A one-two punch approach to cancer treatment
Cancer remains difficult to treat, especially when disease is advanced. Combinations of different cancer drugs are used to suppress development of resistance, but such therapeutic approaches are often limited by toxicity. This project has recently developed a radically different approach to cancer therapy which is not based on combinations of drugs, but rather on the sequential treatment with drugs, thereby avoiding drug combination toxicity. This approach will be developed further in a collaboration between the Netherlands Cancer Institute and Oncosence BV.
This programme will identify novel targets for therapy that will serve as starting point for the development of innovative cancer therapies. The social and economic impact of fundamentally new and effective cancer therapies in four major cancer types is significant.
The approach the programme uses consists of a “one-two punch” for the cancer cells. First, cells are induced to stop dividing and also acquire a major new vulnerability that is subsequently targeted by a second drug that selectively kills cells with the acquired vulnerability. To accomplish this, the programme takes advantage of the notion that a cellular senescence response can be triggered in advanced cancers. Such senescent cancer cells have dramatic changes in gene expression and metabolism that might be exploited for their eradication. Using an animal model of liver cancer, proof of concept is delivered that induction of senescence, followed by treatment with an agent that specifically kills senescent cancer cells, leads to dramatic responses. Here, large-scale genetic screens will be performed in four major cancer types to identify novel genes whose suppression induces senescence or kill senescent cancer cells.
The deliverables of this programme will be a series of novel drug targets that can be used in the “one-two punch” therapeutic approach to cancer therapy.
A one-two punch model for cancer therapy based on sequential drug treatment, exploiting induction of senescence as a stable cancer cell state with major acquired vulnerabilities that can be used to selectively kill them.
