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Thought Leadership Articles

March 28, 2024

C-mods – changing the outlook for colorectal cancer

Colorectal cancer is the third most common cancer globally and the second leading cause of cancer-related deaths worldwide. We at Dewpoint are dedicated to translating our revolutionary condensate science into medicines with the potential to overcome this devastating disease.

This colorectal cancer awareness month, we sat down with Dewpoint’s Head of Biology, Ann Boija, to get her take on the huge potential of condensate-modifying drugs (c-mods) to treat colorectal and a range of other cancers by getting to the core of the disease.

Ann is an expert in gene control, cancer biology and condensate biology. Prior to joining Dewpoint almost three years ago, Ann was leading pioneering research focused on the role of condensates in gene control and cancer therapeutic drug activity, in the laboratory of Dewpoint co-founder, Richard A. Young at the Whitehead Institute of the Massachusetts Institute of Technology. Her work has led to several seminal discoveries in the field, including the realization that the transcription factors’ propensity to phase separate, encoded in intrinsically disordered regions, contributes to the regulation of gene transcription, and that partitioning of anti-cancer drugs into condensates influences their activity. Together, these two foundational discoveries have paved the way for how Dewpoint approaches drugging ‘undruggable’ targets and optimizes c-mods for efficiency and safety.

Dewpoint is working to drug biological targets which had been considered undruggable – including beta catenin and MYC. Can you describe how your approach allows you to overcome the hurdles which have made these and other targets so elusive to drug hunters for so long?

Transcription factors are key biological drivers of malignancies but have been difficult to target due to lack of small molecule binding pockets and high degree of protein disorder. Their structure is “spaghetti-like”, taking on many different configurations, which makes it challenging to develop a drug that can effectively bind to them. Disordered regions are known to drive the formation of biomolecular condensates- which are membranelles organelles recently demonstrated to play key roles in regulating most cellular processes. Aberrant condensates associated with pathophysiology – or condensatopathies – drive disease and serve as an integrated node of dysfunction for various disease processes and pathways. By targeting the condensate and taking advantage of its emergent properties, we can expand the target space to include high value disease targets previously deemed undruggable, including beta catenin and MYC.

At Dewpoint we have built an AI-enabled end-to-end platform that nominates condensate disease targets, and using high content, high throughput screening we are able to identify condensate-modifying drugs – or c-mods, in a disease relevant setting. Condensate assays are then used to optimize c-mods to reverse the disease phenotype and corresponding functional consequences. We have further demonstrated that the c-mods identified using our platform translate into in vivo efficacy across diseases. This highlights the promise of leveraging condensate science to target hard to drug oncology targets with the ultimate goal to develop much needed treatments for patients.

How is Dewpoint tackling colorectal cancer by leveraging condensate biology?

Constitutive activation of beta catenin causes transcriptional reprogramming and uncontrolled cell proliferation which drive colorectal cancer. Now, with c-mods, we have a totally new and unique approach to inhibit beta catenin activity by sequestering it in ‘depot’ nuclear condensates. Our data demonstrates that this approach can normalize transcription and reverse uncontrolled proliferation of malignant cells. Importantly, through condensate modification not only are we able to target this previously undruggable protein but we have been able to hone the process so that we can selectively induce depots in malignant cells with high levels of aberrant signaling, while leaving untransformed colon cells largely unaffected. We are particularly excited about this observation given the challenges around gastrointestinal toxicities seen in the clinic using current treatments.

What are the significant differences between c-mods and other colon cancer treatments?

One key difference is that while many other therapies target single biomolecules, condensate modification allows us to target and repair the entire disease-driving processes. This has the potential for a more transformative effect as it can hit all the components involved in driving the disease simultaneously. Focusing on condensates rather than on unique biomolecule targets also greatly reduces the limitations of genetic differences. We know in cancer there is vast genetic diversity between populations, and focusing on a single biomolecule means that a drug may only be relevant to a small subgroup. As the condensate is a central node of dysfunction in the disease, by targeting this node we may have an impact on larger patient populations.

Take the example of beta catenin and Wnt signaling. It’s a complex signaling pathway with many factors involved, but they converge at the condensate. Consistent with this, we see activity of beta catenin c-mods across genetically diverse colorectal cancers as well as a range of additional Wnt-driven cancers, providing opportunities to treat patients broadly.

What benefits do you believe c-mods can bring to patients?

The use of c-mods as potential cancer therapies is a very exciting scientific step forward and it’s opening new possibilities for us to go after a larger portion of the proteome, to include target proteins that we know are key to driving many diseases. I see great potential in c-mods to be transformative as real disease-modifying treatments across genetically diverse subpopulations. Furthermore, we believe they hold the potential to be safer and more tolerable for patients compared to traditional therapies.

At Dewpoint we are seeing the evidence of our approach both through our oncology programs in colorectal and ovarian cancer and in our neurodegenerative disease program in ALS. I am confident that we will be able to apply our learnings from these programs to a wide range of other hard-to-drug oncology targets with compelling biology for diseases with high unmet need.

As 2024 Colorectal Cancer Awareness month is closing, what is your personal hope for this disease?

I truly believe condensate science has the potential to revolutionize the treatment for cancer patients. I am excited and proud to see the progress we have made thus far in translating condensate science into a drug discovery platform that identifies c-mods with anti-tumor activity in diverse translational models. I am optimistic that we will be able to advance our most promising beta catenin c-mod to IND filing during next year. This will open a new, concrete era of hope for colorectal cancer patients.

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Michael Fenn, PH.D.
Head of External Innovation
Dewpoint Therapeutics
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