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Exploring the Future of Drug Combinations: A Deep Dive into In Vivo Synergy Research in Mouse Tumor Models

3 min read

The world of oncology is ever-evolving, and as researchers and scientists, we are perpetually on the front lines searching for innovative solutions against cancer. One promising direction is the exploration of drug combinations. The idea is both simple and profound: what if we could combine two or more drugs, amplifying their effects to produce outcomes greater than their individual impacts? Welcome to the world of drug synergy!

Why Combine Drugs?

It’s well-known that cancer isn’t just one disease; it is a myriad of diseases with intricate gene and molecular interactions. A single drug might target one pathway, with other pathways potentially left untouched, allowing the cancer to adapt and develop resistance. This is where drug combinations come in. By targeting multiple pathways simultaneously, drug combinations can:

  • Reduce resistance: Multifaceted attacks lessen the chance for the cancer to develop resistance to the treatment.
  • Increase potency: Drugs can amplify each other’s effects, resulting in more profound tumor suppression.
  • Minimize side effects: By using lower doses of each drug, adverse reactions can be reduced while maintaining efficacy.

Assessing Drug Synergy in In Vitro Studies

While the concept of drug combinations is enticing, the challenge has always been to determine which combinations truly work synergistically. Historically, drug synergy was explored primarily using sophisticated statistical methods in cell lines. These in vitro studies, involving cell lines or organoids, offer initial insights into how drugs might interact. They hold invaluable worth for screening potential combinations before they progress to animal or human trials.

Breakthroughs and Challenges in In Vivo Models

However, there’s a significant gap when it comes to animal studies. In vivo drug synergy studies using mouse tumor models have lacked robust statistical methods, leading to potential false positives. Consider the implications: drug combinations that demonstrate “synergy” in animal studies might fail in clinical trials, resulting in a waste of time and resources.

This is where our recent publication in Cancer Research Communications becomes a game-changer. We introduced a method, for the first time, that reliably identifies drug synergy in PDX, CDX, and syngeneic models. This method is unique in its ability to calculate synergy directly from tumor volume data without making assumptions about tumor growth behaviors.

Key highlights from our research:

    • invivoSyn Approach: This method uses an efficacy metric called eGR, which gauges the average tumor growth rate over a study period. It factors in the variability in tumor volumes among mice and calculates synergy scores, combination indexes, and statistical confidence intervals (Figure 1).
    • Validation of In Vitro Drug Synergy in In Vivo Studies: Using invivoSyn, we confirmed that combinations showing synergy in cell lines also demonstrate synergy in mouse models. For instance, the combination of SN-38 and rabusertib reduced tumors more effectively in mice than individual treatments (Figure 2).
    • Direct Assessment of In Vivo Combination Effects: The team’s method directly assessed combination effects in mice, revealing insights into the role of tumor immunity in different models. A notable discovery was the antagonism seen when combining anti-PD-1 and anti-CD8 treatments.
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"Exploring the Future of Drug Combinations: A Deep Dive into In Vivo Synergy Research in Mouse Tumor Models," in Gubra.dk, Mar 26, 2024, https://www.gubra.dk/exploring-the-future-of-drug-combinations-a-deep-dive-into-in-vivo-synergy-research-in-mouse-tumor-models/.
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