Biomedical research into ovarian cancer, one of the most deadly gynecological cancers, opens a new path towards less invasive therapies. A new study led by an IDIBELL-ICO research team, in collaboration with Josep Carreras Leukaemia Research Institute, has discovered that blocking a specific pseudogene, RPSAP52, significantly reduces tumour growth without showing obvious signs of toxicity in the models used. The progress is twofold: besides identifying RPSAP52 as a promising therapeutic target, Dr. Lourdes Farré and Dr. Sonia Guil’s teams have also been able to present it as a valuable prognostic marker in the early stages of ovarian cancer (I and II). According to the results, it could be very useful when classifying patients into risk groups according to their expression level: the greater the expression of RPSAP52, the greater the risk and the worse the prognosis.
The study that includes this double breakthrough, recently published in the European Journal of Cancer, has been led by the team of Dr. Lourdes Farré, principal investigator of the ProCure research group on Tumor and stromal chemoresistance at IDIBELL-ICO, in close collaboration with Dr. Sònia Guil from the Josep Carreras Leukaemia Research Institute (IJC), and with the participation of the Bellvitge University Hospital.
Side A: a key prognostic marker
Pseudogenes structurally resemble conventional active genes, but have lost their natural ability to code for proteins. Despite having lost it, they are often still involved in the regulation of molecular pathways and can have a relevant impact on diseases such as cancer, as seen with BRAFP1, in lymphomas, or PTENP1, in kidney and bladder cancers.
This time, a team of Catalan researchers has discovered that RPSAP52 is an active promoter of tumour growth in epithelial ovarian cancer. The analysis of the data collected in The Cancer Genome Atlas (TCGA) showed an overexpression of the pseudogene in the samples of patients with this cancer.
The high expression of RPSAP52 was associated with a reduction in survival in patients in stages I and II: the higher the expression, the lower the probability of survival. “This makes RPSAP52 a possible good prognostic marker, which could serve to stratify these patients into groups of greater or lesser risk, and help propose the appropriate therapeutic strategy, more or less aggressive, in each particular case,” explains Deepthi Ramesh, first author of the study and researcher at the Josep Carreras Leukaemia Research Institute.
Side B: an effective and toxicity-free therapeutic target
Faced with such high expression of the pseudogene in tumor samples, the IDIBELL-ICO team deepened the study of its effects on the development and formation of cancer. To do this, they generated experimental models, in vitro and in vivo, in which they silenced RPSAP52 expression using antisense nucleotide treatment (GapmeR LNA).
“The inhibition of RPSAP52 was decisive: the cancer cells lost proliferative capacity and tumor growth was significantly reduced,” explains Dr. Farré. She adds that the great advantage is safety: “This treatment did not show toxicity in preclinical models. The low or null expression of RPSAP52 in healthy tissue makes it an ideal therapeutic target that mainly targets cancer cells.”
This promising therapeutic effect is reinforced by a far-reaching mechanism of action: RPSAP52 is closely linked to the PI3K/AKT molecular pathway, activated in 70% of patients with epithelial ovarian cancer. Researchers have found that silencing the pseudogene deactivates AKT. This not only suggests a very broad therapeutic benefit, but would greatly reduce the toxicity of the current alternative, given that direct PI3K/AKT inhibitors have a high toxicity. It could even be useful to help protect the ovary against the toxicity associated with conventional chemotherapy.
The reality of ovarian cancer
Ovarian cancer is the 8th most common cancer among women, and in 85-90% of cases it originates in the epithelial cells of the ovaries or fallopian tubes. It is a particularly difficult cancer to detect, as there are still not sufficiently good tests for early detection, such as, for example, mammograms in breast cancer. Moreover, the symptoms are not evident until advanced stages.
The combination of these two factors is worrying: only 20% of cases are detected in the early stages. According to the American Cancer Society, if diagnosed early, five-year survival would be 94%. But the reality is different: today, the average five-year survival from diagnosis is a little less than 50%.
In this context and taking into account that current treatment tends to be aggressive and based on surgical removal, new therapeutic strategies aimed at the tumor are needed. The study of RPSAP52-blocking is aimed precisely at this need. “It is necessary and urgent to improve both the diagnosis and treatment of ovarian cancer. We need to improve diagnostic tools to get there on time and optimize therapies to focus on the tumor and avoid adverse effects,” concludes Dr. Lourdes Farré. “With research like this and such promising results, we are on the right track.”
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center created in 2004 and specialized in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. IDIBELL is supported by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L ́Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the European Union’s HR Excellence in Research program and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).