A Targeted Approach to Tackling Tumors’ Drug Resistance

A large gap remains in understanding which of the many cancer mutations is actionable — meaning susceptible to drug therapy — and which is simply a passenger or silent mutation.

Mohamed Abazeed, MD, PhD, is working to answer that question. Dr. Abazeed joined Cleveland Clinic in late 2013 from the Harvard Radiation Oncology Program.

As a radiation oncologist with training in radiation science, genomics and molecular biology, Dr. Abazeed designs physical and computational platforms to help discern which mutations are significant and which may not be. His work involves identifying the genetic abnormalities that make tumors resistant to treatment and developing a physiologically relevant model to test gene/drug treatment protocols.

Dr. Abazeed’s research approach initially used more than 1,000 genetically diverse, patient-derived cell lines from a variety of solid tumors. Grown in culture, these cells lines were comprehensively genetically profiled and tested to see how they respond to radiation or particular drugs. “We have developed unique computational platforms based on matching algorithms that allow us to couple the resistance of these tumors with particular genetic alterations,” says Dr. Abazeed.

Xenografts as Patient Avatars

Clinical tissue samples form the basis of the next step in the research process. Dr. Abazeed’s team receives a section of solid tumor within hours of a cancer patient’s surgery. That tissue, which will be fully sequenced to determine its genomic profile, is injected into a mouse to create a xenograft. Better known as patient-derived tumor xenografts, these models preserve the original characteristics of a patient’s cancer and mimic the disease more effectively than cancer cell line-derived models.

This allows Dr. Abazeed’s team — which includes cancer biologist Craig Peacock, PhD, whose expertise is in the development of the patient-derived mice — to evaluate therapies in a more individualized and targeted way, potentially leading to significantly improved clinical trial design.

“That is the concept of a patient avatar,” Dr. Abazeed explains. “We can apply the information taken from the cell line data in terms of what the genetic predictors of response to therapy may be, and we test them using this more physiological system.” In short, the cell line information gives some indication of which therapy may be most effective, and the xenograft provides a specific individual test bed.

Investigators previously employed this approach, but its use has been limited due to the required expertise and access to fresh tissue.

“It doesn’t influence a patient’s treatment directly yet, but you can see how the information gathered from these studies significantly accelerates both clinical studies and potentially therapeutic options for patients,” says Dr. Abazeed. His team injected its first mouse with a patient tumor sample at the Taussig Cancer Institute in March 2014.

Dr. Abazeed’s laboratory is equipped with next-generation genetic sequencers, coupled with industry-modeled, high-throughput profiling capabilities, enabling the investigators to rapidly generate and test novel hypotheses. In addition to Dr. Peacock, who arrived in 2014 from Johns Hopkins University, Dr. Abazeed’s team includes postdoctoral research fellow Brian Yard, PhD.

Dr. Abazeed will first study the cell line/xenograft approach in lung carcinomas. If it proves to be a physiologically relevant system, the team will expand to other solid tumor types.

World-Class Genetics Training

After completing his radiation oncology residency training at Boston’s Brigham and Women’s Hospital, Dr. Abazeed was awarded a two-year postdoctoral appointment at the Broad Institute of MIT and Harvard. The Broad Institute is a premier academic, genomics-focused research organization performing leading-edge cancer genetics research.

While at the Broad, Dr. Abazeed and colleagues discovered that alterations in the NFE2L2 gene are present in 34 percent of lung squamous cell cancers, which makes these cancers resistant to radiation and chemotherapy. Working with Novartis, the team developed a drug, BKM-120, targeted against that mutation.

A Phase IIb clinical trial to evaluate BKM-120 is underway at the Dana Farber Cancer Institute. Dr. Abazeed and colleagues filed a patent on their mutation discovery and the coupling of that mutation to the drug. The clinical trial will help determine whether patients with the mutation respond better to the medication than do those lacking the mutation.

At Taussig Cancer Institute, Dr. Abazeed’s first research project with the mouse xenografts will involve the study of BKM-120, which is also known to counteract the KEAP1 mutation, found in 23 percent of patients with lung adenocarcinomas. “Before moving on to a Phase II study, we want to test this drug/gene combination in a more physiological system,” he explains, “and we believe these primary xenograft models are an ideal link between the bench and the bedside.”

Going forward, Dr. Abazeed will focus primarily on identifying treatments for the low-frequency genetic mutations found in cancers. Because it would be nearly impossible to find enough patients with low-frequency mutations to conduct a statistically meaningful clinical trial, Dr. Abazeed hopes to initiate a new type of clinical study at the Taussig Cancer Institute.
“We would love to implement a clinical trial design that compares traditional chemotherapy to targeted therapies in cancers with multiple low-frequency alterations,” he says.

Photo by Russell Lee.