One of the most unexpected and fascinating discoveries in oncology over the past decade has been the interplay between abnormalities in protein-coding genes and non-coding RNAs (ncRNAs), which are causally involved in cancer initiation, progression, and dissemination. Although, to date, the most studied non-coding RNAs (ncRNAs) are microRNAs (miRNAs), the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. At the conference, entitled “Non-Coding RNAs and Epigenetics in Cancer”, organized by MDPI (Basel, 21–23 June 2017), leaders in the field presented the roles of miRNAs and lncRNAs in cancer and discussed the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.
We had the honour to interview Prof. Dr. Carlo Croce, one of the key speakers at the conference. Dr. Croce is the Chair of the Department of Cancer Biology and Genetics at Ohio State University, specializing in oncology and noted for his research into the genetic mechanisms of cancer. Dr. Croce has received numerous awards, including the 2006 Clowes Memorial Award from the American Association for Cancer Research for his discoveries of the molecular mechanisms of leukemia and the Outstanding Investigator Award from the National Cancer Institute in 2015.
Here, in this interview, we are able to find out his opinion on the role of non-coding RNAs in cancer and discuss about recent progress in the field.
Dr. Croce, you have provided valuable insights into the underlying, genetic basis of cancer onset. You were the first to discover and sequence Bcl-2. Can you describe the latest trends and challenges in translational applications of ncRNAs as biomarkers?
The first clear-cut translation comes from our studies of mir-15 and -16. In 2002, George Calin and I found that in Chronic Lymphocytic Leukemia (CLL) the most common and dominant genetic alteration is the loss of two miRNA, mir-15 and -16, and that was the first evidence that the non-coding genome can contribute to disease, in particular to cancer. Before 2002 when we published this paper, everybody was convinced that only oncogenes and tumour suppressor genes were involved in cancer pathogenesis; in other words, genes that encode for proteins.
Our paper was the first evidence that alteration in the non-coding genome can result in diseases, and it was a revolutionary discovery because it indicated that 90% of the genome that was considered “garbage” is not actually “garbage”. After that, we looked for the target of mir-15 and -16 and we found that a crucial, critical target of these two miRNA is a gene that was discovered by my lab 1984, Bcl-2. Therefore, it became clear from our results that loss of mir-15 and -16, due predominantly to deletion, led to over-expression of Bcl-2. But at the same time that this was going on, a company in the U.S. called Abbott, developed small molecule inhibitors of Bcl-2. After extensive work, they developed the molecule called venetoclax or ABT199. This drug is dynamite; this drug can cause complete remission in patients with CLL, and, in most of the cases, there is no sign of minimal residual disease after treatment. It took a long time, but the drug was approved just last year, in April 2016, while we made the discovery in 1984. It took 32 years from the discovery of the gene to the development of the drug that can save thousands of lives. That indicates how the understanding of the non-coding genome can contribute not only to develop very important biomarkers to study the disease, but to develop drugs. And I am sure that we can go from this regulation of specific miRNAs to the development of new drugs and new therapeutic approaches. MiRNAs and other non-coding RNAs, like lncRNAs, can be used as very powerful biomarkers when they are expressed in the cancer cell for example, but also by looking at these biomarkers in the blood. This is a very important issue because if we can detect aberrant expression of these biomarkers in blood very early during the development of the disease, we might be able to cure the disease and eradicate the cancer when the tumour is non-invasive nor metastatic. Therefore, a lot of progress has been made because of the discovery of the involvement of ncRNA in human disease.
Prof. Dr. Carlo Croce