Precision Oncology: New Tests Look Beyond Genes
The tests are based on research conducted by Columbia University Irving Medical Center (CUIMC) investigators—and could pave the way for a more precise approach to cancer therapy and help find effective drugs when conventional approaches to precision medicine have failed.
“This means that the vast majority of cancer patients who do not have actionable mutations, or have not responded to, or have relapsed after chemotherapy or targeted therapy, now have access to additional tests that can help their oncologist select the treatment best suited to their specific tumor,” says the tests’ lead developer, Andrea Califano, Dr., chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons.
The two tests, DarwinOncoTreat and DarwinOncoTarget, are available exclusively through the Laboratory of Personalized Genomic Medicine in the Department of Pathology and Cell Biology at Columbia University Vagelos College of Physicians and Surgeons. The tests were developed by DarwinHealth, a Manhattan-based biotech firm founded in 2015 by Califano and colleague, Gideon Bosker, MD.
A new equation for precision cancer therapy
Cancer arises when multiple genes inside cells are mutated, causing cells to divide and grow uncontrollably. Current precision medicine approaches aim to disable those mutated genes, and many cancer patients today have their tumors analyzed for mutated genes that can be treated with available targeted therapies. These are called “actionable mutations.”
“Unfortunately, the gene-centric approach to cancer treatment which, for the most part, has relied on using a single drug to attack an individual mutation, has proved effective for only a relatively small percent of patients,” says Califano. “This is because most patients lack actionable mutations and, even among those who do have such molecular alterations, most either fail to respond to the targeted therapy or rapidly develop drug resistance.”
Many scientists now believe that—complementing its initial focus on mutated genes—precision oncology must now also address the activity of otherwise normal proteins and molecular pathways that are ultimately responsible for cancer cells’ malignant behavior. The catch is that while genes can be readily sequenced to assess the presence of mutations, a complete tally of the wayward activity of potentially relevant proteins is much harder, thus thwarting previous attempts to identify the precise set of proteins that controls the cancer cell’s “engine room.”
Using a branch of mathematics called information theory, Califano’s team, along with Mariano Alvarez, PhD—DarwinHealth’s Chief Scientific Officer—developed algorithms that can identify these critical proteins—dubbed “master regulators”—that hold the key to the malignant behavior of cancer cells. The algorithms use mRNA levels—easily measured with conventional methods—of the proteins’ numerous targets as an indirect but highly accurate indicator of protein activity. Importantly, unlike any other available approach, these algorithms uncover the hidden networks of proteins that work together to control abnormal cell activity in an individual patient’s tumor. “These master regulators represent the ultimate on-off switches in the cancer cell’s regulatory ‘malware,’ providing a new class of targets for anticancer therapy,” Califano says.
Putting these tools to work
The two new clinical tests are powered by Califano’s research at CUIMC over the past 15 years, and by further refinements developed at DarwinHealth. One test, DarwinOncoTarget, identifies all proteins in an individual’s tumor that are acting abnormally and for which an FDA-approved or investigational drug already exists. The second test, DarwinOncoTreat, homes in on the entire complement of master regulator proteins responsible for launching and maintaining a specific tumor, to predict the drugs that, by interfering with these proteins, will most likely benefit the patient.
“We are very pleased to be the first institution to provide access to these tests,” says Kevin Roth, MD, PhD, chair of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons. “Making these tests available to cancer researchers and oncologists around the country will give the cancer community new tools to help align cancer treatment to the unique characteristics of a patient’s tumor. The tests are now available in our CLIA-certified Laboratory of Personalized Genomic Medicine, meaning that they meet quality laboratory standards for reproducibility to protect patient safety and can thus be used both in clinical trials and for individual patients.”
Clinical trials relying on the results of these tests are now underway at CUIMC, including a new study of metastatic pancreatic cancer, a phase II trial of HER2-positive metastatic breast cancer patients who have not benefited from trastuzumab (Herceptin) therapy, and a phase II trial for gastroenteropancreatic neuroendocrine tumors.
The two tests are also being considered for inclusion in a multicenter study of pediatric malignancies led by Dana Farber Cancer Institute (The Genomic Assessment Informs Novel Therapy (GAIN) Consortium Individualized Cancer Therapy 2, iCat2 Study).
“DarwinOncoTreat and DarwinOncoTarget may provide an entirely novel precision oncology-based diagnostic platform for patients who either have no actionable genetic alterations or who have not responded to, or have relapsed, following targeted or traditional therapies,” says Mahesh M. Mansukhani, MD, medical director of the Laboratory of Personalized Genomic Medicine.
Andrea Califano is also the Clyde and Helen Wu Professor of Chemical and Systems Biology in the Departments of Biochemistry & Molecular Biophysics and Biomedical Informatics at Columbia University Vagelos College of Physicians & Surgeons.
Kevin Roth is also the Donald W. King, MD and Mary Elizabeth King, MD Professor of Pathology and Cell Biology at Columbia University Vagelos College of Physicians & Surgeons.
The newly available tests utilize novel, proprietary algorithms developed by Columbia University investigators, which have been licensed exclusively to DarwinHealth by Columbia University.