Under the Microscope: Oncology Drug Discovery

Analytical chemist Bo Tokarski trades his lab coat for a four-week sabbatical with BrightEdge, the American Cancer Society's innovation and impact investment arm

Being an employee at Charles River Laboratories has its perks. One of them is the Sabbatical Leave Program offered to employees who have been with the company for at least three years. The program gives employees an opportunity to dedicate four weeks to professional development and/or community service. In September, as part of the sabbatical program, I put aside my duties as Manager of the Analytical Chemistry Department at Charles River's Safety Assessment site in Ashland, Ohio, to work with the American Cancer Society's (ACS) BrightEdge Team.

BrightEdge is the innovation, impact investment, and venture capital arm of ACS. I was intrigued by the idea of working with BrightEdge for a few reasons. First, I worked in oncology drug discovery as part of my doctoral research at Ohio State, so learning more about how oncology therapeutics transition from the academic setting into startup companies was compelling. Second, I didn't know much about venture capital, startup companies, and how fledgling companies gain investment funding. Lastly, I thought that working on an oncology drug discovery project would be a welcome change from, but also a complement to, the day-to-day aspects of safety assessment.

The goal of my sabbatical was to help the BrightEdge team put together a research presentation that captures what successful translation from preclinical models to clinical trials entails, and how historical control data is being utilized in the preclinical setting to advance oncology discovery research. I met with BrightEdge team members every week to discuss their needs and questions about the research project. I also joined meetings about investment opportunities and even got the chance to see the decision-making process regarding multi-million-dollar funding decisions.

As part of gathering information for the presentation, I had the chance to connect with two Charles River oncology experts: Senior Research Director Patrick Fadden, PhD, based at our site in North Carolina's Research Triangle Park, and Julia Schueler, DVM, Therapeutic Area Lead in Freiburg, Germany. They helped answer my questions regarding preclinical assessment of oncology drugs. I learned more about translation being a key challenge in current drug development. I also learned how assays for drug candidate viability are occurring earlier in the development process to achieve success rates down the road, improving performance in human clinical trials.

Translatability: the 3H's of clinical models

So, what is done to ensure discovery assays identify the optimal performers? They must be:

• Human-like: the more "human" an in vivo model is, the better chance of predicting the success of a drug. An example of this is the introduction of human cells (tumor and immune cells) into mouse models in patient-derived xenograft (PDX) models to better replicate the human environment.
• Heterogeneous: often, cell-derived xenograft (CDX) models display a high degree of homogeneity, which is not indicative of the heterogeneous matrix in human cancer tissues. PDX models provide better inter- and intra-tumor heterogeneity, facilitating a microenvironment that more closely resembles humans.
• Harmonized: as assays advance beyond PDX models, consideration for how to design the models with respect to mimicking the human environment needs to be top priority. Examples of advancing models include organ-on-a-chip and 3-dimensional organoid models, all of which need to be further considered, developed, and optimized to assess oncology drug success.

Historical Control Data: The Genesis of Virtual Control Groups

In the context of oncological drug discovery, Charles River has been working to reduce animal usage through the employment of alternative methods and models. This includes advanced in vitro models, cutting-edge ex vivo models, and virtual control groups (VCGs). In the development of VCGs, Charles River has applied historical control data to model the progression of untreated cancer groups.

By assessing 506 different PDX models, represented by over 280,000 mice across 23 immunocompromised strains, Charles River scientists were able to determine a VCG fit nicely over an experimental group for lung cancer models. Thus, there is potential for VCGs to be used in hybrid study designs to reduce the number of animals needed to effectively assess a cancer drug's efficacy. Further research needs to be conducted to assess the viability of VCGs for standard-of-care comparison groups.

As I returned to my role as Manager in Analytical Chemistry, my sabbatical experience provided me with a newfound appreciation for discovery, especially since I rarely get the chance to work on discovery projects. Getting to work with BrightEdge and seeing the decisions regarding startup company investment gave context for how oncology drug development projects are funded. My sabbatical research project facilitated interactions with colleagues Julia Schueler and Patrick Fadden, who provided valuable insight into the immense research Charles River does in support of oncology drug discovery, ultimately helping to establish efficacy.

Seeing drug development from the startup perspective, both in working with BrightEdge and speaking with Charles River discovery subject matter experts, is an experience that has made me appreciate the time, funding, and effort that goes into oncology drug discovery