Periodic Reporting for period 4 - SENCAN (Senescence therapy for cancer)
Reporting period: 2023-04-01 to 2024-03-31
Resistance to therapy remains the main reason why cancer is difficult to treat, in spite of the availability of hundreds of effective therapies. Drug combinations can help fight resistance, but combinations of drugs also result in an accumulation of side effects that often limit the amount of drug that can be administered. The Bernards laboratory has developed a potential solution to this problem by developing a so called “one-two punch” approach to cancer therapy. In this approach, two drugs are given sequentially to patients, but still show major synergy. The sequential approach avoids the toxicity often seen with drug combinations given simultaneously, while the drugs are designed to have strong synergy despite the fact that they are not given at the same time. To accomplish this, cancer cells are first induced to enter into a dormant state called senescence with a first cancer drugs. These dormant cancer cells have undergone major changes that can form the basis for their selective killing with a second drug.
In 2019 the Bernards laboratory published the first proof of concept of this “one-two punch” approach for the treatment of liver cancer. The main aims of the SENCAN program are to find drugs that induce this state of dormancy in the cancer cells and to find ways to kill these dormant cancer cells.
There were three major aims. First, find novel targets in cancer to induce senescence. We have developed a genome scale CRISPR screening technology to identify genes whose inactivation causes senescence. This involves a “suicide switch” that kills proliferating cells and a fluorescent reporter that is activated in senescent cells. Using this approach we identified autophagy-related genes as targets for senescence induction (PMID: 34158393). We also used compound screens to find drugs that induce senescence. This resulted in identification of for instance AURORA kinase inhibitors as potent senescence inducers in a broad spectrum of cancer cells. The second aim involved the identification of vulnerabilities of senescent cells. We used both CRISPR screens and RNAseq to find exploitable vulnerabilities of senescent cells (PMID: 34320349; ). Most important was our finding that senescent cells upregulate Death Receptor 5 (DR5). Consequently, we found that DR5 agonistic antibodies, like conatumumab, are potent and selective agents to kill senescent cancer cells (PMID: 36414711). In aim 3, we validated that a combination of a pro-senescence drug (identified in aim 1) and an agent to kill senescent cancer cells (identified in aim 2) was highly effective in killing senescent cancer cells PMID: 36414711; PMID: 31578521). We have dubbed this novel therapeutic approach to treat cancer the "one-two punch" approach, as it allows sequential drug treatment (avoiding combination toxicity) but yet the two drugs do show combination synergy (PMID: 35241831).
In 2019 the Bernards laboratory published the first proof of concept of this “one-two punch” approach for the treatment of liver cancer. The main aims of the SENCAN program are to find drugs that induce this state of dormancy in the cancer cells and to find ways to kill these dormant cancer cells.
There were three major aims. First, find novel targets in cancer to induce senescence. We have developed a genome scale CRISPR screening technology to identify genes whose inactivation causes senescence. This involves a “suicide switch” that kills proliferating cells and a fluorescent reporter that is activated in senescent cells. Using this approach we identified autophagy-related genes as targets for senescence induction (PMID: 34158393). We also used compound screens to find drugs that induce senescence. This resulted in identification of for instance AURORA kinase inhibitors as potent senescence inducers in a broad spectrum of cancer cells. The second aim involved the identification of vulnerabilities of senescent cells. We used both CRISPR screens and RNAseq to find exploitable vulnerabilities of senescent cells (PMID: 34320349; ). Most important was our finding that senescent cells upregulate Death Receptor 5 (DR5). Consequently, we found that DR5 agonistic antibodies, like conatumumab, are potent and selective agents to kill senescent cancer cells (PMID: 36414711). In aim 3, we validated that a combination of a pro-senescence drug (identified in aim 1) and an agent to kill senescent cancer cells (identified in aim 2) was highly effective in killing senescent cancer cells PMID: 36414711; PMID: 31578521). We have dubbed this novel therapeutic approach to treat cancer the "one-two punch" approach, as it allows sequential drug treatment (avoiding combination toxicity) but yet the two drugs do show combination synergy (PMID: 35241831).
We have identified targets and drugs that can be used to induce the state of dormancy in cancer cells that is referred to as “senescence”. Several drugs that were used for other indications have been identified that induce senescence in cancer cells, which greatly expedites their potential use in the clinic for cancer therapy. We have also identified tools to kill these senescent cancer cells. Again, we have identified drugs that were used in the clinic for other indications, which again shortens the time required to bring these discoveries to the clinic.
Finally, we have demonstrated the utility of the “one-two punch” approach to cancer therapy that exploits the sequential induction of senescence followed by killing of senescent cancer cells in multiple animal models of cancer. The leader of the SENCAN program has established a company to bring these discoveries to the clinic as soon as possible.
Finally, we have demonstrated the utility of the “one-two punch” approach to cancer therapy that exploits the sequential induction of senescence followed by killing of senescent cancer cells in multiple animal models of cancer. The leader of the SENCAN program has established a company to bring these discoveries to the clinic as soon as possible.
Conventional cancer therapies consist of combinations of drugs to gain greater efficacy. The approach proposed here is to obtain synergy between cancer drugs without having to administer the drugs at the same time. The concept here is: “ combination synergy without combination toxicity”. This will potentially enable highly effective cancer therapies with reduced toxicity. Moreover, senescence induction has never been exploited for therapeutic purposes in oncology, as such this project is significantly beyond the state of the art.