#Eureka

It is widely known that cancer is a not a single disease, but rather a collection of different diseases. Even within the same cancer type or tumour there is a lot of heterogeneity. At the same time, similar genetic alterations are found in different types of cancer, opening avenues towards pan-cancer treatments based on genetic footprints. Loss of function mutations in RNF43 and ZNRF3 are for example found in malignancies of the colon, pancreas, stomach, ovary, endometrium, and liver. In these tumours, the functional loss of these genes disrupts the Wnt/b-catenin signalling pathway. Normally, RNF43 and ZNRF3 orchestrate a feedback mechanism leading to reduced amount of Wnt receptors on cellular surfaces. Disruption of this system in cancer leads to increased levels of these receptors and a consequent Wnt-hypersensitivity which drives tumorigenesis.  
 
The mechanism of action described above creates a vulnerability for tumours: ligands for the overly abundant Wnt receptors form a druggable target. Several clinical trials are currently underway to treat cancers harbouring RNF43 mutations with drugs targeting the Wnt system. Genetic analysis of RNF43 in different tumour types however reveals a large diversity of mutations, making it hard to identify which mutations are true drivers of tumorigenesis. More insights into the effect of these mutations is warranted to improve the selection of individual patients which can benefit from treatment strategies targeting the Wnt system. 
 
This is where the lab of Oncode Investigator Madelon Maurice at the UMC Utrecht comes in. In a collaborative effort with multiple labs, among which those of Oncode colleagues Jan Paul Medema and Michiel Vermeulen, her group has identified a subset of mutations which all lead to the production of a truncated form of RNF43. “We started looking into a truncated form that we named onco-RNF43,” Madelon Maurice explains. “Using colon cancer organoids, we figured out that this form of the protein hampers a second feedback mechanism which controls Wnt signalling. Disruption hereof leads to hyperactivity of the pathway, but this happens independent of the presence of Wnt signalling ligands”. This is a crucial insight for treatment strategies currently being investigated, as they specifically target the ligands. For patients with the type of mutations described by the lab of Maurice, it is safe to say that these treatments strategies most likely will not help in defeating the tumour. 
 
The study was published over the summer in the well known EMBO journal. “It is our mission to understand the molecular events that turn a normal cell into a cancer cell, and to use such understanding to design better therapies,” says Geert Kops, scientific director of Oncode. “By collaborating, the teams of Madelon, Michiel en Jan Paul have now uncovered an unexpected cancer-driver event. Their new insights into how certain gene mutations can cause cancer may open new possibilities in treating patients whose cancer harbours these mutations.” 
 
The manuscript was co-authored by Maureen Spit, Nicola Fenderico and Ingrid Jordens. Both Maureen and Nicola are PhD alumni from the lab of Madelon Maurice, where Ingrid currently works as a senior postdoctoral researcher. The team has produced a nice video abstract which further explains the mechanism they have uncovered.

It has been some years now since the introduction of the first drug targeting the immune system to combat cancer. A true game-changer, as for many patients this has meant a large improvement in survival and quality of life. The class of drugs termed as immune checkpoint inhibitors (ICIs) has however a clear limitation as many patients do not respond as resistance mechanisms to these type of drugs are common. The development of novel ICIs has yet to address this issue.  
 
Room for improvement as a deeper understanding of the biology of ICI resistance is imperative to derive the next generation of IO therapeutics. That’s where Immagene comes into the picture. At the start of September, Immagene B.V. launched as a private biotech company with  a clear goal: developing next-generation precision immuno-oncology treatments. The company based in Amsterdam was launched following a successful fundraise from Oncode Bridge Fund, Swanbridge Capital, and Innovatiefonds Noord Holland.  
 
“We are delighted to welcome our investors into the company”, says Dr. Maarten Ligtenberg,  Chief Executive Officer at Immagene. “It is exciting to enter the IO space to develop first in class therapeutics to overcome resistance and fully unleash the antitumor activity of patients’ immune system.” To do so, the company is building a pipeline of highly promising first-in-class IO therapies identified through an innovative screening strategy. This strategy was developed in the labs of the founding scientists: Oncode Investigator Dr. Daniel Peeper, Dr. Christian Blank, and Dr. Maarten Ligtenberg at the Netherlands Cancer Institute (NKI) and Oncode Institute. 
 
“We are excited with the launch of Immagene as our first spin-off active in the therapeutics domain”, adds Chris De Jonghe, Valorization Director at Oncode. “It is fascinating that Immagene originates from a close collaboration between a medical oncologist and molecular scientists at our partner institution the Netherlands Cancer Institute (NKI), to find novel solutions to overcome treatment resistance. Thanks to the entrepreneurial mindset of the founders, Immagene can convert promising molecules from the lab into potential innovative treatments for patients.” She concludes: “this is a wonderful illustration of Oncodes three strategic pillars: excellent science, collaboration and pro-active valorization.”