Cancer Whack-A-Mole: Melanie Krook, PhD

Melanie Krook, PhD

We often talk about cancer as if it’s a single thing, a clear and definitive entity that can be found and eliminated. We want to “beat cancer” and “find a cure for cancer.” But cancer isn’t a monolith. Cancer tumors are made up of individual cells. And these cells are changing all the time, at different rates, and for different reasons. This means that cancer is really a kaleidoscope of cancerous cells. A mosaic that continuously changes, evolves, and evades. This is why some cancer treatments lose their effectiveness over time; the cancer cells change and the makeup of the tumor transforms, developing resistance to the therapies.

So how do we beat this Whack-A-Mole? Can we predict where the next mole is going to pop up so that we’re ready to whack it with the right therapy?

Melanie Krook, a post-doc in Sameek Roychowdhury’s lab at Ohio State, is searching for the answer to these questions. With her work, she is trying to understand how molecular and genetic changes in tumor cells lead to their resistance to therapies and if these changes can be predicted based on characterizing the mutations in the tumor.

I met Melanie while we were both in grad school at Michigan. Our labs and offices were in the same hallway, and we often celebrated and commiserated the ups and downs of grad school (and Notre Dame football) together. In grad school, she studied the role of a signaling receptor called CXCR4 and how it was involved in the growth and metastasis of Ewing sarcoma, a pediatric bone cancer. During her time in grad school, she characterized the differences in expression of CXCR4 in Ewing sarcoma tumors in different cellular contexts, underscoring the tumor’s heterogeneity.

Tumor heterogeneity describes the different traits and characteristics that are found both within a single tumor and between different tumors. These differences can arise from genetic mutations or from environmental cues that affect gene expression within tumor cells. These differences have been a major challenge to developing diagnostics and successful treatments for cancer.

Now, as a post-doc, Melanie has continued to investigate tumor heterogeneity, studying a receptor called the fibroblast growth factor receptor (FGFR). This receptor is involved in a variety of cellular processes, including proliferation, migration, survival, differentiation, and angiogenesis (outgrowth of new blood vessels). In healthy individuals, FGFR signaling is necessary and important for normal growth and development. But when FGFR signaling is improperly activated, often through genetic alterations, it can contribute to the development of cancer. Improper FGFR signaling is associated with numerous tumor types, including bladder tumors.

In response to FGFR’s association with various tumor types, multiple companies have been developing FGFR inhibitors as a therapy against these tumors, and multiple inhibitors are currently in clinical trials. Unfortunately, it appears that in many patients, the tumors eventually develop resistance to the inhibitor.

A valuable feature of the Roychowdhury lab is the direct connection between the research lab and the clinic. Tumor biopsies can be collected from patients and analyzed in the lab, and patient progress can be followed during a treatment regimen with FGFR inhibitors. Resistance to therapies can be tracked, and tumor specific mutations can be identified and characterized in lab. The close ties between the patients in the clinic and research conducted in the lab underscores the real-world value and impact that Melanie’s work could eventually have on patients. Using information gained from the clinical samples, Melanie has been working to characterize the changes within the tumor in order to better understand how resistance develops. She and the lab identified a mutation that was associated with FGFR inhibitor resistance. This led to the question of what other signaling pathways are involved in FGFR inhibitor resistance?

In the case of this specific mutation, Melanie observed that this mutation in FGFR inhibitor-resistant tumor cells was associated with higher levels of activation of another cell signaling pathway, the PI3K/AKT/mTOR signaling axis. This signaling pathway is involved in a host of cellular processes, including proliferation, motility, and survival, and its errant activation has been implicated in a variety of cancers. This pathway has been extensively studied and targeted in cancer, and drugs that target this pathway are readily available.

Melanie wondered if inhibiting this upregulated PI3K/AKT/mTOR pathway would impact how sensitive the tumor cells would be to FGFR inhibitor treatment. In other words, would blocking mTOR re-sensitize resistant cells to FGFR inhibitor treatment?

To answer this question, Melanie employed a combination therapy approach, treating FGFR inhibitor-resistant tumor cells with both a FGFR inhibitor and a mTOR inhibitor. She found that there was a synergistic effect with the two drugs. This means that when used together, the drugs had outsized effects and were more impactful than they would have been if they had been used individually.

In the future, these results could lead to a meaningful impact on patients. You could imagine a situation where patients are given a FGFR inhibitor treatment, and their progress is tracked. If resistance is observed, the tumor could be biopsied and analyzed to determine the newly arisen mutations. If the mutation involved hyperactivation of the PI3K/AKT/mTOR pathway, the patient could be given a mTOR inhibitor along with the FGFR inhibitor, re-sensitizing the patient to the FGFR inhibitor and improving the patient’s outcome.  

Returning to the Whack-A-Mole metaphor, Melanie’s work has provided a glimpse into the future where we’re able to predict where the next mole may pop up, as well as an understanding as to what kind of mallet will be needed to whack the mole back down. Melanie was focused on the FGFR pathway and a single secondary mutation, and while her results are promising, there’s still a lot of research to be done. However, similar approaches could be used to investigate additional mutations, signaling pathways, and tumor types. Melanie is continuing to work on elucidating the mutations associated with drug resistance and, in the future, her work may lead to meaningful impact on the lives of patients.

Special thanks to:

Melanie Krook, PhD, post-doc researcher, Roychowdhury Lab, Ohio State (Melanie.Krook@osumc.edu)