A Personal Vision
The new director of Neuro-Oncology favors team research and new clinical-trial designs to develop novel drugs for brain tumors
BY BOB HECKER
Vinay Puduvalli’s career trek from medical school in his native India to director of the at The Ohio State University was born of biological intrigue and patient compassion.
“As a house officer, I helped care for a 29-year-old woman with a highly malignant brain tumor, a glioblastoma,” recalls Puduvalli, MBBS, who recently was recruited from The University of Texas MD Anderson Cancer Center to Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James). “She’d become a new mother shortly before her diagnosis, and then she learned that she had less than a year to live.
“It was heart-wrenching. I became deeply interested in brain tumors overnight,” he adds. “The fundamental intellectual challenge of understanding why a cell goes off-track in the brain and develops into this malignancy, combined with the intensely human aspect of cancer, fueled my interest in neuro-oncology.”
After earning his medical degree, Puduvalli journeyed to the United States to study and practice both neurology and oncology. “In those days, in India, clinical demands were high and the idea of doctors doing research was alien; there was no infrastructure for it and no one to guide someone who wanted to do this,” he says.
After a year of basic research training at the University of Texas Medical Branch in Galveston, he completed a residency in neurology at the University of Texas Health Sciences Center and a fellowship in neuro-oncology at MD Anderson. He joined the MD Anderson faculty in 1999 and eventually became director of clinical research in the Department of Neuro-Oncology before coming to Ohio State in January 2013.
“With his wealth of experience and success in cancer patientcare, clinical trials, and basic and translational research, Dr. Puduvalli is an outstanding addition to our faculty,” says Russell Lonser, MD, chair of the Department of Neurological Surgery, which contains the Division of Neuro-Oncology.“
Dr. Puduvalli has expertise in developing treatments for brain and spine malignancies using a combined approach of targeted therapies, innovative clinical trial designs and rational combinations of anticancer agents,” says OSUCCC Director and James CEO Michael A. Caligiuri, MD. “His expertise includes clinical care of patients with brain and spine malignancies, as well as neurological complications of cancer. He also has a lab program focused on understanding the role of epigenetics in brain tumor and glioma stem cell biology, and translating these findings to new treatment options. His knowledge and skills are contributing to our vision of creating a cancer-free world.
Arnab Chakravarti, MD, chair and professor of Radiation Oncology, co-director of the Brain Tumor Program, and the Max Morehouse Chair in Cancer Research, describes Puduvalli’s recruitment to Ohio State as a “game-changer” for the neuro-oncology program. “Dr. Puduvalli brings a wealth of experience both in the clinical and translational sciences and brings with him fundamentally new strategies to find curative therapies for tumors, some of which are almost universally fatal.”
The American Cancer Society (ACS) expected more than 23,000 new cases of brain and other nervous system cancers in the United States in 2013 and an estimated 13,000 deaths from these malignancies. About 42 percent of all brain tumors are gliomas, and at least 80 percent of malignant gliomas are glioblastomas. These high-grade astrocytomas are the most common and deadliest of adult malignant primary brain tumors. The median survival is 15 months.
The problem, Puduvalli notes, is that these tumors are highly invasive and impossible to entirely remove surgically. Even with radiation and chemotherapy, there is only limited control of the tumor. The tumors grow within the protected environment of the brain and are highly resistant to most treatments. Furthermore, the number of treatments available for these and other central nervous system malignancies is limited.
Puduvalli’s research is directed toward developing new targeted therapies for these tumors and designing innovative clinical trials that rationally combine novel and standard anticancer agents. He is leading several trials involving epigenetic therapies and novel targeted agents. He and his laboratory personnel are investigating brain-tumor and glioma stem-cell biology with a focus on drug resistance and accelerating apoptosis (programmed cell death). His lab works closely with other Ohio State investigators to launch multidisciplinary efforts to fight brain cancers.
Puduvalli’s vision for the Division of Neuro-Oncology is to translate more discoveries into treatments and to do so in a way that takes into account patients’ quality of life. Ohio State, he says, has the multidisciplinary resources and the will to help realize this vision. He believes this will bring together the strong efforts in clinical care, patient support and survivorship already established at the university.
“Leadership at the OSUCCC – James is strongly invested in the success of its faculty,” he says. “In addition, the OSUCCC – James administration has a single-minded focus on excellence that is supported by extensive resources and talent in the medical center and the university.”
Puduvalli will strengthen the integration of clinical neuro-oncology research with the existing brain-tumor research group housed primarily in the Dardinger Neuro-Oncology Center. Their work involves preclinical models, viral therapies, tumor profiling and targeted-agent identification. Puduvalli plans to collaborate closely with the Department of Neurological Surgery, the Department of Radiation Oncology, and Ohio State’s Neurosciences Signature Program, led by Ali Rezai, MD. Recognizing the impact of brain tumors in pediatric patients, his group is developing collaborations with Nationwide Children’s Hospital. He will also work closely with the departments of Pathology, Radiology, Physical Medicine and Rehabilitation, and Psychiatry.
“We are part of a major land-grant university, and we want to make best use of this unique resource,” Puduvalli says. “Neuro-oncology must connect with the many university groups involvedi n cutting-edge research, such as pharmacy, veterinary medicine, bioengineering, biomedical informatices and newer areas such as nanotechnology. We can then achieve the critical mass that creates synergy. When appropriate, we will work with pharmaceutical companies to bring novelt reatments for our patients.
“Our ultimate goal is to rapidly and effectively translate research findings into better treatments and to become the ‘go-to place’ for malignant brain and spine tumor treatment in the region and, eventually, nationally.”
“Gliomas are the most devastating of primary brain tumors,” Puduvalli says. “Basic research is giving us a deeper understanding of their biology. As a result, the next generation of treatments will be tailored to the molecular features of brain tumors rather than to their pathological characteristics. One area of our research is the role of epigenetic changes in tumor biology.”
Epigenetics refers to chemical changes in genes that affect their expression but do not involve changes in the DNA sequence such as mutations. Consequently, epigenetic changes in tumors are potentially reversible.
Puduvalli and his lab are investigating whether epigenetic mechanisms help cancer cells survive, proliferate and resist therapy. “We use insights gained from our lab research to generate clinical trials using drugs that modify epigenetic responses in malignant glioma,” he says. “This concept drives a significant part of the basic and clinical components of my research.” Puduvalli currently leads clinical trials that utilize some of these agents in combination strategies for patients with glioblastoma.
One of his trials (NCT00555399) focuses on overcoming resistance to the therapeutic agent cisretinoic acid. The drug pushes malignant cells to develop more benign behavior, but epigenetic changes in the cells can thwart the process. “So we’re combining the drug with a class of epigenetic-targeting agents called histone deacetylase (HDAC) inhibitors to overcome the resistance and enhance the therapy,” Puduvalli says.
A second trial (NCT01266031) uses the HDAC inhibitor vorinostat to help patients overcome resistance to bevacizumab, an angiogenic inhibitor that tumors often evade. “There is a huge opportunity for developing drugs that target and shut down epigenetic mechanisms in specific contexts so that even conventional therapies can work better,” Puduvalli says.
“Cancer cells hijack normal cell mechanisms to their benefit. Their ability to use normal growth factors, blood vessel development, signals from surrounding tissues and immune suppression works to their advantage for growth and proliferation. Much of our research is directed toward disabling the mechanisms they use to hijack these processes without affecting normal cells. Gaining insights into various aspects of tumor biology is a powerful tool for doing that.”
Puduvalli’s research also addresses the need for advanced clinical trial designs when evaluating targeted drugs.
Traditional clinical trial designs are built around the older chemotherapeutic agents, but most of the newer agents don’t quite fit that model,” he says. “There are so many new agents emerging that, if we use traditional models, we would spend decades determining which drugs make the cut for further study. If you take into account drug combinations, there are even more options to explore.
“It’s imperative that we use new clinical trial designs to screen these agents more efficiently,” Puduvalli adds.
In one case he and his group are using a Bayesian adaptive study design, which uses interim data to influence the ongoing trial.
“In traditional trial models,” Puduvalli says, “you must complete the study to gain the full power of analysis of comparison and do not use the information gained along the away. A Bayesian design uses information as it emerges to inform the decision-making of the trial in real time. This potentially allows the trial to be completed in a more efficient way and helps pick the winner among several treatments.”
Such designs can also be used in phase I trials to more efficiently identify the right dose for a new drug and in phase II trials to identify the right patients for the right treatments.
“We also can test whether a patient’s specific tumor markers will predict responses to targeted treatments,” he says. “In fact, we can test multiple markers and agents within the same trial. Combined with insights into tumor biology from lab studies, this is the way toward personalized and highly effective treatments for malignancies, which is the holy grail of cancer research.”
Puduvalli believes it is the Division of Neuro-Oncology’s mission and responsibility as part of Ohio State’s nationally recognized cancer program to offer the community the widest possible array of evidence-based treatments. This involves a team approach with close partnerships between Neurological Surgery and Radiation Oncology.
“More molecular-based data are emerging for selecting the best therapies for patients, but these are not easily accessible in the community setting. I think we as an academic medical center have a strong obligation to fill that gap,” Puduvalli says. “Given the paucity of standard treatment options for brain tumor patients, our patients deserve access to every reasonable cutting-edge therapy available. We will continue developing new treatments that improve life span and maintain patients’ quality of life, and we will do more to connect with academic partners regionally and across the country to make innovative care available to all. Ohio State aims to be a leader in that effort.”
Puduvalli, Lonser and Caligiuri agree that this trend should be exciting to community oncologists and their patients.
“It’s all about translating basic science findings to the application of effective therapies,” Lonser says. “It’s leading to more and more clinical trials at Ohio State for neuro-oncology patients.”
“Doctors will find us to be willing and collaborative partners who will open doors for their patients to receive the latest treatments,” Puduvalli adds. “We view this as a true collaboration to benefit patients no matter where they are referred from.”
For incentive, he need only remember the young woman in India whom he helped treat for glioblastoma many years ago as a neurosurgery house officer.
After assisting in her surgery, Puduvalli was assigned to inform her family of both the severity of the tumor and that the surgery could not remove it all. Her only remaining option at that time was radiation therapy to prolong her life. “Beyond that, we had nothing to offer her, a fact I found very frustrating.”
Through team research and the pursuit of science-based therapies, he hopes to erase such scenarios.