Thought Leadership Articles

May 9, 2024
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Harnessing condensate science to overcome the challenges of ovarian cancer

“I believe we are on our way towards a MYC c-mod, says Bede Portz, Dewpoint’s ovarian cancer program lead. Our early prototype MYC c-mods have demonstrated significant tumor growth inhibition in animal models of ovarian cancer.”

Every year over 200,000 women die of ovarian cancer globally, and with current treatment options being limited, this number is predicted to rise. At Dewpoint we believe that condensate science holds the key to developing more effective and better tolerated treatments for ovarian cancer and other solid tumors.

For greater insight on our progress, approach and aspirations we spoke with Dr. Bede Portz, Dewpoint’s ovarian cancer program lead and condensate science expert.

Prior to joining Dewpoint, Bede was a Bright Focus Foundation postdoctoral fellow at the University of Pennsylvania in Dr. James Shorter’s lab, where he worked on developing therapeutic RNAs to combat aberrant phase transitions in neurodegenerative diseases and on non-coding RNA (ncRNA) condensation. Bede did his Ph.D. training in the Center for Eukaryotic Gene Regulation at Penn State.

What is it about condensate science that excites you?

I love biology. If you endeavor to understand how cells work and a new and testable concept emerges that potentially undergirds tons of cell biology, that’s exciting.

Condensates are membrane-less organelles which form and dissipate dynamically inside the cell via a process called phase separation. They are responsible for allowing cells to organize proteins in time and space to regulate chemical reactions and for turning key processes on and off. I’d always wondered how complex processes were regulated within cells, but condensate science has allowed us to understand cellular biology in a whole new way. As an extension of this, we are also able to understand more and more about the pathophysiology of disease through condensates.

There is an increased appreciation in the field that condensate malfunctioning is strongly associated with a variety of diseases. We call this association condensatopathy. These can manifest as condensates containing the wrong components or having the wrong dynamics or material properties. Depending on the context, condensatopathies can result in toxic gain or loss of function, or sometimes both, and it is this misregulation that explains the complex functional outcomes of multiple types of errors that are integrated inside the condensate. At Dewpoint we are currently working to develop small molecules that can modify the aberrant condensates. This has opened countless new potential points of intervention and possible therapeutic avenues and it’s this potential that makes me so excited about condensate science.

Dewpoint is working to develop a treatment for ovarian cancer by targeting the MYC protein. This is a protein that many others have tried and failed to drug. What is it about your approach that you think will make it successful?

Through our ovarian cancer program, we are indeed going after one of the targets that scientists consider to be almost a ‘holy grail’ in oncology. MYC is an oncoprotein responsible for regulating the expression of genes that drive cancer proliferation.  It has been found to be dysregulated in up to 70% of cancers. So obviously other researchers have been trying for years to find ways to target MYC.

We believe that MYC exerts its function in activating genes and amplifying their expression through a condensate. MYC condensates act as an inflection point between stimulus and response – the cell receives signals and it’s deciding via a MYC condensate on the response, for example proliferation. By modulating MYC condensates, we aim to stop cancer cell proliferation.

The high incidence of MYC over proliferation in such a wide range of cancers means that it has huge potential. Right now, we are really focused on proving the approach in ovarian cancer, where upwards of 30% of tumors have MYC amplification, more than the normal number of copies of the MYC gene, pointing to MYC dysregulation being a driver of ovarian cancer. In the future though, I believe that we could apply our approach to many other types of cancer, with equally high unmet need, such as pancreatic and esophageal cancers.

What progress has Dewpoint made towards the development of a MYC c-mod?

I believe we are on our way towards a MYC c-mod. We have developed an assay matrix centered around MYC condensate phenotypes that identifies c-mods that modulate MYC condensates selectively, in cell models of high grade serous ovarian cancer that recapitulate patient-relevant genetics. These compounds in turn selectively modulate MYC-driven gene expression. This assay matrix has been deployed in the improvement of the drug-like properties of our c-mods. The most exciting data have been generated in vivo, with early prototype MYC c-mods demonstrating significant tumor growth inhibition in animal models of ovarian cancer. The degree of tumor growth inhibition elicited by the initial molecules is comparable to the standard of care chemotherapy regimen. Progress like this so early in the medicinal chemistry campaign even defied the expectations of many on the team. There is work to be done, but data so encouraging motivate any amount of effort. 

What are your overarching ambitions for your ovarian cancer program?

The unmet need in ovarian cancer is sky high and the survival rates are not good. This is partly because the cancer is often not detected until the disease is advanced, but also because the existing treatment options are limited. We still rely a lot on chemotherapies. Not only are they really tough on patients from a tolerability point of view, but ovarian cancer regularly develops resistance to them which affects their efficacy.  Other treatment options exist, but they’re not really used with curative intent.

So, our goal is fundamentally to develop a treatment that is more effective and better tolerated than other drugs used to treat ovarian cancer today.

Do you think c-mods can overcome the issue of resistance in oncology?

The resistance problem is one we think about all the time, and it’s critically important. Overcoming resistance has really been built into the program as a key goal since its genesis and at multiple levels. If you think about what condensates do in cells generally – they’re involved in responding to signals and stress, they’re involved in making decisions to grow or to not grow, to execute biochemistry or to not. And these are processes that are hijacked in cancer and that can contribute to resistance. Specifically, MYC itself is implicated in resistance, so it follows that MYC condensates could be mediators of resistance.  It follows that targeting MYC condensates could be effective in ovarian cancers that have become resistant to the standard of care chemotherapies. We are working hard to understand this.

How do c-mods compare to other oncology therapies in terms of specificity?

If we take the example of ovarian cancer, it is genetically a highly unstable and heterogeneous disease. That is a factor that contributes to its poor treatment response and the emergence of resistance. Broadly, cancer therapy falls into two types, targeted therapies that attempt to exploit specific mutations, and broad acting chemotherapies that attack fundamental mechanism of cell growth and division. From a targeted perspective, one looks for specific mutations associated with specific subtypes of ovarian cancer and exploits them with very targeted therapies. These can be effective, but resistance can emerge, and these treatments may be viable options only for very small patient populations harboring specific mutations. Conversely, if we go broad with a chemotherapy, we can treat large sets of patients, but as we are targeting the basic machinery of cell proliferation which is needed not just for tumor cells but also for healthy cells, we end up with drugs with very poor tolerability.

I believe with c-mods may really achieve the best of both worlds, an approach which gives the benefits of a targeted therapy while exploiting a mechanism that’s sufficiently general to be applicable to a very broad number of patients, irrespective of specific mutations.

Take, for example, the mutations associated with ovarian cancer – there is frequent MYC amplification leading to its dysregulation. But there are also mutations in proteins involved in sending signals for cells to grow, signals that are integrated via MYC condensates. You could envision a targeted therapy against one of those signaling proteins that harbors a particular mutation, but where do those signals converge? They all converge in MYC condensates, located on the genome, which act as integrators of stimulus and response. If the functional unit of MYC is a condensate, this might represent an Achilles heel that is specific to a driver of ovarian cancer, but that also exploits upstream drivers, and regulators of MYC. We call compounds that act on the MYC condensate ‘direct c-mods’, and compounds that modulate the upstream drivers and regulators ‘indirect c-mods’.

With condensates being such a new scientific approach, what new technologies and tools have you had to employ to optimize your drug development?

At Dewpoint, we’ve developed an integrated platform that brings together our huge database of condensate knowledge with our experimental science and the latest AI, and imaging. We call it ERSAi.

ERSAi is a c-mod discovery toolbox – the digital twin of our experimental platform – that allows us to optimize the process of drug discovery from target selection to optimization of lead compounds in disease-relevant models. Cell biology is amazingly complex, but this platform of tools allows us to embrace this complexity and create approaches that cast a wide enough net to capture mechanisms that can modulate condensates – either directly or indirectly – but in a specific enough way to allow us to develop targeted therapies.

For our ovarian cancer program, we have used ERSAi to deconvolve the information from our phenotypic screening data and toolbox of secondary assays to accelerate discovery. From the outset of the program, ERSAi provided the opportunity to look at various genetic models of ovarian cancer in our assays to capture the disease relevant composition of condensates and their regulation. We’ve been using AI to build image analysis tools that are fit-for-purpose to decipher the information encoded in the condensate phenotypes of disease-relevant cells and to test and refine hypotheses in a sort of loop.  It’s not a static toolbox, it evolves as we learn more. In service of the program, we’re building new tools to decipher the information encoded in these models and that is a powerful approach.

You’ve been at Dewpoint for more than 3 years, what are the achievements that you are most proud of over this time?

Pride is a dangerous feeling as it can distract you from what really matters. Our goal here is to make a drug that can treat ovarian cancer– today we are still working on that goal.

But, I’m frequently proud of the team. I’m most proud when the team demonstrates a relentless optimism, a willingness to tackle complex problems. To approach a problem in a more unconventional way, to do the harder experiment or build the AI tool that unlocks the next advance for the program. 

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Michael Fenn, PH.D.
Head of External Innovation
Dewpoint Therapeutics
mfenn@dewpointx.com
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