Cancer’s New Vocabulary: Life-saving, Turnarounds, Cures
When the little boy was admitted with relapsed leukemia, his prognosis looked grim. He had already had all the chemotherapy his 5-year-old body could take, plus a bone marrow transplant. But he had a stroke of luck on his side: The boy’s disease had landed him back at Columbia just a few months after Andrew Kung, MD, PhD, chief of pediatric hematology, oncology, and stem cell transplantation, began an ambitious program—Precision in Pediatric Sequencing, or PIPseq for short—to sequence the tumor genomes of all high-risk and relapsing pediatric cancer patients. The child’s sequencing revealed a mutation that is not generally present in the type of leukemia he had but is instead associated with sarcoma in adults. That meant doctors had one more treatment to try, a targeted therapy known to be effective against cancers with this exact genetic glitch and less toxic than conventional chemotherapy.
“We would never have thought to try this particular drug in this particular condition,” says Dr. Kung. “But that one medication was able to take a terminally ill child, with 80 percent leukemia in his peripheral blood, and treat his disease such that within a month, the leukemia was no longer detectable in his blood.”
Such turnaround successes, once rare in cancer, are becoming more frequent at Columbia. A year after Dr. Kung’s program started, he expanded it to provide tumor sequencing to every pediatric cancer patient at Columbia. It was the first such universal sequencing program in the country for children with cancer, and its success has been so dramatic that the medical center plans to extend it to all adult patients. PIPseq is just one part of a many-pronged strategy to transform Columbia’s cancer center into the best cancer center in the country, if not the world, says Stephen Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center.
When Dr. Emerson came to Columbia in 2012, cancer care at the medical center was ripe for reinvention. He set out to recruit top researchers and clinicians—Dr. Kung was his first recruit—and to inspire faculty both old and new to build bridges from the university’s outstanding cancer genomics faculty and burgeoning translational immunology program to two pillars of cutting edge cancer therapeutics: precision medicine, which aims to personalize treatments based on genomic changes in patients’ tumors, and immunotherapy, which aims to rev up patients’ immune systems to recognize and attack tumor cells. “There was no question that the time was right for Columbia to make a radical push against cancer. It has all the tools ready to do so,” he says.
It was a vision he shared with Gary Schwartz, MD, who arrived at Columbia in January 2014 as chief of hematology and oncology and the cancer center’s associate director for research. A member of the National Cancer Institute’s Investigational Drug Steering Committee, Dr. Schwartz is renowned for his work in cancer drug development; his laboratory has developed multiple medicines now in clinical trials. A panoply of programs launched since Dr. Emerson and Dr. Schwartz arrived have positioned Columbia as a top-tier facility equipped to offer innovative therapies unavailable at most other cancer centers. “We’re seeing cures in cancers that I never thought were curable before,” says Dr. Schwartz. “That’s why it’s such an exciting time to be an oncologist—and such an exciting time to lead the program at Columbia.”
Cancer biology has undergone a complete transformation over the past half-century. In the 1940s and ’50s, researchers believed that cancer was caused by cells dividing too rapidly. “It turns out, this hypothesis was wrong,” says Dr. Emerson. With advances in the understanding of genetics, researchers began to suspect that defects in the DNA of cancer cells might be involved.
In 1960, scientists at the University of Pennsylvania noticed an unusually stubby chromosome in a karyotype made from cultured blood cells taken from two patients with chronic myeloid leukemia. What they soon figured out was that a piece of that chromosome had split off and fused with another chromosome, changing the genetic code to produce a new protein that caused the leukemia. It was the first demonstration that chromosomal abnormalities could cause cancer, and it paved the way for a new model for thinking about the disease.
The Columbia Combined Cancer Panel that queries 467 cancer-related genes was designed by the Laboratory of Personalized Genomic Medicine at CUMC in collaboration with Columbia oncologists. The New York State Department of Health approved the panel in August. The Columbia Combined Cancer Panel joins the TruSeq Targeted Cancer Panel as state-approved oncology tests available within the Laboratory of Personalized Genomic Medicine.
A sequencing-only test, the Columbia Combined Cancer Panel is done within Columbia’s certified and accredited personalized genomic medicine lab. Samples accepted for testing include paraffin embedded tissue, fresh and frozen tissue (with or without microdissection to enrich for tumor), blood, and bone marrow.
The laboratory offers more than 14 clinical diagnostic tests in oncology. Cancer whole exome and transcriptome sequencing is available by waivers on a case-by-case basis while awaiting final state approval.
It took around four decades for researchers to invent, test, and get approval for a drug that targets this genetic mutation. That drug, imatinib (Gleevec), first approved in 2001, added years to the lives of patients whose prognosis until then had generally been a mere few months. Since then, researchers have identified many more therapies targeted to fix specific genetic mutations commonly identified in cancer cells. For example, researchers discovered that about half of all melanomas carry mutations in a gene called BRAF that drive uncontrolled cell growth, and medicines developed to inhibit the gene have benefited patients enormously.
Precision Medicine in Cancer
In its simplest sense, this is precision medicine: sequencing cancer genomes to identify defects in genes that can drive cancer growth and designing drugs that act as guided missiles, blocking the function of such genes or of the pathways on which they signal. Columbia’s sequencing panel tests 467 cancer-related genes, but sights are set on molecular profiling of complete cancer genomes. PIPseq, the program Dr. Kung launched in pediatrics, sequences the entire exome—the part of the genome that encodes proteins—and the RNA from tumors. “From the DNA and RNA sequence of the tumor, we are able to determine in most cases precisely what went wrong that resulted in the development of the cancer,” explains Dr. Kung. Yet PIPseq was a gamble. According to the scientific literature, comprehensive sequencing yields actionable information less than a quarter of the time. Dr. Kung and his colleagues believed that if they took a more expansive view of how to use the sequencing data they could do much better. They were right: Just 18 months after the program’s launch, the team is finding that sequencing influences clinical decisions some 65 percent of the time.
Not all of these cases match the experience of the 5-year-old boy with leukemia. Sometimes, sequencing suggests just the opposite—that a particular treatment will not help—thus allowing clinicians to avoid giving potentially toxic therapies that would have no clinical benefit. In about 15 percent of all patients, the sequencing has identified potentially inherited mutations, which may be present in other family members. All in all, however, the program’s success rate is one the team never would have imagined. “It’s a true paradigm shift,” says Dr. Schwartz. “It’s been miraculous.”
Dr. Schwartz is now working with NewYork-Presbyterian Hospital administrators to expand the program beyond pediatrics so all cancer patients benefit. A major issue for precision medicine in oncology is that most insurance companies will not cover sequencing. Programs like PIPseq that demonstrate the technology’s benefits so unequivocally will eventually persuade insurers to cover it. “We don’t want to roll this out until we can do it fairly,” Dr. Schwartz says, “until we have a system in place where everybody can have their tumor sequenced, regardless of their coverage.”
With tumor sequencing in the clinic becoming routine, a big issue facing the field of precision medicine is how to use the information that this powerful technology delivers. Columbia researchers are participating in a National Cancer Institute study in which patients’ treatments are matched to the gene mutations that their cancer carries, rather than to the type of cancer (such as lung cancer or melanoma) that they have. This so-called MATCH trial, which stands for Molecular Analysis for Therapy Choice, will include a few dozen arms, with about 35 or 40 patients in each, at select medical centers around the country. Kevin Kalinsky, MD, an expert in breast cancer, is participating in the arm for mutations in a gene called AKT; patients will be treated by an investigational drug that has been shown to be safe but is not yet approved.
Columbia faculty are studying and treating cancer in nearly every department of the medical center. A few highlights of their work:
Adolfo Ferrando, MD, PhD, who leads the cancer center’s lymphoid development & malignancy program, has led a research team that used sophisticated new DNA techniques to find that many children with T-cell acute lymphoblastic leukemia suffer a relapse because they harbor mutations that activate an enzyme that inactivates an important chemotherapy drug. “This discovery may lead to improved treatment for patients. The most immediate thing to do now is to develop diagnostic tools to monitor for the mutation and, if we see it, these patients should probably receive a different drug.”
Jeffrey Bruce, MD, co-director of the Brain Tumor Center in the Department of Neurological Surgery, leads an NIH-funded translational brain tumor research effort that studies immunotherapy and drug delivery systems. In a paper published in the journal Neurosurgery, Dr. Bruce described a small clinical trial that showed the potential of “convection enhanced delivery,” which allows chemotherapy drugs to be pumped straight into the tumor, bypassing the blood-brain barrier. “We know there are limitations for treating brain tumors and we’re constantly looking for a better understanding of these tumors from a molecular point of view to come up with better treatments.” Eileen P.
Connolly, MD, PhD, is part of a team using intraoperative radiation therapy to deliver a single dose of radiation to a tumor bed at the time of surgery. NYP/Columbia was one of the first hospitals in the metro area to offer IORT to early-stage breast cancer patients. Dr. Connolly will lead a study to see if the use of IORT may be beneficial to a wider group of patients. Read more in this issue’s Clinical Advances.
Dawn Hershman, MD, (Medicine, Public Health), and Jason Wright, MD, (Obstetrics & Gynecology), have collaborated on several studies that answer important patient care questions by creatively using and analyzing “big data.” Notable is research addressing concerns that power morcellation, when used in minimally invasive surgery to remove the uterus, may spread undetected cancers. Drs. Wright and Hershman reviewed insurance records to identify the prevalence of uterine cancers in women undergoing the procedure and found that tumors were more common than many experts thought. “Patients considering morcellation should be adequately counseled about the prevalence of cancerous and precancerous conditions prior to undergoing the procedure,” the study’s authors wrote, and their work has informed public debate about the procedure.
Growing evidence suggests that the type of cell in which cancer originates also shapes the cancer’s susceptibility to treatment. Cathy Mendelsohn, PhD, uses a technology called fate-mapping to label specific types of bladder cells with an indelible marker that is passed on to each one of the cells’ progeny. “If we understand how bladder cancers arise, and why some lesions invade and others don’t, we may be able to develop more precise techniques for diagnosis and better therapies for treatment.”
Columbia University Medical Center and the Mailman School of Public Health now host one of six new sites launched by the NIH’s Breast Cancer and Environment Research Program. The Columbia site is led by Mary Beth Terry, PhD, (public health), and Rachel Miller, MD, (P&S). The site will focus on prevention and add to the growing knowledge of environmental and genetic factors that may influence breast cancer risk across the lifespan.
Finding the Master Regulator
But this simple model of using a drug to inhibit a mutated cancer gene may not be enough to take precision medicine as far as it can go. “We are starting to run out of land in terms of identifying mutations that pop up frequently, can be targeted pharmacologically, and elicit a big response,” says Andrea Califano, a systems biology expert. Many mutations can occur in a single tumor, he says, and, indeed, patients on targeted therapies almost always relapse because of other pre-existing mutations, sometimes present in less than 1 percent of the tumor cells, that induce drug resistance. That means these mutations must somehow converge on other genes to activate the key genetic programs that the tumor needs to thrive. The Columbia team has found that only a handful of these master regulator genes exist, and they are virtually identical even in cells and patients with different mutations.
The team uses complex computer algorithms to reveal the master regulator based on the expression of their targets using tumor specific regulatory networks. So far, the approach has been tested extensively in animal models, and researchers at Columbia and other cancer centers are testing the approach in cancer patients. After identifying the handful of master regulators that represent the key vulnerability of an individual cancer, the researchers match them to a library of compounds to find which compound or combination can best abrogate their concerted activity. Then, the patient’s cancer is transplanted into a mouse model, creating a kind of avatar, and the compound’s efficacy is tested against the specific tumor. The ultimate goal, after these steps are complete, is for the compound to be tried directly in the patient.
Moving Discoveries to Patients
With just 40 or 50 drugs in existence that are known to target particular genes or pathways, testing the newest therapies just coming out of the discovery process is where the rubber hits the road in cancer treatment. “The increasing understanding of cancer biology—and the ability to translate it into effective therapeutics—has outpaced nearly every other field in medicine in recent times,” says Richard D. Carvajal, MD, director of experimental therapeutics at the cancer center. “So to really give world class cancer care, you need to access the newest drugs. Those are always going to be in phase 1 clinical trials.”
Providing such access is exactly why Dr. Carvajal joined Columbia. Since his arrival in 2014, he has established a phase 1 clinical trial program that has already tested more than two dozen medicines based on the most cutting edge research. Such early-stage clinical trials have changed dramatically in recent times. In principle, the goal is not to test efficacy but to determine how well people tolerate an experimental medicine that has never been tried in humans. A decade ago, the likelihood that patients would be helped in such early-stage trials was miniscule, less than 5 percent, Dr. Carvajal estimates. “What has changed is that we are much more rigorous in matching the patients and their cancers to the right treatment, so even in these first-in-man trials, patients can get a significant amount of benefit.”
Dr. Carvajal oversaw the building of the Adult Research Infusion Unit, a state-of-the-art facility opened in June to treat patients enrolled in phase 1 clinical trials. Patients might spend 10 or 12 hours receiving treatment while specially trained nurses monitor their responses and take samples that measure how the drug is being metabolized in the body. The specimens are taken next door to a laboratory where they are processed according to specific trial protocols. “There are only a few cancer centers in the world that can do these trials—and do them right—so it’s a big deal that we’re one of them,” says Dr. Carvajal.
About a third of the therapies tested in the unit target a gene or molecular pathway. “It’s a remarkable time to do research of this kind,” says Nicole Lamanna, MD, who directs clinical trials for chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults. Recently, two novel agents, ibrutinib and idelalisib, have been approved by the FDA and have significantly changed the outlook for CLL patients. Both drugs are B-cell receptor kinase inhibitors that target the BCR signaling pathway, which plays an important pathogenic role in CLL.
“In patients with refractory CLL, we’re seeing a high frequency of responses and also durable responses with these novel agents,” says Dr. Lamanna. “Now we’re trying to figure out how to use these new drugs in combination with more traditional cytotoxic chemoimmunotherapies to see if we can get a better response.” She also is conducting trials to see if the new drugs—which are taken orally—can work alone or in combination with monoclonal antibodies to spare older patients the toxicities of harsh chemotherapy regimens. These are not cures for CLL, but Dr. Lamanna is confident that clinicians will be able to develop more personalized strategies as scientists learn more about the biology of CLL.
Columbia doctors are focused on extending the potential of immunotherapy to many types of cancer. They see promise in a new generation of potent agents and combination immunotherapies that work across a broad range of tumors.
Other therapies being tested at Columbia are designed to rev up the immune system. For decades, cancer biologists searched for a way to incite a patient’s own immune system to attack tumor cells. About seven years ago, researchers identified molecules sitting on the surface of white blood cells that act as immune system brakes. Antibodies that blocked these so-called immune checkpoints released the brake, unleashed the immune system against cancer cells, and showed immense potential in treating cancer. “We are just learning how to use these drugs and how to bring them into practice,” says Dr. Emerson.
Naiyer Rizvi, MD, who directs Columbia’s cancer immunotherapeutics program, was in awe when he first saw these agents work in lung cancer, about seven years ago. The first immune checkpoint inhibitor to be studied in patients, ipilimumab blocks the CTLA-4 checkpoint and was approved for melanoma in 2011 but it did not seem to work in most other cancer types. A new class of immune checkpoint inhibitors blocking the PD-1 pathway has since revolutionized the approach to cancer with significant activity in many tumor types. The first lung cancer patient Dr. Rizvi treated with the PD-1 inhibitor nivolumab was a man with metastatic lung cancer to the adrenal gland. After his first infusion of the experimental treatment, he came to the emergency room for morphine to treat his persisting excruciating cancer pain. When he woke up the next day, his pain was gone and it never came back. After two years of treatment with the drug, he has remained cancer-free. Dr. Rizvi went on to lead one of the phase 2 trials that led to nivolumab’s approval for lung cancer this year.
Jeffrey Bruce, MD, the Edgar M. Housepian Professor of Neurological Surgery Research, co-director of Columbia’s Brain Tumor Center, and director of the Bartoli Brain Tumor Research Laboratory
Andrea Califano, PhD, the Clyde’56 and Helen Wu Professor of Chemical Biology (in Biomedical Informatics and the Institute for Cancer Genetics), professor of biochemistry & molecular biophysics, and chair, Department of Systems Biology
Richard D. Carvajal, MD, associate professor of medicine at CUMC, director of experimental therapeutics, and director of the melanoma service
Eileen P. Connolly, MD, PhD, assistant professor of radiation oncology at CUMC
Stephen Emerson, MD, PhD, the Clyde’56 and Helen Wu Professor of Immunology (in Medicine), professor of microbiology & immunology (in the Herbert Irving Comprehensive Cancer Center), and director of the Herbert Irving Comprehensive Cancer Center
Adolfo Ferrando, MD, PhD, professor of pediatrics and of pathology & cell biology Larisa J. Geskin, MD, associate professor of dermatology in medicine and director of the Comprehensive Skin Cancer Center in the Department of Dermatology
Dawn Hershman, MD, professor of medicine at P&S and professor of epidemiology at the Mailman School of Public Health
Kevin Kalinsky, MD, assistant professor of medicine at CUMC
Andrew Kung, MD, PhD, the Robert and Ellen Kapito Professor of Pediatrics and chief of the pediatric hematology, oncology, and stem cell transplantation division
Nicole Lamanna, MD, associate professor of medicine at CUMC
Cathy Mendelsohn, PhD, professor of urological sciences (in urology), of pathology & cell biology, and of genetics & development (in the Institute of Human Nutrition)
Rachel Miller, MD, professor of medicine (in pediatrics) and environmental sciences at CUMC
Naiyer Rizvi, MD, professor of medicine at CUMC, director of thoracic oncology, and director of immunotherapeutics for the division of hematology and oncology
Gary Schwartz, MD, the Clyde’56 and Helen Wu Professor of Oncology (in Medicine), chief of the hematology/oncology division, and associate director of the Herbert Irving Comprehensive Cancer Center
Yvonne Saenger, MD, assistant professor of medicine at CUMC and director of melanoma immunotherapy
Mary Beth Terry, PhD, professor of epidemiology, Mailman School of Public Health
Jason Wright, MD, the Sol Goldman Associate Professor of Gynecologic Oncology (in Obstetrics & Gynecology) and chief of gynecologic oncology
That approval came three months after Dr. Rizvi arrived at Columbia with the aim of extending the potential of immunotherapy to many different types of cancer. What is especially powerful about the approach, he says, is how the immune system’s activation generates T cells that remember the cancers as foreign, making the drugs’ curative effects likely durable. That should circumvent the frequent problem of relapse with chemotherapy and molecularly targeted therapies. Many of the first round of patients who underwent this approach remain cancer-free today. “We’re out more than five years now for some patients, so I think it’s somewhat safe to say that these people are cured,” Dr. Rizvi says. “The new generation of agents and combination immunotherapies are even more potent, and they seem to work across a broad range of tumors.”
State-of-the-art care is available at Columbia in all cancer types. Skin cancer is one example. The Comprehensive Skin Cancer Center led by Larisa J. Geskin, MD, offers mole mapping technology, extracorporeal photopheresis, photodynamic therapy, chemotherapy, biologic therapy infusion services, total skin electron beam radiation, and stem cell transplantation. “The comprehensive nature of the services we provide to patients with cutaneous malignancies is unique in the New York City and tri-state area,” says Dr. Geskin. “My dual training in dermatology and oncology allows for productive bridging between the clinical disciplines to provide care for patients throughout all stages of skin cancer, including rare malignancies and cutaneous lymphomas, with input from a variety of specialists in a truly multidisciplinary fashion.” The dermatology department has been an integral part of the Herbert Irving Comprehensive Cancer Center for many years and is known for its innovative work in skin cancer in basic and translational science. This includes clinical trials, which resulted in FDA approval of vismodegib, a novel hedgehog pathway inhibitor that treats basal-cell nevus syndrome. “We work closely with Drs. Schwartz and Carvajal in developing new therapies and conducting phase 1 clinical trials in melanoma and skin lymphomas.” In a first-of-its-kind nationwide clinical trial, investigators will use molecular signatures to predict the risk of relapse in patients in the early stages of melanoma and initiate a preemptive immunotherapy.
Challenges in Immunotherapy
Patients’ responses to immunotherapy are highly inconsistent. In lung cancer, for example, approximately 20 percent of patients respond to immunotherapy, and researchers do not know why others do not respond. A study led by Dr. Rizvi, published in April in the journal Science, provided the first hint of an answer: It seems that the more mutations a patient’s cancer has developed, the likelier that patient is to respond to immunotherapy, probably because the more mutations that exist, the more likely the immune system can be harnessed to target these “immunogenic” mutations. Indeed, melanoma, which cancer researchers call the poster child of immunotherapy, tends to acquire the highest number of mutations. “Traditionally, people have never really thought that mutations play a role in immunotherapy, but it turns out they do,” Dr. Rizvi says.
Response to immunotherapy can look much different than response to other types of cancer therapies, says Yvonne Saenger, MD, director of the melanoma immunotherapy program and another recent recruit to Columbia. “In melanoma, you often see swelling of the tumor before you see the response, and it can be a challenge for the clinician to decide whether to continue the treatment,” she says. Her lab is working on identifying biomarkers in blood and tumor tissue that can help clinicians track a patient’s progress and prognosis.
From understanding the genomic landscape, immune profiles, and other factors dictating response to determining how long patients should remain on such treatments, many questions remain to be answered for immunotherapy to reach its full potential.
And checkpoint inhibitors are just the start. “I think there are other ways we will be able to use immunotherapy,” Dr. Rizvi says. Researchers are identifying additional checkpoint targets to study and exploring other avenues. For example, Columbia researchers are working to genetically modify patients’ T cells as a way to increase the immune system’s cancer fighting potency, an approach that so far is much more experimental. Dr. Saenger’s team is conducting studies with a cancer-killing virus called T-VEC, the first virus therapy shown to be effective against cancer in clinical trials. Researchers also are exploring whether combining different types of therapies can drive up the potential of immune system-based treatments. “We definitely have a lot of work to do,” Dr. Rizvi says, “but I think the potential to cure many more patients is significant and well within our reach.”