DRUG REPOSITIONING FOR TREATMENT OF THERAPY-RESISTANT TUMORS

MENACHO MÁRQUEZ, MAURICIO; ANSELMINO, LUCIANO E.; BAGLIONI, MARÍA VIRGINIA; MALIZIA, FLORENCIA; CESATTI LALUCE, NAHUEL; ROZADOS, VIVIANA; SCHAROVSKY, GRACIELA; RICO, MARÍA JOSE

Mar del Plata

Simposio; Congreso; Reunión Conjunta SAIC, SAI&FAIC, SAFIS 2022; 2022; 2022

Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer in men and the second in women. Most cases of CRC are diagnosed at advanced stages, when the probability of developing resistance to treatment and distal or local recurrence of the tumor is higher. Since the 1950s, 5-fluorouracil (5-FU) has been the mainstay of chemotherapy for CRC treatment. However, epidemiological studies determined that almost half of patients develop resistance to 5-FU-based chemotherapies.On the other hand, triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat.For both types of tumors, the available treatments are generally associated to severe side effects.In order to counteract this situation, new treatment strategies are being implemented, such as the improvement of early diagnosis, the discovery of predictive biomarkers and the development of new drugs/drug combinations for treatment. In line with this, drug repositioning explores the reuse of non-cancer drugs to treat tumors, rather than using new drugs. In our work, we evaluated the effect of repurposing drugs on TNBC and 5-FU resistant CRC. By a combination of in vitro and in vivo studies, we demonstrated that treatment with drugs such as metformin and propranolol affects viability, epithelial-mesenchymal transition and migratory potential of both CRC and TNBC cells. Indeed, we showed that combined treatment affects different steps leading to metastasis in TNBC and is also effective preventing the development of 5-FU resistant CRC, suggesting that combination of metformin and propranolol could be useful as an adjuvant treatment for both type of tumors and an alternative for chemo-resistant CRC, providing a low-cost substitute therapy without associated toxicity.In a second approach, we used bioinformatics algorithms to identify genes associated with tumor recurrence after 5-FU-based chemotherapy in CRC patients. Then, we selected compounds with high probability to reverse the resistance-associated gene expression profile obtained. Combining this strategy with in vitro and in vivo studies, we demonstrated that in silico drug repositioning emerges as an interesting alternative to discover drugs potentially reverting resistance associated to cancer treatment.