learn more about our investments and hope you will consider making a donation to continue to support melanoma research.

The Latest in Melanoma Research: News from the Two Biggest Cancer Meetings

By Louise Perkins, PhD
Chief Science Officer

There’s been a lot of news on melanoma treatments in the last couple of weeks coming out of the two largest cancer conferences held each year: the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual meetings. The results – particularly in the area of immunotherapy – really are exciting for the field of melanoma and cancer, at large.  On the Diane Rehm Show this week, melanoma was described as the “poster child for immunotherapy,” which it certainly has been.

So what’s new, and what does it mean now and for the near future?

Melanoma drugs circa 2014

In September and December 2014, two new melanoma treatments were approved by the FDA for advanced metastatic melanoma. These are the anti-PD-1 drugs pembrolizumab (pembro, Keytruda®) and nivolumab (nivo, Opdivo®). Pembro and nivo release the so-called “brakes” on the immune system, to help the body’s own immune system fight cancer. Another drug, ipilimumab (ipi, Yervoy®), is an anti-CTLA-4 drug and was FDA-approved in 2011.  Check out our video that describes how these immunotherapies work.

The latest news from early 2015
Researchers have been trying to answer a few important questions about these new immunotherapies, such as:

  1. Is anti-PD-1 (pembro, nivo) treatment better than anti-CTLA-4 (ipi) in patients who have not had any prior therapy?
  2. Do anti-CTLA-4 and anti-PD-1 in combination work even better than either treatment alone for patients who have not had any prior therapy?

MRA-funded investigator Jedd Wolchok, MD, PhD, and colleagues addressed the latter question in a Phase 3 trial at ASCO. The study involved more than 900 previously untreated metastatic melanoma patients and compared three different therapies:

  1. Ipi alone
  2. Nivo alone
  3. Ipi and nivo in combination

They found that nivo either alone or in combination with ipi had better results for patients than ipi alone.

This is similar to what was reported at AACR by Antoni Ribas, MD, in a Phase 3 study of the other anti-PD-1 drug pembro, which showed that pembro was better than ipi in previously untreated patients.  More trials are underway to confirm whether or not the combination allows patients to live longer (overall survival) versus single-agent therapy.

One important piece to note is that recent studies found that the increased benefit of the combination also comes with increased side effects; in fact, approximately one-third of patients discontinued therapy due to side effects.

At ASCO, Michael Atkins, MD, summarized these clinical findings that have been presented over recent months:

  • Nivolumab is better than ipilimumab alone
  • Pembrolizumab is better than ipilimumab alone
  • Nivolumab and ipilimumab in combination are better than ipilimumab alone

What does this mean for melanoma patients?

Believe it or not, things are moving amazingly fast. So what does all of this mean for patients in June 2015, just 9 months after the first anti-PD1 treatment was approved by FDA?  Well, one leading cancer guideline group, the National Comprehensive Cancer Network, already updated its melanoma treatment guidelines in March to recommend that oncologists consider a single-agent anti-PD1 (either nivo or pembro) as first line treatment for advanced metastatic melanoma patients (pembro and nivo were FDA approved for patients who have progressed on prior therapies).

More research is needed to determine if and when and for which patients the combination of anti-PD-1 and anti-CTLA-4 should be used.