Attracting and cultivating talented early-career scientists has long been a hallmark of the culture at Fox Chase. Glenn F. Rall, associate chief academic officer and co-leader of the Immune Cell Development and Host Defense Program, sat down with four recently hired researchers — James S. Duncan, Sergei Grivennikov, Neil Johnson, and Stephen M. Sykes — to talk about what’s exciting at the bench.
Glenn F. Rall, PhD: Steve, let’s start with you. What’s the focus of your work in acute myeloid leukemia (AML)?
Stephen M. Sykes, PhD: We’re interested in determining the molecular mechanisms that distinguish malignant cells from normal cells as well as the methods that malignant cells use to resist chemotherapy.
James S. Duncan, PhD: Isn’t AML really diverse genetically?
Sykes: Very genetically diverse — this is one of the great problems within the disease. For many targeted therapies, the general approach is to identify a mutation that’s common within a cancer and then develop a drug that targets that mutation. The problem with AML is that it’s so genetically diverse, you would almost need an M-16 full of different targeted therapy bullets to try to treat the disease on a broad scale. We focus on finding molecular pathways that are not necessarily mutated, but are abnormally regulated across a broad spectrum of AMLs, that we can try to target to treat the disease.
Sergei Grivennikov, PhD: I work on the connection between inflammation and cancer. When large populations of people take non-steroidal, anti-inflammatory drugs like aspirin, we see a lower rate of many types of solid tumors. We study these mechanisms at work to see how human inflammatory cells can promote tumor growth. Cytokines are one such possible mechanism. They’re already implicated in many autoimmune diseases and there are many well-working cytokine inhibitors used to treat autoimmune diseases like arthritis and inflammatory bowel disease. We postulate that many of those inhibitors can potentially be applied to treat or prevent cancer.
Neil Johnson, PhD: I’m interested in mutations in the BRCA1 and BRCA2 genes. When these genes are defective, cells become more sensitive to different types of DNA-damaging agents; and we’re interested in the biology behind why that is. We’re particularly studying BRCA1 and protein products from these mutant alleles to see how they affect the biology of the DNA damage response and the response to therapeutics, as well as how these cells can become resistant to certain types of chemotherapy.
Rall: If you were to project your research or even the field forward five years or so, what do you imagine will come from studies in this pretty well-established field?
Johnson: This has an almost-immediate utility for personalized medicine. What people are starting to recognize is that there are lots of different types of BRCA mutations — the location of the mutation and type of mutation are different in different patients, and those variations have different effects on the phenotype of the disease and the response to therapeutics. Over time, I think patients will be grouped by their BRCA mutation type, and that will affect what therapy they’re administered and their prognosis.
Duncan: Our lab is interested in drug resistance as well but our focus is kinase inhibitors. Historically, people have utilized technologies that have allowed them to look at single kinases in a relatively linear fashion. Our goal is to study the kinome as a whole entity and to see how tumors can evade current therapies by altering their kinome state. Our technology allows us to determine what fraction of the kinome becomes either active or inactive within a tumor following drug treatment. Using this information, we can design new and effective kinase inhibitor combination therapies to better treat cancer. Currently, we’re focusing on genetic alterations in ovarian cancer that have specific effects on the kinome, such as KRAS or PTEN mutations. ■