Development of new drugs to overcome resistance to anti-angiogenic therapy in renal cell carcinoma

Identifier:  TFG:2124

Handle: https://hdl.handle.net/20.500.11797/TFG2124

Authors:  Vallverdú Saltó, Anna Maria

Abstract:
Angiogenesis is a fundamental mechanism for tumor progression that induces blood vessel formation. In turn, it increases levels of oxygen and nutrients in the growing tumor mass. Targeted therapies inhibiting angiogenesis are currently used to treat several cancer types, such as renal cell carcinoma. However, these treatments fail to produce long-term effectiveness in most patients, due to tumor adaptation and subsequent resistance to therapy. Furthermore, there are no guidelines to follow after anti-angiogenic first-line treatment. Transcriptome characterisation pointed out several altered pathways in resistant tumors, highlighting an overexpression of the resistant factor 1 (RF-1). Several studies have already validated RF-1 as a good anti-tumor target. Considering its emerging role in cancer progression and angiogenesis, different RF-1 inhibitors have been synthesized. IRF-1 is an anti-RF-1 drug used together with chemotherapy. This small molecule inhibitor was tested in an in vivo model of resistant renal cancer and failed to significantly reduce tumor progression, besides presenting bad stability and pharmacokinetics. Consequently, efforts have been focused on the design of more effective RF-1 inhibitors. Virtual screening of RF-1 revealed different structures that were most likely to bind to the target and inhibit its enzymatic activity. Three candidates, HIT101, HIT102 and HIT103, showed the strongest affinity with RF-1 and were further evaluated in two genetically modified renal cancer cell lines. HIT103 was the most active compound against RF-1 in proliferation assays, although HITs effect on cell migration was not clearly elucidated. In consequence, further experiments are required to reveal how the novel HITs allow to overcome resistance of renal tumors to anti-angiogenic therapies.