It has been nearly a decade since the Precision in Pediatric Sequencing (PIPseq) program at NewYork-Presbyterian/
Dr. Jennifer Oberg
Dr. Jovana Pavisic
Jennifer Oberg, EdD, MA, is Director of Research for the Pediatric Cancer Foundation Developmental Therapeutics Program and Assistant Professor in Pediatric Hematology, Oncology, and Stem Cell Transplantation at Columbia. The nationally recognized program provides cutting-edge anti-cancer therapies not ordinarily available in the community for patients with incurable solid tumors and hematologic malignancies. Dr. Oberg has been involved in precision medicine endeavors since 2013 when PIPseq was launched and today she also leads that program.
Jovana Pavisic, MD, MA, is a pediatric oncologist in the Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation at NewYork-Presbyterian Morgan Stanley Children’s Hospital. In 2019, Dr. Pavisic completed a fellowship in pediatric oncology at Columbia, where she became involved in the PIPseq program and also was mentored by Andrea Califano, Dr., Chair of the Department of Systems Biology at Columbia. She then joined the faculty there as Assistant Professor in Pediatric Hematology, Oncology, and Stem Cell Transplantation on a research track and received a Florence and Herbert Irving Clinical Research Career Award, a highly competitive grant that enabled her to dedicate her time more exclusively to research.
Together, Dr. Oberg, Dr. Pavisic, and their Columbia colleagues continue to build on the exceptional endeavors of PIPseq as they seek to identify the molecular drivers of each pediatric patient’s tumor to better personalize treatment recommendations.
Since the launch of PIPseq, we have also integrated a community-based sequencing program for any patient diagnosed with high-risk cancer residing in the New York, New Jersey, and Connecticut Tri-State area.
— Dr. Jennifer Oberg
“This program was specifically implemented to promote clinical decision making,” says Dr. Oberg. “Tumor whole exome and transcriptome sequencing is a standard component of our protocol for patients with relapsed/refractory disease with a predicted survival of <50 percent and patients newly diagnosed with unusual tumors for which no standard of care therapy is available. Since the launch of PIPseq, we have also integrated a community-based sequencing program for any patient diagnosed with high-risk cancer residing in the New York, New Jersey, and Connecticut Tri-State area. Doctors can submit their patients’ tumor samples to Columbia and we will clinically sequence those tumors to guide their physicians in making decisions about treatment.”
“My interests are in understanding how we can better use cancer genomic data to guide treatment and to make treatment more personalized and effective for patients,” says Dr. Pavisic, who continues to work with Dr. Califano and his systems biology lab.
Dr. Califano’s lab has pioneered innovative, systems biology approaches to systematically identify the molecular drivers that lead to cancer development, progression, and to the emergence of drug resistance, including at the single-cell level. He has developed the clinical OncoTarget™ and OncoTreat™ tests to analyze whole transcriptome sequencing (RNASeq) data of a patient-derived tumor sample. OncoTarget identifies aberrantly activated proteins for which a clinically relevant targeted inhibitor already exists and OncoTreat predicts drugs that will shut down the molecular drivers of a patient’s cancer based on extensive drug perturbation data generated across cancer cell lines. The tumor-specific dependencies are then matched with FDA approved drugs as well as investigational drugs in Phase 2 and 3 clinical trials. Dr. Pavisic is now studying the potential application of these approaches to pediatric cancers.
“Dr. Califano has generated computational algorithms that look at how we can use cancer gene expression data to infer which regulatory proteins are very highly active in patient cancer cells and then predict drugs that are going to reverse the dysregulated proteins,” explains Dr. Pavisic. “My work focuses on how we can leverage the OncoTarget and OncoTreat tests developed and validated in adult cancers to improve treatment of pediatric cancers. Dr. Califano’s lab has added a novel repertoire of algorithms analyzing tumor sequencing data that we can now run for our pediatric patients at Columbia to understand the dysregulated proteins driving a patient’s cancer and the drug candidates that can reverse their activity, which can't be done anywhere else. Through PIPSeq and our collaboration with Dr. Califano and Columbia’s pathology department, we have been able to make these tests compliant and available clinically to our pediatric patients.”
“We are able to provide clinical grade whole exome and transcriptome sequencing for newborns through early adulthood,” notes Dr. Oberg. “About one-third of the patients that we are sequencing have a brain tumor, including diffuse intrinsic pontine glioma, ependymoma, medulloblastoma, and glioblastoma. These are the high-risk neuro-oncology patients. We also are sequencing a wide range of extracranial solid tumors such as osteosarcoma and Ewing sarcoma, adrenal tumors, and liver tumors...any cancer that falls into the high-risk or rare categories. We have even sequenced a patient with mesothelioma, which is very, very rare in the pediatric setting. So we do see patients with an extraordinary wide range of tumors.”
“As the program is directed to patients with high-risk and rare cancers and includes many patients with relapsed or refractory disease, which tend to occur more in adolescents and young adults, we do follow patients who relapse into their 20s and 30s,” adds Dr. Pavisic. “About two-thirds of patients we sequence are diagnosed with solid tumors. About 90 percent of patients with pediatric blood cancers, especially with leukemia and lymphoma, are surviving their disease. Since they don't fall into the high-risk or relapsed/refractory category, we generally do not perform genetic testing in this population.”
“While major strides have been made in the availability of standard therapies to cure many young patients with cancer, a number of these standard therapies involve combinations of cytotoxic chemotherapy,” says Dr. Pavisic. “For diseases such as acute myeloid leukemia or osteosarcoma and others that are hard to treat, we’ve maximized the amount of cytotoxic chemotherapy that we can administer safely. Therefore, the next step of improving care for these patients is finding less toxic, more targeted therapies. This is where precision medicine also comes into play. Advances in treatment are going to involve identifying the molecular drivers of each patient’s cancer to determine drug therapies that can target the cancer with fewer adverse effects.”
The sequencing that we’re performing is to identify drug targets for more targeted therapy, but it’s also to understand prognosis so we can determine which patients may need more aggressive care.
— Dr. Jovana Pavisic
"At the same time, for some of these cancers that we are having success with, we want to be able to de-intensify therapy when possible for patients who are expected to do well,” continues Dr. Pavisic. “Part of precision medicine is also understanding prognostic biomarkers and how we can define patients who will need more aggressive therapy or not. The sequencing that we’re performing is to identify drug targets for more targeted therapy, but it’s also to understand prognosis so we can determine which patients may need more aggressive care.”
According to Dr. Pavisic, another layer of understanding encompasses genetic predisposition to cancers, which is a fairly common occurrence in pediatric cancers. “Even in patients without a family history of cancer, a genetic linkage is uncovered in up to 10 percent of patients in our sequencing program,” says Dr. Pavisic. “This information greatly affects how we treat the patients and how we do surveillance down the line. All of these pieces come into play when we are trying to improve care for patients. But research in pediatrics is uniquely challenging due to smaller patient populations and limited data for many drugs in pediatric patients. So Columbia is collaborating with institutions around the country to accrue enough patients and data for these rare and difficult-to-treat pediatric cancers.”
In 2020, the Herbert Irving Comprehensive Cancer Center at Columbia was selected as one of 10 NCI-designated Cancer Centers awarded supplemental funds to participate in the National Childhood Cancer Registry (NCCR). The goal of the NCCR is to generate a comprehensive population level data set of pediatric oncology patients that can stimulate discovery projects related to tumor biology and identify targets for pediatric specific drug development to improve care and outcomes of pediatric patients with cancer. Dr. Oberg and Dr. Pavisic are leading the Columbia effort.
Dr. Oberg and Dr. Pavisic stress the importance of their collaboration, which bridges the research world and the clinical world. “While tremendous progress has been made in the treatment of pediatric cancers, oncologists are still challenged by those that fail to respond to treatment or develop resistance to treatment and recur. The key to our success in the battle against these cancers lies in the biology of each child’s cancer,” says Dr. Oberg. “Columbia faculty have been at the forefront of research in this field and continue to lead in a very thoughtful way to bring their discoveries to patients.”