Patient-specific Cancer Care
Neuro-oncology Zeroes in on Specific Disease Pathways to Personalize Brain Tumor Treatment
Anti-cancer agents targeted to work at the cellular level have revolutionized cancer treatment, expanding medicine’s arsenal against the disease. By identifying and binding to primary and metastatic cancer cells, the biological agents have improved efficacy and reduced toxicity.
Now, neuro-oncologists at the Mischer Neuroscience Institute (MNI) at Memorial Hermann-Texas Medical Center and UTHealth Medical School are taking brain tumor treatment to the next level, typing tumors molecularly and delivering more personalized treatment.
“Having the capability to identify specific cancer genetic signatures allows us to choose one chemotherapeutic drug over another, a dramatic change in the way we treat primary and metastatic brain tumors,” says fellowship-trained neuro-oncologist Sigmund Hsu, M.D., an assistant professor in the Vivian L. Smith Department of Neurosurgery at UTHealth Medical School. “Before the discovery of these signatures, we made decisions about treatment based on the location of the tumor in the body and how it looked under the microscope during pathological examination. Advancements made through cancer research have allowed us to move away from the shotgun approach to treatment and moved us a step closer to finding the silver bullet.”
Brain Tumor Research
Dr. Hsu is principal investigator of one of the first clinical trials to use immunotherapy in combination with standard anti-angiogenic therapy for cancer. Called “ReACT: A Phase II Clinical Trial Targeting the EGFRvIII Mutation in Glioblastoma Patients with Relapsing Disease,” the study is investigating whether adding an experimental vaccine called rindopepimut, also known as CDX-110, to the commonly used chemotherapeutic drug bevacizumab can improve progression-free survival of patients with relapsed EGRFvIII-positive glioblastoma multiforme (GBM).
The ReACT trial is a significant step forward in using next-generation sequencing (NGS) for the treatment of GBM. “Mutations that lead to epidermal growth factor receptor (EGFR) overexpression or overactivity have been associated with a number of cancers including GBM, in which a specific mutation called EGFRvIII is often observed,” says Dr. Hsu, whose clinical and research interests include the discovery of new and more effective therapies for patients with primary brain tumors, treatment of metastatic cancer to the brain and spinal fluid and the evaluation and treatment of neurological problems in cancer patients. “While we’ve used NGS and genetic-based treatment for brain metastases of melanoma, lung cancer and breast cancer, we’re still in the infancy of using genomics for primary brain tumors such as GBM.”
Expanding Neurooncology Service
The arrival of Dr. Hsu in 2012 added strength to MNI’s expanding neurooncology service, which focuses on providing the best state-of-the-art treatment and access to investigational trials for appropriate patients. He was recruited to MNI by fellowship-trained neurologist and neuro-oncologist Jay-Jiguang Zhu, M.D., Ph.D., who is director of the Institute’s Clinical Cancer Program and an associate professor in the Vivian L. Smith Department of Neurosurgery at UTHealth Medical School.
“Thanks to next-generation sequencing, we understand more about the underlying DNA mutations that drive cancer growth, which has allowed us to adapt treatment to the specific genetics of the tumor,” says Dr. Zhu, who focuses his practice on primary brain tumors and primary central nervous system (CNS) lymphomas as well as brain metastases
and leptomeningeal spread of systemic malignancies. “As we learn more, we’re replacing traditional cytotoxic treatments with less toxic, potentially more effective therapies that target changes in a patient’s unique DNA that promote the survival of cancer cells. These breakthrough approaches to treatment with more clinical trials available at MNI have allowed us to increase our volumes by nearly 50 percent since 2009.”
Last year, MNI was chosen as a site for the FoundationOne™ Registry, to which physician researchers report data gathered using the company’s proprietary genomic profiling technology to expand patients’ treatment options. FoundationOne’s next-generation sequencing interrogates the entire coding sequence of 236 cancer-related genes plus 47 introns from 19 genes that are often rearranged or altered in solid tumor cancers. By identifying mutations in these genes, the technology gives physicians more information about which unique tumor types are more likely to respond to certain chemotherapeutic drugs or may be a good match for a clinical trial.
Physicians affiliated with MNI are also investigating other ways to reduce cytotoxicity in the treatment of brain tumors. Dr. Zhu is principal investigator of three clinical trials that give eligible study participants access to new and advanced treatments. The first is a Phase III multicenter, randomized, controlled trial designed to test the efficacy and safety of an experimental, portable, battery-operated medical device called the NovoTTF-100A for newly diagnosed GBM patients in combination with temozolomide, compared to temozolomide alone. The device, which patients wear on their scalp, provides a constant, safe, low-voltage electric field that has been shown to reduce tumor cell survival and division capacity.
Dr. Zhu is also principal investigator of a randomized, double-blind, controlled Phase IIB clinical trial testing the efficacy of the vaccine ICT-107 for newly diagnosed GBM patients following resection and chemoradiation. ICT-107 is an autologous vaccine consisting of dendritic cells from the patient’s own immune system, which are isolated from blood by apheresis and pulsed with synthetic peptides from six GBM-specific stem cell-associated antigens – MAGE-1, HER2, AIM2, TRIP-2, GP100 and interleukin 13 receptor alpha. The sensitized dendritic cells are then returned to the patient by subcutaneous injection as an immunotherapy to attack the tumor.
The third trial, an open-label Phase I/II (Safety Lead-in) study of trans sodium crocetinate (TSC) with concomitant radiation therapy and temozolomide in newly diagnosed GBM, examines the safety and efficacy of the radiation sensitizing effect of TSC in combination with fractionated radiation.
Brain Tumor Research Program
Dr. Zhu and Min Li, Ph.D., director of MNI’s Cancer Research Program, work together as part of the Institute’s new Brain Tumor Research Program.
An associate professor in the Vivian L. Smith Department of Neurosurgery and the department of Integrative Biology and Pharmacology at UTHealth Medical School, Dr. Li directs a laboratory where researchers are investigating molecular and cellular mechanisms of cancer pathogenesis and developing new therapeutics for human cancers, including pancreatic cancer and brain tumor. His research has both basic and translational components and expands in multiple directions, including zinc transport, nutrition uptake and metabolism, protein-protein interaction, microRNA , drug resistance, and cancer prevention and therapy.
“Our objective is to gain understanding of the molecular changes in patient tumor specimens,” Dr. Zhu says. “Understanding those changes will give us prognostic factors that enable us to determine which patients will respond well to a given drug or treatment with multiple drugs. Some genes have already been identified, and Dr. Li is looking for others with prognostic value. Knowledge of the molecular changes that take place in cancer cells will help us define treatment targets for specific patients, and aid in choosing chemotherapies or specific molecular-based treatments. Our ultimate goal is to provide personalized cancer care, maximize efficacy and minimize toxicity
for each patient."
In the pediatric arena, the promising results of translational studies conducted by David Sandberg, M.D., FAANS, FACS, FAAP, director of pediatric neurosurgery at Children’s Memorial Hermann Hospital in the Texas Medical Center, have demonstrated the safety of infusing chemotherapeutic agents directly into the fourth ventricle of the brain.
These studies led to a pilot clinical trial, available only at Children’s Memorial Hermann Hospital and The University of Texas MD Anderson Cancer Center, for children with recurrent tumors in this area of the brain. This radically new approach to chemotherapy allows Dr. Sandberg and team members to circumvent the blood-brain barrier and deliver agents directly to the site of disease, minimizing side effects by decreasing systemic
“The collaboration with MD Anderson is good news for children and adolescents with brain tumors,” says Dr. Sandberg, who holds joint appointments as associate professor in the Vivian L. Smith Department of Neurosurgery and the department of Pediatric Neurosurgery at UTHealth Medical School, and is also an associate professor in the department of Neurosurgery at MD Anderson Cancer Center. “Using novel approaches to surgery and chemotherapy, we have the potential to minimize side effects from treatment and achieve better long-term survival rates.”
In addition to the single-center clinical trial for recurrent medulloblastoma, ependymoma and atypical teratoidrhabdoid tumors using direct infusion of chemotherapy into the fourth ventricle, other novel approaches are being investigated by the combined research team, including administration of natural killer cells into the fourth ventricle to attack tumor cells via cell-directed therapy.
As Mischer Neurosciences continues its expansion across the city, neurooncology services are available at several campuses, including Memorial Hermann-TMC, Memorial Hermann Memorial City Medical Center, Memorial Hermann The Woodlands Hospital, Memorial Hermann Southwest Hospital and TIRR Memorial Hermann. “MNI’s infrastructure expansion and Memorial Hermann’s acute care presence across Houston have allowed for the extension of neuro-oncology expertise and capabilities outside the Texas Medical Center,” says Dr. Zhu, who also consults on patients with brain tumors at TIRR Memorial Hermann, the top rehabilitation hospital in the southern half of the United States.
In 2013, TIRR Memorial Hermann extended its cancer rehabilitation programs throughout the Greater Houston community and added survivorship wellness programs at key locations. “Many people return to normal life after cancer treatment, but a growing number, as a result of their diagnoses, are learning to cope with a decline in function related either to the disease or to the effects of chemotherapy and radiation therapy, which have complications of their own,” says Jacob Joseph, M.D., clinical chief of Specialty Rehabilitation Programs at TIRR Memorial Hermann and an assistant professor of physical medicine and rehabilitation at UTHealth Medical School. “We see a lot of people who are excited to be alive after their cancer treatment, but then they discover they’re living with issues that affect their quality of life. These patients have led us to make a concerted effort to address survivorship issues in greater depth.
Dr. Zhu considers the collaboration with TIRR Memorial Hermann an important part of the comprehensive continuum of care offered through the Mischer Neuroscience Institute. “The traditional goal of neuro-oncology has been to ensure that patients live as long as possible with enhanced quality of life,” he says. “We’ve added to that a new goal: to maximize function and help our patients maintain meaningful life roles insofar as possible at every stage of treatment and recovery.”TIRR is a registered trademark of TIRR Foundation.