The journal Cancer Discovery published new findings by researchers at Karolinska Institutet, Sweden. They show that pharmacological activation (or a drug) of the protein p53 can boost the immune response against cancerous cells. These findings could be important for the development of combination therapies that will allow more patients with cancer to access immunotherapy.The protein p53 is known as the "guardian" of the genome because it can react to damage to the cellular DNA. Half of all cancers are caused by mutations in the gene that codes the protein. In many other cases, p53 is disabling by MDM2.It is well-known that p53 can silence certain sequences within our genome, which are called endogenous retroviruses. The DNA elements that are evolutionarily inherited from viruses can be silenced by p53, thereby preventing genome instability. Researchers now demonstrate that the protein can activate these sequences in cancer cells. This could lead to an anti-tumour immune response.This was an amazing discovery. "This was an amazing discovery. When we blocked MDM2 suppressor, p53 activated endogenous Retroviruses that induced antiviral responses and boosted production of immune-activating Interferons," Galina Selivanova, lead investigator, Karolinska Institutet, Department of Microbiology and Tumor, says.Researchers used a substance coded ALRN-6924 by Aileron Therapeutics to block MDM2 in mouse models. Two patients who took part in the clinical trials of ALRN6924 were also able to see an increase in interferon response.Professor Selivanova says, "This proves that there are synergies to be exploited between substances which block MDM2 as well as modern immunotherapies." For patients who aren't responding to immunotherapy, a combination of these could be very beneficial.In the way that it activates the immune system to fight off cancer cells, immunotherapy (or immuno-oncology) is described as a breakthrough in modern cancer treatment. It is not effective for all patients and interferons may be a biomarker to determine if immunotherapy will work."If we can raise the levels of interferons, then we can increase the chance that the immunotherapy will work."Professor Selivanova is a pioneering researcher on how mutated protein 53 can be activated using special molecules. One of these molecules, APR-246, has been undergoing clinical trials at Aprea Therapeutics under the name Eprenetapopt, which she co-founded.She says, "We are now interested in examining if Eprenetapopt can produce the same interferon boost as a patient with severe cancers and have the same potential for increasing access to immunotherapy."###Karolinska Institutet conducted the study and was funded by the Swedish Cancer Society and the Swedish Research Council. Aileron Therapeutics employs Vincent Guerlavais and Luis A. Carvajal as well as Manuel Aivado, Manuel Aivado, and D. Allen Annis, co-authors.Publication: "Pharmacological activation p53 triggers virus mimicry response, thereby abolishing tumor immuno evasion and pro-tumor immunity." Xiaolei Zhang, Madhurendra Sing, Gema Sanz, Santos and Vincent Guerlavais. Luis A. Carvajal. Manuel Aivado. Yue Zhan. Mariana M.S. Oliveira and Lisa S. Westerberg, D. Allen Annis John Inge Johnsen, Galina Selivanova. Cancer Discovery, online 6/7/2021. doi: 10.1158/2159-8290.CD-20-1741.
