Drug Discovery in Academia: Karson Kump

Karson Kump, MS

You watch tv and see a pharma company’s ad its latest drug, or you read about a major milestone from a biotech start up. You may think that these companies are where drug discovery happens. But drug discovery and development aren’t just for pharma companies and biotech startups. Academia plays an important role, too.

When I wrote about drug development in the context of the startup company where I work, I briefly discussed how the company’s technology was originally discovered in the lab of David Zacks at the University of Michigan. This was mostly presented in the context of being a launching pad for the company. I didn’t spend much time exploring what drug discovery and development was like in academic labs.

But academic labs are actively involved in drug discovery, pursuing new therapeutic molecules and novel approaches for treating diseases. One example of this is the work of Karson Kump, a graduate student in the Chemical Biology PhD program at the University of Michigan.

Karson is a member of Zaneta Nikolovska-Coleska’s lab, which focuses on identifying and developing small molecules that bind and inhibit interactions between proteins. In this case, the proteins of interest are members of the Bcl-2 family. This family of proteins plays an instrumental role in regulating the fate of a cell by governing the constitution of its mitochondria.

The mitochondria are a central nexus for the cell death pathways. When death is triggered, some members of the Bcl-2 family, like Bax and Bak, form holes in the mitochondria, releasing mitochondrial proteins into the rest of the cell and propagating the cell death signaling cascade.

The pro-death members of the Bcl-2 family are regulated by other Bcl-2 family members, including Bcl-xL, Bcl-2, and Mcl-1. These proteins bind to Bax and Bak, locking them up and preventing them from forming holes in the mitochondria.

Normally, this is a finely tuned process that maintains the proper balance of cell death and survival. However, in cancer, this balance is thrown out of whack. Many blood cancers, like various lymphomas and leukemias, possess a mutation that results in the overexpression of pro-survival Bcl-2 family members.

Overexpression of Bcl-2, for example, is commonly found in these cancers. This leads to an abnormally high amount of the Bcl-2 protein in the cell, meaning that activation of the mitochondrial death pathway is increasingly challenging, giving these cancer cells a means to avoid cell death. So, it would seem logical that inhibiting Bcl-2 function would help sensitize these cancer cells to death. And people are doing just that, with multiple drug companies pursuing Bcl-2 inhibitors.

But there are limitations to Bcl-2 inhibitors. Cancers can develop a “survival dependence” on one of Bcl-2’s relatives. This means that the cancer cells can use another structurally and functionally similar Bcl-2 family member to survive. This renders the cells insensitive to the Bcl-2 inhibitors and helps promote the continued survival of the cancer cells. Alternatively, while the initial responses to Bcl-2 inhibitors could be promising, the cancer cells can develop mutations that lead to overexpression and abnormal abundance of other pro-survival Bcl-2 family members, such as Mcl-1 and Bfl-1.

This is where Karson and the Nikolovska-Coleska lab come into play. The lab works on two aspects of the Bcl-2 protein interactions. On one side, Karson and the lab works to screen and identify which Bcl-2 protein family member is contributing to the cancer’s survival. The lab has optimized a profiling assay which looks at mitochondrial health of the cancer cells to identify which Bcl-2 family member is contributing to the cancer’s survival. Once the offending protein is determined, the lab can identify the optimal drug combinations to kill the cancer. The lab has partnered with the University of Michigan’s hematology and oncology department to test patient samples with the goal of designing and executing clinical trials to better utilize the lab’s functional biomarker assay of Bcl-2 protein dependence. Karson interacts regularly with physicians to help them better understand the underlying biology of the cancers they treat. It is hoped that the lab’s profiling assay could one day be used as a diagnostic technique that complements the existing genetic screens and other precision medicine techniques being developed to better hone a cancer patient’s treatment paradigm.

Another facet of Karson’s work is the discovery and development of new compounds to inhibit the Bcl-2 family members. He and the lab have developed dual inhibitor molecules that bind and inhibit Mcl-1 and Bfl-1, two pro-survival members of the Bcl-2 family. These proteins are often overexpressed in cancers that are resistant to Bcl-2 inhibitors. In some cases, Mcl-1 levels are elevated, while in other patients, Bfl-1 concentrations are abnormally high. Occasionally, both Mcl-1 and Bfl-1 are aberrantly high. The two proteins are quite closely related, sharing very similar structures and binding targets. By designing dual inhibitors, a single compound could be used to hit both targets, simplifying the treatment strategy for cancer patients. These drugs would help re-sensitize the patient’s tumor cells to existing therapeutics.

In the lab, Karson’s expertise ranges from the ability to design new molecules that target protein binding to testing the compounds in biological systems. Some days, Karson uses specialized software to visualize drug interactions and protein binding. Other days, he may be culturing cancer cells to test new drug combinations or analyzing patient samples from a clinical trial at the university’s cancer center. While the synthesis of the new compounds is normally handled by other lab members who have more extensive expertise in the chemistry needed to make the new molecules, Karson is still involved, as he helps facilitate the smooth execution of the lab’s various chemistry, biology, and clinical activities. Collectively, the lab can execute the drug discovery pathway from drug design through preclinical testing.

In some ways, Karson’s description of how a small academic lab like the Nikolovska-Coleska lab functions reminds me a lot of how a small biotech startup works. Both work to develop therapeutics for a specific target in a limited therapeutic field. This contrasts with the diverse work in wide-ranging therapeutic areas conducted by massive pharma companies. Small labs and biotech startups are also limited by their resources and manpower, regardless of the expansive hypotheses and great ideas that can be generated every day.

Even with these limitations, Karson was drawn to the Nikolovska-Coleska lab precisely because of its translational potential to impact patients. Karson, who had gotten into both med school and grad school, decided to go to grad school in order to have a broader impact. Knowing that he eventually wanted to move beyond academia, he picked a lab that would expose him to work that could more easily translate to the clinic, industry, and other applications. Through his work, he got a chance to pitch his work to venture capital groups and got a sense of what life was like for a startup.

In many ways, the work that Karson does in the lab isn’t that different from the experiences I’ve had in the biotech startup world. While we approach things from slightly different angles and encounter slightly different challenges, there’s the ultimate quest to find a new drug to help improve the lives of patients.

Special thanks to:

Karson Kump, MS, PhD graduate student, Nikolovska-Coleska Lab, University of Michigan (kjkump@med.umich.edu)