DDR (from the English DNA Damage Response): three letters that indicate the complex molecular mechanism of response to DNA damage, an area on which scientific research has been focusing for years to develop new therapeutic strategies that can be effective against some solid tumors. Now new Italian research conducted by Candiolo’s IRCSS and the University of Turin, just published in the American Academy of Cancer Research’s Clinical Cancer Research journal, shows the effectiveness of this approach in colorectal cancer. In particular, the researchers found that in one out of three cases, colorectal cancers, even the most aggressive and unresponsive to molecularly targeted therapies, could benefit from the use of drugs targeting the damage response systems. DNA that is partially defective in cancer cells making the ‘surviving’ systems essential for cancer survival.
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The strategy of the GDR
The life of our cells is not infinite. Only cancerous ones conquer immortality by proliferating without control. At a certain point, ‘normal’ cells undergo the cellular senescence process that stops any proliferative event, a mechanism that represents a weapon against the development of tumors, precisely because of its intrinsic ability to block cell growth. To understand what triggers this process during aging or when the cell is at risk of cancer, for years we have been studying what is called the ‘Response to DNA damage’ in an attempt to decipher the molecular signals that activate the cellular senescence process and its dynamics and to understand how cellular senescence blocks tumor development.
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The research of Candiolo’s IRCCS
Researchers from Candiolo’s Irccs conducted the study on 112 cell lines of colorectal cancers with different genomic profiles. The results, confirmed on patient-derived organoids, indicate that drugs targeting proteins involved in DNA repair systems could become a concrete answer for many patients today without therapeutic opportunities: “Every day we are exposed to chemicals or physical agents, such as benzene or UV rays, which can damage DNA: these lesions are continuously resolved without consequences for normal cellular functions thanks to a complex DNA repair system “, he explains Sabrina Arena, Irccs Candiolo and Department of Oncology of the University of Turin, author and creator of the study. “This process is even more important in tumors, where some of these DNA repair systems are defective and it is therefore essential that those still functioning can carry on their activity to allow the tumor to ‘survive’. These systems give tumors greater aggressiveness but can prove to be an ‘Achilles’ heel’ and an excellent molecular target, because if they are ‘silenced’ the cancer cells succumb to damage to the DNA “.
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A composite biomarker
Active ingredients of this type are already in phase I-III of clinical trials. Also for this reason, according to the authors, it would be appropriate to hypothesize the use of a ‘composite biomarker’, which includes the evaluation of some of these possible therapeutic targets, so as to more rationally stratify patients with colorectal cancer and identify those who they would be most likely to derive a clinical benefit from the use of new drugs targeting systems involved in DNA damage repair. Parp inhibitors are drugs that affect these systems and are already used in the clinic for breast and ovarian cancers; today other new generation drugs inhibit other components of the DNA repair system and could therefore become a precious opportunity also in metastatic colorectal cancer that does not respond to other molecularly targeted therapies.
The results
The research, carried out thanks to the contribution of the Piedmontese Foundation for Cancer Research (Fprc) and the Italian Association for Cancer Research and Treatment (Airc), therefore had the objective of understanding whether new generation drugs can be useful in tumors for which there are currently no effective therapeutic opportunities. “We performed a drug screening using active ingredients targeted to proteins involved in DNA repair systems, some already in clinical trials in phase I-III, in 112 preclinical models of colorectal cancer different by genetic profile, which included cell lines and organoids made from patient tumor samples, ”he explains Alberto Bardelli, Irccs Candiolo, Department of Oncology of the University of Turin, and co-author of the study. “The data show that about 30% of cases, including those refractory to current therapies, may respond to at least one of these new generation drugs capable of inhibiting the function of several proteins involved in DNA damage repair. It is important to develop new diagnostic methodologies that make it possible to identify who could benefit from this type of therapies, for which clinical trials are already underway to demonstrate their real effectiveness on patients: a biomarker that evaluates the different possible targets could help to stratify the risk. and identify candidates who may best respond to treatment. There is still a long way to go, but these results lay the scientific and experimental foundations for new and more effective therapies to be applied in the future to other types of cancer as well ”.