Designing a Better Cancer Drug: Mekanistic Therapeutics, LLC

Developing drugs for treating cancer can sometimes feel like a game of Whack-A-Mole. Like moles in the game, tumors pop up, and just as we’re ready to hit them with a therapeutic mallet, they evolve and evade our strike, rendering once effective treatments useless. Tumor cells have a long history of developing resistance to our drugs, leading to major hurdles in the fight against cancer.

To try to overcome these hurdles, some researchers have been working to predict when and where the next mole will pop up by identifying relationships between signaling pathways within the tumor cells. The goal of this approach is to predict how the tumor will evolve so that we can be ready with the appropriate therapeutic response. A downside to this approach is that it can lead to a complicated treatment strategy involving the use of multiple cancer therapies. This would be like having to handle multiple mallets and knowing precisely when to use each mallet so that you strike the right holes in the proper sequence in a Whack-A-Mole game. While doable, this approach could be challenging.

But what if we could design a better mallet? What if we could design a mallet that could hit multiple holes simultaneously, avoiding the need for complicated strategies with multiple mallets?

The Mekanistic team (L-R): Dr. Judy Sebolt-Leopold, cofounder & CEO/CSO; Dr. Christopher Whitehead, cofounder & COO; David Lowenschuss, CBO

This is the approach being taken by Mekanistic Therapeutics and its cofounders, Drs. Judy Sebolt-Leopold and Christopher Whitehead. Judy and Christopher have spent their careers in cancer drug research and development, accumulating decades of experience spanning pharma, biotech, and academia. They have used their accumulated knowledge to design a better way to fight cancer, founding Mekanistic in 2015 and spinning the company out of the University of Michigan.

Mekanistic’s new mallet is a novel molecule called MTX-211. This compound was specially designed to simultaneously inhibit multiple key signaling pathways that cancer cells rely on for growth and survival. The company’s drug targets two proteins called PI3K and EGFR.

EGFR, or epidermal growth factor receptor, is a receptor found on the surface of cells. In healthy contexts, it regulates the development of epithelial cell proliferation, survival, and differentiation. But in cancer, EGFR is frequently mutated, leading to its hyperactivation. This means that the receptor is constantly turned on, producing a stream of pro-survival signals that gives tumor cells a survival advantage and helps them develop resistance to therapeutics. Similarly, PI3K, or phosphoinositide 3-kinase, is a major player in a signaling axis that regulates a variety of cellular processes, including proliferation, motility, and survival. Errant activation of PI3K has been implicated in a variety of cancers, with its activity promoting proliferation, survival, and tumorigenesis.

EGFR and PI3K are important hubs in a variety of signaling processes in cancer cells, signaling pathways that help these cells evade and escape current therapies. Similar to what we’ve seen in the work by Karson and the Nikolovska-Coleska lab on the Bcl-2 proteins, Mekanistic believes that by targeting such vital signaling pathways, the drug can kill the cancer cells and prevent the tumor from developing resistance mechanisms.

While EGFR and PI3K have been implicated in a variety of cancers, the company has chosen to initially focus on head and neck cancer, a major unmet medical need that is driving innovative research. A major challenge for treating head and neck tumors is that they are often resistant to immunotherapies, which occurs in over 85% of patients. The effect of these immunotherapies – drugs designed to modulate the immune system to recruit it to fight cancer – is often limited because of the “cold” nature of the tumors. These tumors have ways to avoid the immune system, so even if immunotherapies can activate immune cells to fight tumors, these cells can still have a hard time locating the tumor cells. In other words, imagine if the effect of immunotherapies on immune cells is like creating a souped-up race car to win a race. But you can’t win the race if you don’t know where the finish line is. This is the challenge with using immunotherapies against certain tumor types.

By targeting EGFR and PI3K, Mekanistic avoids this challenge by targeting mechanisms intrinsic to the cancer cell survival, rather than relying on the immune response to attack the tumor. The company has performed a variety of preclinical in vivo studies showing that administering MTX-211 as a single agent therapeutic dramatically shrinks the tumor burden and significantly improves the long-term survival rate in multiple models of head and neck cancer.

When compared to an immunotherapy, such as PD-1 inhibitors, MTX-211 treatment leads to better survival over time in these preclinical models. Interestingly, when given in combination with an immunotherapy, there is an even higher rate of survival, suggesting that while MTX-211 could be a successful treatment on its own, it may be even more effective with a partner therapeutic. Returning to the car race metaphor, this would be like having the PD-1 inhibitor treatment lead to souped-up immune cell race cars, while MTX-211 treatment drains the gas tank and slashes the tires of the cancer cell race cars. Hopefully with treatments like these, the patients win.

The approach that Mekanistic is pursuing has led to promising data with its novel drug. Importantly, this coincides with a market need that is expected to grow. By 2025, the market for head and neck cancer therapies is expected to expand to over $2.7 billion, with a majority of this market predicted for immunotherapies. But if you’ve built a better mallet that’s superior than or improves upon the effect of immunotherapies, there’s a clear market need and opportunity for a company like Mekanistic.

While head and neck cancers are the company’s current focus, EGFR and PI3K play vital roles in a variety of cancers, underscoring the company’s belief that MTX-211 could be an effective treatment in these cancers. Mekanistic has received NIH grant funding to actively pursue the use of its therapeutics in a range of cancers, including colorectal and glioblastoma.

To complement the non-dilutive grant funding that the company has been awarded, Mekanistic is actively fundraising so that it can perform IND-enabling studies and move one step closer to Phase I clinical trials. With this funding, the company hopes to accelerate its activities and get its drug to patients and improve their outcomes.

To learn more about Mekanistic, please contact David Lowenschuss, JD, Chief Business Officer, Mekanistic Therapeutics, LLC (dlowenschuss@mekanistic.com)

Special thanks to Christopher Whitehead, PhD, MBA, cofounder & COO, Mekanistic Therapeutics, LLC (cwhitehead@mekanistic.com)

Thanks to Qiagen and Todd Festerling for sponsoring the blog.