At Novartis Biomedical Research, oncology teams around the world are taking on some of the biggest challenges in cancer drug discovery. Together, they’re leveraging cutting-edge technologies to understand how cancers grow and resist treatment, and to translate those insights into breakthrough medicines that can improve patients’ lives.
In San Diego, California, one Oncology Drug Discovery team plays a distinctive role: Their focus is a fast-evolving approach called “induced proximity,” which they’re using to take aim at cancer targets that have long been considered difficult, or even impossible, to drug.
Jake Haling, Head of Oncology Drug Discovery in San Diego, talked about the potential of this therapeutic approach, and what it could mean for patients:
What is “induced proximity”?
It's a term to describe a variety of drug discovery techniques that bring disease-causing proteins into close, physical proximity to other biomolecules to modulate protein function and hopefully produce a disease-modifying effect. It’s an alternative to traditional chemistry approaches in drug discovery that rely on a chemical compound occupying and binding to an active site of a disease-causing protein.
One of the best-known examples is targeted protein degradation, or TPD, but there are some newer modalities like RIPTAC that work through different mechanisms.
At Novartis, we are working across several induced-proximity strategies. The goal is to find the best “event‑based” mechanism to go after key cancer‑driving proteins in diseases such as prostate, breast, lung, and gastrointestinal cancers.
At Novartis, we are working across several induced-proximity strategies. The goal is to find the best ‘event based’ mechanism to go after key cancer driving proteins in diseases such as prostate, breast, lung, and gastrointestinal cancers.
What’s RIPTAC?
The acronym itself stands for “Regulated Induced Proximity Targeting Chimeras.” It’s an induced proximity approach that uses what could be described as a “catch-and-kill”-based mechanism. It involves a molecule that anchors onto a tumor-specific protein while also capturing a separate protein within the same cancer cell—one that’s essential for cell survival. This approach has the potential to effectively kill cancer cells, but since these molecules are specifically targeting cancer-driving proteins, they would spare normal, healthy cells. It has the potential to be transformational across a variety of cancer indications.
Which cancers does your team focus on?
We take a disease-focused approach in terms of which cancer types we pursue. Our core areas include prostate cancer and breast cancer. We may have successful, approved medicines in these spaces, but then we look to go further. We ask how we can build on our learnings to create the next generation of medicines to address unmet needs that still remain for patients. For instance, there are many subtypes of breast cancer—can we develop a new therapy so that patients have the right medicine for their specific cancer subtype?
We're also invested in gastrointestinal (GI) cancers, including both colorectal cancer and pancreatic cancer. There haven't been many transformational medicines for these diseases, which is why we think this is an important and innovative space for us to be involved in.
How has oncology drug discovery changed during your career?
One thing that’s changed is that, as more and more medicines make it to the clinic, the clinical learnings feed back into drug discovery and we're able to iterate on that process. What that means is that we learn from patients. We get to understand what needs aren't being met in these patient populations, whether it's a cancer subtype that's not seeing the response you'd expect, or pain points in the patients' experience as they undergo treatment.
So we're not necessarily starting from the ground up—finding a good protein or gene first and then designing a treatment for the target. Instead, we identify an unmet medical need from the clinic, understand the underlying mechanisms and vulnerabilities of the specific cancer, and then we proceed to identify the best protein or gene to target so that we can develop an impactful therapy.
One thing that’s changed is that, as more and more medicines make it to the clinic, the clinical learnings feed back into drug discovery and we're able to iterate on that process.
What are the big challenges right now?
Many of the well-known targets like HER2, BRAF, and EGFR have been pretty thoroughly targeted. I think the whole industry is waiting for the next wave of breakthroughs, and to see whether that's going to be on the drug-engineering side or the target side. I have to lean towards the engineering side because I feel like we know the targets, we just can't hit them the way we want to.
Take β-catenin, for instance. It plays a critical role in GI cancer tumorigenesis, but it’s very difficult to drug and, even if you’re able to, it's not very cancer-specific. There’s normal tissue that also requires β-catenin signaling, which makes it complicated to target.
MYC is like that too. It’s been talked about for 40 years as a key cancer dependency but we still haven't figured out the best way to capitalize on the large amplification of MYC in key cancer indications.
The field hasn’t yet figured out a way to leverage what we know about some of these seemingly “undruggable” targets. I believe that induced proximity has the potential to help address some of these challenges to drive effective therapies for patients.
What’s an area in your field that you’d like to explore?
Tumor suppressors. We talk a lot about oncogenes, but P53 is the most commonly mutated gene in all of cancer and it's a tumor suppressor. There are some interesting theories out there for correcting P53 mutations to activate it again in these cancers.
So I think reactivating tumor suppressors could be a promising direction. I don't know the best way to do it yet, but I think there are some real possibilities out there for innovation.
What do you hope to see in the future?
I’d like to see a transformational breakthrough in pancreatic cancer or one of these other harsh GI cancer diagnoses. We're seeing a rise in colorectal cancer cases across the board and pancreatic cancer is just a devastating disease. If we could see an approval for a targeted therapy that has the potential to be curative, that would mean the world to me.
