Reflections from AACR 2023

DDW’s Megan Thomas provides highlights from AACR 2023, the American Association of Cancer Research’s annual meeting from 14-19 April 2023 in Orlando, Florida, US. 

Meet the incoming AACR President 

Having said goodbye and thank you to Dr Lisa Coussens, AACR President for 2022-2023, Dr Philip Greenberg was inaugurated as President at this year’s meeting to serve for the 2023-2024 period.  

Philip D Greenberg

Dr Greenberg is the Rona Jaffe Foundation Endowed Chair and professor and head of the Program in Immunology, Clinical Research Division, at Fred Hutchinson Cancer Center. He is also a professor of medicine and immunology at the University of Washington School of Medicine. An internationally recognised leader in the field of cancer immunobiology, Greenberg has made groundbreaking contributions to examining host T-cell responses to pathogenic viral infections and cancers. His work has led to crucial insights into the understanding of the mechanisms by which T cells distinguish tumour cells from normal cells and has fueled the advancement of adoptive T-cell therapy approaches in various cancers, including leukemia and pancreatic cancer. His research has also demonstrated that CD4-positive helper T cells work both collaboratively and independently of CD8-positive cytotoxic T cells to eradicate tumour cells. This work has since been applied to the development of treatments for late-stage melanoma and leukaemia, and is in development for several other malignancies. 

During a press conference, Dr Greenberg was asked what parting words he hopes to be sharing this time next year when passing on the presidential baton. He said: “What I hope I can say next year is that we accomplished many of the initiatives that I’m hoping to get going this year, and even for the ones that we haven’t accomplished, that we are making very clear progress. I think a focus is going to be on having action items, monitoring that action, and knowing all through the year that either we’re making progress or not and if we’re not, why not and what can be done. It’s going to be a lot to do, it’s going to require a lot of resources from the AACR. Fortunately, this is an organisation that’s committed to actually putting resources back into cancer research. So, I really look forward to the coming year and being in beautiful San Diego next year.” 

Meet the biotech  

Sygnature Discovery is an integrated drug discovery and non-clinical solutions provider, offering expertise across a range of therapeutic areas and biological target classes. DDW spoke with Allan Jordan, Vice President of Oncology Drug Discovery at Sygnature Discovery at this year’s AACR meeting in Orlando. He looks after all of Sygnature’s integrated and standalone oncology projects, making sure that the company is doing the best science for its customers, driving programmes forward as efficiently as possible towards the clinic. 

Trends in cancer drug discovery  

Reflecting on the biggest trends in cancer drug discovery over the next 10 years, he said: “I think we’re going to see a continuance of heterobifunctional degraders. I think they are still just at the cusp of really understanding how we use the molecular degrader and how we optimise them towards something that is clinically relevant, rather than a research tool which shows we can degrade the protein and understand the pharmacology but isn’t necessarily endowed with all the right properties to be a drug. I think we’re moving in that direction.” 

We are seeing the heterobifunctionals in the clinic, but Jordan suspects we’ll begin to see an even greater interest in the molecular glues – smaller molecular entities that bring together those productive complexes that lead to protein degradation – but using molecules which have much better physical or chemical properties, and therefore are much easier to dose patients, have better tolerability, better compliance, and hopefully better selectivity.  

Moreover, Jordan thinks we’re going to see a continuance of targeted therapies. “We’re still seeing those at the meeting at the moment”, he said, and thinks they still hold great promise for patients the better we understand patient genetics. He said: “We saw patient transcriptomics from CRUK this week, particularly all the data coming out from the TRACERx study, looking at the evolution of lung cancer. I think understanding that evolution of cancer on a much more detailed genetic level will help us understand new vulnerabilities in cancer, not just in lung cancer, and the learnings from that will apply to other cancer types. From that, we’ll understand better how to use targeted therapies.” 

Jordan also commented on a resurgence in antibody drug conjugates (ADCs), noting the higher drug loading, better payload stability, better tissue penetrance, and thinks that will continue. However, what he found particularly interesting at the meeting is the emergence of more small molecule immune oncology agents that are actually starting to look as though they might work. He said: “We’ve seen a lot of things in the past with things like the IDO inhibitors, the TDO inhibitors, the A2a antagonists… all of which were heralded to be fantastic immuno-oncology modifiers which could reenergise the immune system with a small molecule. But frankly, up until this point, all the clinical data has been quite disappointing. Whereas now, we’re starting to see the emergence of quite encouraging clinical data. So, maybe we’re just on the cusp of starting to see small molecules which can either recapitulate or improve on the situation that we’ve got with the CTLA for anti PD1- or anti PDL1 antibodies.” 

Jordan added that, as a chemist by training, it’s great to see that small molecules still have a significant part to play in cancer research and cancer therapies. He said: “Everything we do at Sygnature in terms of discovering novel therapeutic entities is still based around that small molecule chemistry, be it heterobifunctional, degraders, molecular glues, engineering of the ADCs to get better payload stability and better delivery to patients… Chemistry is still driving a significant number of those advances.”

Challenges to overcome 

Jordan thinks we still underestimate the challenge of tumour heterogeneity. He said: “The biggest challenge for me is we need earlier clinical intervention with patients. So, we need to detect cancers earlier before they’re heterogeneous and before they have intrinsic resistance. That’s really the way we’re going to make step changes in patient care: to identify our patients earlier and treat those patients earlier with kinder, better tolerated small molecule or antibody-based therapist. The only way we’re going to do that was improved diagnostic techniques.” 

At the meeting, Jordan says we are seeing improvements in circulating tumour DNA, circulating tumour cell diagnosis, as well as ways of detecting tumours before they are detectable through standard methodologies, such as CT scans. He thinks that’s going to be the step change: earlier, more robust, more accurate diagnosis; finding patients that are at high risk and monitoring them more effectively so we can intervene earlier before that intrinsic resistance comes through and when our treatments actually may give them significant improvements in length of life and quality of life. He said: “A lot of the treatments where we see the progression-free survivals are actually quite modest – three, four, six months – we have to do better for the patients. We have to give them 12 months, 18 months, two years, five years, 10 years. We’re not delivering that step change in patient care. Earlier diagnosis, better therapeutics, novel therapeutics, new mode of action… those together will deliver that step change in patient care. I think that’s what we’re starting to see emerging from the meeting.” 

Poster presentation  

Jordan was presenting a poster at AACR 2023 on heterobifunctional degraders. He said he sees incredible interest in the idea of protein homeostasis and the question of not just how to inhibit a protein target, but get rid of it from the cell completely. He said: “There are two approaches to do that, either molecular glues, smaller molecular entities; better PK, probably better tolerability for our patients. But in the heterobifunctional degrader space, we see from our customers two challenges. One is: I have a protein of interest, and I don’t know whether it can be degraded. So, we’re trying to understand in a very short timeframe if they can make a heterobifunctional molecule, and show the protein is able to be degraded using this this prototype type approach.” 

As such, Sygnature has developed a platform where they can very rapidly make perhaps 200 prototypical degraders from a protein of interest warhead that their customers bring and get very rapid proof of concepts.  

But that platform is scalable, so the other challenge they see is where a customer has maybe 10 or 12 targets they’re interested in and they don’t know which one to prioritise. “So, we can take our platform, we can run it in parallel across multiple targets, and then take a holistic view of the data, figuring out which targets can be degraded by a particular E3 ligase, or with which linker chemistry, which compounds have the better physical or chemical properties and are more likely to be able to be optimised towards a drug, and then use that as a funnel to prioritise the targets we think will give clinical benefit in the most expedient manner.” 

Meet the exhibitor  

At AACR, Integrated DNA Technologies (IDT) announced the launch of a new core solid tumour panel for cancer research. The new solution will help researchers optimise operational efficiency and the identification of solid cancer tumors. DDW caught up with Ellie Juarez, BU manager  – NGS Commercial Product Management at IDT, to learn more.

The IDT platform

The IDT Archer FUSIONPlex Core Solid Tumor Panel is a first-line cancer research testing solution that has been expanded and optimised for additional single nucleotide variant (SNV) and indel coverage to streamline fusion detection and variant calling through a single assay. The new RNA-first sequencing offering for solid tumours uses a single RNA/TNA input sample and provides a scalable, easy-to-use solution that offers time, resource and cost savings for researchers. Juarez said: “Ultimately, it’s a single workflow and so that streamlines the product. It’s a 1.5 days total assay time, and so that allows for someone who’s doing cancer research to get both SNV and fusion detection from a single input instead of having to do separate assays for RNA, and DNA. In our collateral, we have 57 genes with SNV/Indels; we show that we can pick up those SNVs at the same quality as if we were doing a separate DNA assay alone. It’s really all driven by Archer technology. All of that, of course, comes with analysis at the back end. The Archer platform comes with our analysis component that has an output of a VCF, variant calling file. So, that is a super streamlined workflow, and lyophilised reagents, and that allows for a lot of modularity and not a lot of freeze-thaw steps.”

For Juarez, the most important thing to remember when it comes to this offering is that IDT has a very comprehensive NGS portfolio for oncology research, especially considering the launch that they did at AGBT of their MRD custom panels with a five-day turnaround time where customers can go directly to their website, order their panel, of up to 2000 probes and 50 panels at a time. She said: “We have a full library prep suite, cfDNA and FFPE kit that’s super important for liquid biopsies, which have been a really hot topic at this conference. Walking around, that’s all I’m seeing: a lot of liquid biopsies and a lot of circulating tumour DNA, and people trying to get large datasets from biobank samples. DNA quality is pretty low, and our library prep is really tailored for that.”

Trends at AACR 

Speaking about the trends of what people are asking and are interested in on the exhibition floor, Juarez said: “I think people are just looking for quicker answers, and so that really was kind of the driving force of developing this product. A single product, quick workflow, getting you the answers as quickly as possible. I think in the advent of a lot of genomic data for oncology research, people just want to get more data, more answers, and a quicker outcome, whatever that is for them.”

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