From scientific meetings to our own dinner tables, conversations about better treatments for cancer are among the most frequently discussed health care topics. Everyone wants them—the doctors and scientists who treat and research cancer, those of us who worry we may one day hear the words “you have cancer,” and most certainly the hundreds of thousands who have already been diagnosed. Whether it’s old-school chemotherapy or a brand-new immunotherapy, when we say “new treatment,” the form this much-sought progress usually takes is a drug—either a new one made from the ground up or an existing one that scientists modify to attack cancer cells.
Much has changed since the early days of developing cancer drugs. Pharmaceutical companies have largely pulled out of drug discovery, leaving academic cancer researchers with the charge to bring cancer medicines forward. To answer the challenge, Kimmel Cancer Center Director William Nelson is restructuring research programs to provide Cancer Center investigators with the laboratory resources they need to maintain their leading edge, fostering collaborations and partnerships to get drugs made and moved ahead. Ultimately, he envisions a reconfigured drug discovery program to garner the scientific and financial resources needed to reduce the time from discovery to clinical trial. “So much time is lost when investigators have to hunt for money to move drug discoveries to the clinic,” says Nelson. “We have the expertise to provide the specialized research support and expertise to get promising medicines to patients faster.” Delays in funding are one of the biggest challenges for drug discovery and development.
The biggest funding gap comes at the most critical time, just about the time a drug discovery is ready to go to patients. It takes about $2 million to $3 million to make this leap, and this is where many promising projects die. “Our investigators can lose a year or two searching for funding to move forward,” says Nelson. No one understands this better than James Berger and Jun Liu, who are at the epicenter of drug development for the Kimmel Cancer Center. Liu, a medicinal chemist, and Berger, a biophysicist, lead the Chemical and Structural Biology Program. They are experts in deciphering how drugs travel through the body, where they go, how long they stay there, and how they change the behavior of cells and genes along the way.
“Drug discovery and development are hard and expensive, but if we don’t do it, it’s not going to get done because pharma has divested itself of it,” says Berger, a member of the prestigious National Academy of Sciences. Nelson believes the Kimmel Cancer Center can help shift the curve in a more positive direction through better research models and expert help along the way. “We have deep expertise in biological cancer targets. We have people who have worked on a target for 20 years and may have even discovered it,” says Berger. “They understand its potential and drawbacks better than anyone. If we give these people a little support, it won’t take much to figure out if it will work.”
Finding new uses for old drugs is one approach that offers both cost savings and a faster route to the clinic. Liu helps researchers search for new uses of existing drugs from a large collections of known drugs called drug libraries. Libraries of FDA-approved drugs used to treat other diseases, catalogs of drugs abandoned by pharmaceutical companies, and libraries of biologics or natural drugs that target and block the communication of specific disease-driving genes provide fertile terrain for scientists hoping to mine for existing drugs they can potentially repurpose as cancer-targeted therapies. Over the last decade, Liu has cataloged a collection of known drugs that could potentially find a new application in cancer. With more funding, he and his team have plans to grow its scope and size. To be most useful, drug libraries must be continually updated to stay current as new drugs hit the market. “A drug that is very well-characterized may have some activity against other targets, including cancer targets,” says Liu.
Clinical trials of known, FDA-approved drugs can advance more quickly because side effects and dosing have already been studied. Liu is building new molecular libraries that have promise to become cancer drugs. He has already successfully traversed the landscape in his own research, applying a drug library find to cancer and moving it to clinical trials and, ultimately, commercial licensing. “If you discover a new indication for an existing drug, you bypass some of the drug discovery work and cost,” says Liu. “All of the early hurdles are skipped, and you cross easily what we call the ‘valley of death.’” This metaphorical place is very real to investigators who uncover promising cancer targets and drugs, only to see their ideas languish and fizzle out because they are unable to secure funding. The symbolic terminology genuinely reflects a critical crossroads that connects laboratory research to its translation into clinical trials of promising new treatments. Liu’s drug library approach is not a slam dunk. Drugs typically require chemical changes to create a cancer specific formulation. “Drugs have to be stable and have to be absorbed and accumulated at a certain concentration in humans,” says Liu. “They can’t just kill cancer cells in a test tube in someone’s laboratory. We must be able to give it to humans, if it is going to become a new cancer medicine.”
This is familiar work to Cancer Center clinicians and investigators. Paclitaxel is now a mainstay in the treatment of a variety of cancers, but when the drug was first developed decades ago, it was nearly abandoned in the transition from bench to bedside because patients could not absorb the drug into their bloodstream where it could circulate and kill cancer cells. The Kimmel Cancer Center’s Ross Donehower was among the team that developed premedications that allowed paclitaxel to be safely given to cancer patients. In the late 1980s, the Cancer Center became the first in the nation to report promising results in clinical trials of the drug to treat ovarian cancer, but paclitaxel—acclaimed at the time as the most promising new anticancer drug in 15 years—might never have reached patients if not for the persistence of Donehower and team. Today, Liu is doing similar work with an anti-fungal drug called itraconazole, which is used to treat toenail fungal infections. In 2006, Liu found the drug among a library of 3,000 FDA-approved drugs. He selected it for its ability to stop two cancer-promoting processes—one known as angiogenesis, where tumors develop blood vessels to get the nourishment they need to grow and spread, and the other, a cancer-initiating biological pathway called Hedgehog. “We were amazed to find a single drug with multiple anticancer properties,” says Liu.
In animal studies, he found the drug was particularly effective against prostate cancer cells. Since the drug was already FDA approved, Liu was able to work with Kimmel Cancer Center prostate cancer experts to move the drug into clinical trials in less than five years. Liu continues to study how the drug works at the molecular level, and has developed new chemical formulations to address liver toxicities and apply the therapy to other types of cancer. His most recent research uses the drug as a much-needed treatment alternative for people with basal cell skin cancers. “This cancer is a lifetime threat for patients who have it. They get many tumors on various parts of their bodies, and when the tumors grow to a certain size, they have to be removed with surgery,” says Liu.
Until his itraconazole discovery, there were limited treatment options for this cancer. Cancers that occurred on the face in tricky places, such as eyelids, were excruciatingly difficult to remove surgically and often left both physical and emotional scars. Liu says itraconazole works in more than half of basal cell skin cancers and allows patients to avoid surgery. “These results show that we can quickly move our discoveries from bench to bedside,” says Liu. Laboratory scientist Gregg Semenza also found success using drug libraries. Nearly 20 years ago, he discovered a cancer target called HIF-1-alpha. It helps cancer cells acquire the oxygen and nutrients they need to survive and grow by stimulating blood vessel growth. But HIF-1 also has a cancer-preventive property. It can block cell division by preventing cells from copying their DNA. “Cancer cells want HIF-1 around to stimulate blood vessel growth, except when they want to divide,” says Semenza.
True to form, cancer cells have developed a system for accomplishing these seemingly incompatible tasks. They use two related proteins long known to be involved in cell growth. One protein enters the picture just before cells begin to copy their DNA, attaches to HIF-1 and causes it to be destroyed, removing it as an obstruction to the copying process. After cells finish copying their DNA, the second protein enters and has the opposite effect. It restores HIF-1, protects it from destruction and stimulates blood vessel growth. Semenza found several drugs in libraries that inactivate the HIF-1-alpha-protecting protein that are currently being tested in cancer clinical trials. This research earned him a prestigious Lasker Award in 2016. Semenza’s work intersects with another application of an FDA-approved drug for cancer. In 2010, Nelson and prostate cancer researchers Vasan Yegnasubramanian and Elizabeth Platz found that digoxin, a drug used to treat heart failure, appeared to stop the growth of prostate cancer cells. Research by Liu and Semenza showed that one of the ways digoxin works against prostate cancer is by targeting and blocking HIF-1. Although early trials with digoxin in prostate cancer did not work against prostate cancer as hoped, the researchers believe the target is a good one and are now studying other drugs that inhibit HIF-1.
Liu and Berger believe there are many other existing drugs that have yet-to-be-realized anticancer properties. “There is no such thing as a perfectly specific drug,” says Berger. “There is always some degree of cross-talk.” Liu and Berger attribute some of this early success in finding drugs that may have anticancer properties and moving them to the clinic to the infrastructure that was put in place by Michael Carducci and Philip Cole, who like Albert Owens, Michael Colvin and Donehower, helped grow the Kimmel Cancer Center’s drug discovery efforts. Carducci and his prostate cancer colleague Emmanuel Antonarakis took itraconazole to their patients, and Carducci, who directs and coordinates clinical research among all Kimmel Cancer Center locations, and a cancer drug discovery expert in his own right, is connecting Liu and Berger to other clinical cancer experts and researchers across all cancer programs and cancer types.
Berger and Liu understand the small bumps along the drug discovery route that can derail a project. There is an art to figuring out how to move a target along and deciphering when a problem is fixable or when it means it’s time to abandon a project. Drug discovery is not a linear process. “If a researcher doesn’t get a hit from a drug library, it doesn’t always mean the idea is bad,” says Berger. “It could be related to the testing assay. A good assay should provide a handful of compounds that may work against the cancer target. If you don’t start with a good assay, it could produce 100 hits, the majority of which are false positives, and then you don’t know where to start.” He and Liu can work with researchers in this case to advise them on the design of a better assay to measure the function, presence and activity of the cancer target.
Liu and Berger have set up a web-based portal that helps cancer researchers walk through questions that help them determine if they have a good target, if there is already a compound that hits the target and whether or not their target is patented by another researcher. “We want to cast a wide net and allow our scientists to take some chances to see if ideas pan out,” says Berger.
“At the same time, we built in checkpoints to shift approaches if things aren’t working.” His mantra is one borrowed from successful but risky industries: “Fail often, but fail early.” His and Liu’s goal is to foster a mindset and environment that provides researchers and clinicians the freedom to explore novel ideas. This is a philosophy that has become the signature characteristic of Kimmel Cancer Center research programs, but it also puts into place a mechanism for failing projects to be redirected or stopped before millions of dollars have been spent. “Academic research brings a lot of people working in a lot of systems to the drug discovery arena,” says Berger. “That gives us the ability to generate many fresh ideas and take a lot of shots on goal. We don’t expect all of them to pan out.” Even when a project doesn’t work out, Liu says, more often than not, it still informs. “Every step along the way contributes. Someone may discover a small molecule that never becomes a drug, but if the early research is good, it will be the foundation for a pharmaceutical or biotech company to come in with its own expertise,” he says.
“This is important because even if our experts don’t see the project all the way through, we have still contributed to the drug discovery process.” This is certainly the case with recent discoveries coming from the Bloomberg~ Kimmel Institute for Cancer Immunotherapy. Researchers identified several proteins that cancer uses to shield itself from the immune system. Drugs that block these proteins allow the immune system to see cancer and attack it. There are several proteins involved in this process, but among the most notable so far are PD-1 and PD-L1. Our Cancer Center experts didn’t discover the drugs that block these proteins, but the drugs were built upon the researchers’ science, and these Cancer Center experts have collaborated throughout the process.
Pharmaceutical companies have now developed more than 20 drugs that are FDA approved or in clinical testing that tear down these shields and make cancer cells vulnerable to immune attack. Bristol Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab) are two examples of new FDA-approved immunotherapies that target PD-1 and PD-L1, and are having quite remarkable responses in patients. “Nivolumab plus ipilimumab was the first immunotherapy combination FDA approved for any cancer,” says Suzanne Topalian, a Bloomberg~Kimmel Institute associate director. “Immunotherapy combinations are an active area of research, with several hundred ongoing trials of various combinations.” Ipilimumab blocks another shielding protein called CTLA-4. In clinical trials, Topalian says combining the two immunotherapies had a more powerful immediate affect against melanoma skin cancer than either drug but also had increased toxicity. Right now, the drugs don’t work for everyone, but for a small subset of patients, immunotherapy has literally meant the difference between life and death. Nivolumab is FDA approved for treatment of advanced nonsmall-cell lung cancer patients whose cancers progress on standard therapy, and pembrolizumab became the first immunotherapy to gain FDA approval as the front-line treatment for nonsmall-cell lung cancer patients whose cancer cells have a lot of a PD-L1 protein.
Pembrolizumab works so well in this PD-L1 subset of lung cancer patients, extending survival well beyond what chemotherapy was able to do, that these patients can now forgo chemotherapy and start with immunotherapy. Recently, a front-line combination of chemotherapy and pembrolizumab was approved for patients with advanced lung cancer, making this the second FDA-approved immunotherapy combination therapy. Lung cancer expert Julie Brahmer led the clinical trial that produced the data used to earn the FDA approval for nivolumab and prembrolizumab. “These results represent a landmark in the history of immunotherapy in cancer. Results showed immunotherapy could be used to treat common cancers and brought it out of the realm of specialized treatment into the broader realm of oncology. Nivolumab has produced the longest follow-up to date of an immune checkpoint inhibitor. Five-year overall survival quadrupled in nonsmall-cell lung cancer, compared with what we would expect from chemotherapy,” says Brahmer. “We are doing further studies of these survivors to determine why they had such a good outcome. We also want to better understand which patients can stop treatment at two years and which of them need to continue treatment beyond two years.”
Many patients continue to have an immune response after the drug is stopped, but right now experts don’t have a way to distinguish those who need more therapy from those who can stop treatment. “Based on these data, I think we can shorten the amount of time patients are treated. But we need to identify those patients who develop immune memory,” says Brahmer. “I think we can safely say not all patients need indefinite treatment. We want to personalize therapy. We are continuing to look for biomarkers for response and long-term control.”
Helping with the biomarker discovery is Topalian, Bloomberg~Kimmel Institute Director Drew Pardoll, and pathologists Janis Taube and Bob Anders, who developed the test that detects and measures levels of PD-L1 in lung cancer patients. It cemented the FDA approval because it allows doctors to identify patients who are likely to benefit. Biomarker discovery is pivotal to Nelson’s drug discovery and development plans. “The key reason drug research is so costly and frequently fails,” he says, “is that often in trials, drugs do not look good because we test them on everyone instead of testing them on the specific patients we think it will help.”
The Kimmel Cancer Center is leading the way in precision medicine approaches that use biomarker tests to guide cancer treatment. Just weeks ago, another FDA approval for prembrolizumab hinged on a biomarker test. This time, the approval came for patients with a spell-checklike failure in their DNA called mismatch repair deficiency. This failure allows DNA errors to go uncorrected, contributing to many different types of cancer, including colon, breast, prostate, bladder, ovarian and pancreas cancers. However, these errors also arouse the immune system. Mismatch repair deficiency in cancer was discovered by cancer genetics experts Bert Vogelstein, Ken Kinzler and their Ludwig Center team in 1993. It was linked to immunotherapy response in 2013 through a Bloomberg~Kimmel Institute collaboration between cancer genetics and cancer immunology researchers. The discovery set the stage for the first-ever FDA approval of a drug based on cancer genetics, not cancer type. “It’s incredibly exciting that we now can prescribe pembrolizumab for patients with mismatch repair deficient cancers. This could reach 2 to 3 percent of all advanced solid tumor patients. We now have a reason to test for DNA mismatch repair deficiency in almost any disease given the potential for durable clinical benefit,” says Dung Le, who ran the groundbreaking clinical trial.
These kind of results support Nelson’s belief that creating silos for cancer by site is counterproductive to drug discovery and development in the high-tech era that allows us to see the genetic structure of every cancer. Nelson believes what is inside the DNA of a cancer cell may be much more informative for guiding treatment than the area of the body in which it occurs. “Typically, it has taken about 15 years and $1 billion to discover and develop a drug. We are making discoveries that promise to reduce that to a couple of years and a few million dollars just by changing the way we select patients for clinical trials,” says Nelson. “If we begin studying drugs in the patients they are likely to help, everyone benefits. Patients do better, research progresses more quickly and costs come down.”
Liu and Berger believe they can get drugs moving forward with a fraction of what it used to cost. A $20 million investment would provide the resources they need to help Kimmel Cancer Center investigators through the laboratory stages of drug discovery and development to screen targets, develop the assays to measure the amount of drug that gets to the target, complete animal studies, and generally support the science needed to figure out if the drug works and how it works. “Just because you have something that binds to a protein doesn’t mean it’s going to cross the cell membrane. And just because something crosses the cell membrane doesn’t mean it’s going to kill cancer,” says Berger.
This kind of work is a bit costly, but it is essential to finding new treatments, and it does not get federal funding. “NIH has a very finite pool of dollars, and everyone has a lot of creative ideas they would like funded,” says Berger. “To some extent, drug discovery is a bit of a fishing expedition, and that’s why NIH and pharma don’t like it. It’s hard and it’s uncertain, but it’s also the only path forward.” If there were a guaranteed drug that was sure to work against cancer at the end of the research, everyone would fund it. But medicine isn’t an exact science, and the truth is that many times the early work turns up nothing. Still, Berger echoes Liu when he says even the things that fail inform them about the next steps. “In science, you very rarely get to a point where you say ‘That was a dead end’ or ‘That was a waste of time,’” says Berger. “Instead, it’s usually, ‘Gee, now we know this, and now we should go in different direction and try this.’” Berger says any first-of-its-kind drug— a potential game-changer—requires the opportunity to follow leads and a willingness to take risks.
However, when it comes to limiting risk, the Kimmel Cancer Center’s track record in drug discovery and development makes it a good bet. This success is attributable to its people, says Berger. “We have arguably the most knowledgeable researchers in the fields of cancer genetics, epigenetics and immunology, ” he says. “Everything we enjoy today comes from basic science conducted 10, 20, 30, 40 or more years ago. Scientific discovery is not linear. The path forward is not always clear, but every finding adds to our knowledge and builds upon the foundation, and we have the experts and the willingness to collaborate that make it possible to put all of the pieces together.” It is this depth of expertise in all of the critical areas of cancer research and a culture that supports sharing information and working together that make it an incubator for new cancer drugs. The Kimmel Cancer Center is also a center that works lean and mean. “It is not the biggest cancer center, but it is, by any form of measurement, one of the most accomplished,” says Berger. The missing ingredient in what would otherwise be a nearly perfect recipe for drug discovery and development is sustained funding. Discovery is slowed because researchers get so far, but they have to stop and apply for more funding before they can move forward. Precious years are lost to the search for funding. “If we want to work quickly with focus, it takes funds that currently don’t exist,” says Liu. “If we had both, we could do more great things. ” Berger and Liu want the Chemical and Structural Biology Program to be that resource for cancer researchers. “We have to make drugs that attack one part of us without attacking another part,” says Berger. “Investigators get stuck, and they don’t know who to turn to.”