Meet four researchers whose work may change the face of cancer treatment
Research is at the heart of the battle to make progress against cancer. Especially key to this battle are the efforts of translational researchers—those who find ways to place the groundbreaking work of basic science researchers into the hands of bedside physicians. In this way, research may pay off in the form of life-extending treatments. The four investigators profiled here are doing just that at the NYU Cancer Institute at NYU Langone Medical Center. These translational researchers are helping to cast new light on the roots of cancer development, exploring promising hypotheses, and collaborating with a range of other experts. The avenues they are pursuing could end up saving lives.
Hoping to circumvent breast cancer drug resistance
Of the many women who survive breast cancer, thousands do so with the help of trastuzumab (Herceptin®) or lapatinib (Tykerb®). These anticancer agents, called "monoclonal antibodies," work by inhibiting a protein called HER2. But not every woman who receives one of these drugs beats her disease. Francisco J. Esteva, MD, PhD, Cancer Institute Associate Director of Clinical Investigation and professor of medicine, is conducting clinical research to decipher and overcome the mechanisms underlying cancer cell resistance to these novel therapies and other drugs used in breast cancer treatment, in hopes of getting the drugs to work for more patients.
"Some targeted therapies work well, but some cancers learn to escape their effects. We need to figure out why this happens," says Dr. Esteva. "We are trying to develop new therapies based on what we know about the mechanisms of drug resistance."
Dr. Esteva, who joined The Cancer Institute faculty in August after 15 years at Houston's MD Anderson Cancer Center, has been a leader in the study of biomarkers to predict treatment response in patients with breast cancer, particularly those with tumors that overproduce HER2. For example, his group showed that activation of two molecular pathways involved in cancer, called SRC and PI3K, is associated with trastuzumab resistance. In 2002, Dr. Esteva and his colleagues published one of the first clinical trials combining trastuzumab with another anticancer drug, called docetaxel, in patients with HER2-positive metastatic breast cancer.
In 2004, he led the original team of investigators who showed that adding another monoclonal antibody called pertuzumab to trastuzumab therapy was more effective than trastuzumab alone, and increased cancer cell death. Pertuzumab (Perjeta®) was approved by the U.S. Food and Drug Administration (FDA) in June 2012 for use in combination with trastuzumab and docetaxel in certain women with HER2-positive advanced breast cancer, and more recently has shown promise for treating early-stage disease. More recently, his laboratory team has been studying mutations in HER2 that may predict resistance to trastuzumab and lapatinib.
At The Cancer Institute, Dr. Esteva is focusing on clinical and translational research to explore the underpinnings of drug resistance by analyzing tissue samples from patients with breast cancer. He looks forward to working with the members of different departments and hopes to establish collaborative multidisciplinary programs to move the field forward.
"The Cancer Institute has all the elements needed to succeed," he notes. "The breast cancer program has made significant contributions to our basic understanding of the disease and to novel treatments in the clinic. Moving forward, we will expand our drug development program, with a focus on investigator-initiated clinical trials, and lead innovative biomarker studies that will result in new standards of practice in medical oncology and other specialties. To achieve this goal, we must engage basic scientists and clinical investigators so that together, we can make a big difference in women's lives."
Seeking better strategies to defeat breast cancer
Komal Jhaveri, MD, assistant professor of medicine, began her medical career in her native India and trained in nuclear medicine. "I was fascinated by the concept of functional imaging to see how an organ works," she explains. Along the way, she encountered patients with cancer and chose to add oncology to her career focus. "I wanted to connect with patients emotionally and intellectually at this important point in their lives," she explains. "Blending my nuclear medicine training with oncology has turned out to be a happy marriage."
Dr. Jhaveri joined The Cancer Institute in July 2012 after internal medicine training at St. Luke’s Roosevelt Hospital, followed by a fellowship in hematology/medical oncology at Memorial Sloan-Kettering Cancer Center. She is conducting several clinical trials aimed at improving the treatment of women with breast cancer, particularly those with advanced disease. Among the avenues of investigation she is pursuing are:
- A Phase I clinical trial of the investigational drug ganetespib in combination with paclitaxel in women with HER2-positive metastatic breast cancer. Ganetespib inhibits a protein called HSP90, which cancer cells need to thrive.
- A Phase I clinical trial of the investigational drug KD019 in combination with trastuzumab in women with HER2-positive metastatic breast cancer. KD019, which is a pill, attacks four different pathways involved in the growth of this cancer type.
- Research with Robert Schneider, PhD, which has identified two pathways—called PI3K AKT and JAK STAT— that are overactivated in inflammatory breast cancer (an aggressive form of the disease). There are drugs in early development which target these pathways. This research was presented at the Annual Meeting of the American Society of Clinical Oncology in June—the nation's largest gathering of cancer professionals.
- Studies of novel ways to monitor the growth of breast cancer that has spread to the brain, which can be difficult to distinguish from radiation-induced scar tissue using conventional MRI. Dr. Jhaveri hopes to assess the combination of positron emission tomography (PET) and MRI to see if it is more sensitive for detecting breast cancer metastases in the brain than conventional imaging. By accurately monitoring breast cancer spread, doctors can better tailor treatment. NYU Langone Medical Center is one of only a handful of centers nationwide, and the only one in New York City, with the technology to perform simultaneous PET/MR imaging.
"If we want to advance research and make critical discoveries that will change cancer care, there are many pieces to the puzzle. We need basic and translational scientists, dedicated and passionate clinicians, and motivated patients with supportive families," Dr. Jhaveri contends. "All of these are available at The Cancer Institute. I enjoy being part of a team to improve the outcome of women with breast cancer, and hope that we can one day say that we all did it together."
Focusing attention on the challenge of bladder cancer
In nearly a third of the people diagnosed with bladder cancer, the disease has invaded the muscle wall. About half of these patients will succumb to the disease, with an average survival of only 13 to 15 months. But despite 30 years of research, only one drug, cisplatin, has been approved by the FDA for the treatment of muscle-invasive and metastatic bladder cancer. Unfortunately, cisplatin can be very toxic, and many patients can't tolerate it.
"That's a big clinical challenge," notes Arjun Balar, MD, assistant professor of medicine. "And this is an uncommon cancer that does not get a lot of attention." Dr. Balar is trying to improve these statistics by conducting clinical research, fostering collaborations with other institutions, and promoting research aimed at deciphering the complex molecular characteristics of the disease. His goal is to develop better tolerated and more effective treatments that can be personally tailored to individual patients.
Among the clinical research projects in which Dr. Balar is participating are the following:
- Assessment of a novel "dose-dense" method of giving cisplatin before bladder removal surgery (cystectomy) according to a particular dose and schedule designed to eradicate micrometastases (small amounts of cancer cells that have spread to other parts of the body) more effectively and shrink the tumor. This Phase II study is being conducted in collaboration with Memorial Sloan-Kettering Cancer Center and the University of North Carolina.
- A Phase II multicenter study evaluating docetaxel given in combination with the investigational drug OGX427 in patients whose metastatic bladder cancer has continued to grow despite initial therapy. OGX427 inhibits a protein called HSP27 which cancer cells need to grow and spread, and also may mediate chemotherapy resistance. The drug may make a patient’s metastatic bladder cancer cells more susceptible to docetaxel.
- The establishment of a Genitourinary Cancer Tumor Registry to collect blood, urine, and tissue samples and corresponding clinical data to be support research.
- Participation in the Bladder Cancer Working Group with other investigators and clinicians at NYU Langone Medical Center, who meet monthly and share their research findings. In one line of inquiry, the scientists are studying the expression of a protein called XIAP to see if it can serve as a marker of bladder cancer outcome.
- A collaboration with the Bladder Cancer Advocacy Network to study the molecular profile of a very aggressive disease called micropapillary bladder cancer.
Dr. Balar came to The Cancer Institute after finishing his fellowship at Memorial Sloan-Kettering Cancer Center. He sees patients with all types of genitourinary cancers, including bladder, kidney, prostate, and testicular cancers. He currently cares for patients at the NYU Clinical Cancer Center and at the Smilow Prostate Center in a multidisciplinary clinic with urologic oncologists.
"There was an opportunity here to play a role in genitourinary medical oncology by contributing my expertise in a non-prostate urologic cancer. To be the missing piece in an almost-whole pie is very rewarding," he concludes. "There is a very dedicated and motivated group here that is very supportive of the kind of research I want to do."
Exploring the behavior of cancer stem cells
While great strides have been made in the treatment of cancer, the fact remains that some 80 percent of metastatic cancers—those that have spread from the original tumor site to other parts of the body—return after treatment. Markus Schober, PhD, assistant professor of dermatology and cell biology, and his laboratory team are scrutinizing the role of a distinct population of cells that may be the culprits for the lack of treatment success: cancer stem cells. The scientists are studying how cancer stem cells differ from normal stem cells. They are seeking molecules that may explain cancer stem cell behavior and hoping this knowledge could be used to develop more effective treatments.
Healthy stem cells have the potential to create the different kinds of cells comprising normal tissues in the body. Likewise, cancer stem cells can initiate the growth of new tumor cells. But just how they accomplish that feat, especially in the face of large doses of toxic chemotherapy drugs, remains unexplained. "Cancer stem cells maintain long-term tumor growth. To make progress against advanced cancers, we need to learn how to target them with more effective therapies," says Dr. Schober.
Here's what is known: Stem cells are immature cells which can develop, or "differentiate," into mature cells with specialized functions. When cancer stem cells differentiate, they can trigger tumor development. Cancer stem cells also tend to be different from one another in various ways, and this “heterogeneity” makes it difficult to identify them and target them with drugs. When treatment fails to eliminate every last cancer stem cell, patients have a greater risk of developing new and often more aggressive tumors.
Why is it so challenging to cure certain cancers? Cancer stem cells are often hidden in protected niches, where they elude the lethal effects of cancer therapies. Confounding matters further is their ability to transition between closely related but distinct states that can make them resistant to treatment. Furthermore, cancer stem cells can also accumulate new mutations as cancers develop new features that further increase their chance of survival, even when treated with multiple chemotherapy drugs. This ability to change is called "plasticity."
The heterogeneity and plasticity among cancer stem cells and their many similarities to stem cells in normal tissues make it difficult to kill all cancer cells without affecting normal tissues. "How can we deal with this heterogeneity?" asks Dr. Schober. "Can we find mechanisms that are common to all cancer stem cells and essential for their self-renewal, yet do not apply to normal stem cells? Or can we find ways to modify the cells' environment to enforce one common behavior that can be targeted by drugs? This is why giving combinations of different anticancer drugs is typically more effective than using a single drug."
He and his fellow investigators use animal models of squamous cell skin cancer because the cancer stem cells display great heterogeneity and the tumors are easily accessible. The researchers have been able to transplant cancer stem cells into mice, see where tumors form, track their conversion between distinct states, and pinpoint the cells that have the potential to trigger new tumor growth. Using this model, Dr. Schober and his team have found that the area around cancer stem cells—known as the "microenvironment," an increasing area of study in cancer biology—may cause cancer stem cells to become resistant to therapy.
"I believe that the tumor microenvironment plays an important role in defining heterogeneity among cancer stem cell populations," Dr. Schober surmises. "If we can understand how the heterogeneity of cancer stem cells is established and maintained and how this behavior influences a tumor's response to therapy, perhaps we can test patients' tumors upfront to determine what the most effective treatment would be to eliminate the tumor-initiating stem cells, and cause their tumors to disappear."