PP-1 (Pfizer)

Breast cancer (BC) is the leading cause of cancer death in women, with hormone-dependent BC accounting for about 80 % of cases, primarily affecting postmenopausal women with gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) elevated. Treatments targeting the gonadotropin-releasing hormone receptor (GnRHR), such as the agonist leuprorelin (LEU) and antagonist degarelix (DEGA), are used for hormone-dependent tumors. While the functional role of gonadotropin receptors in extragonadal tissues remains uncertain, recent studies suggest LH contributes to tumor development and progression. Tumor progression involves reorganization in the actin cytoskeleton, induction of adhesion, and cell migration, driven by proteins such as Src and the focal adhesion kinase (FAK), which are related to invasive behaviors. The overexpression of both protein kinases generates an invasive and metastatic phenotype, then inhibitors targeting Src (PP2) and FAK (FAKi) have been developed to counteract this effect. This study combined GnRH analogs with Src and FAK inhibitors to target BC progression. We found that LH treatment influenced gene expression linked to tumor development. Examining the GnRHR-LEU and GnRHR-DEGA complexes revealed structural differences affecting ligand binding. In an orthotopic tumor model, DEGA reduced tumor growth, while LEU had the opposite effect. Combining DEGA with PP2 or FAKi enhanced tumor inhibition, improving mice survival. These findings provide valuable insights into the essential regulatory role of gonadotropins in genes involved in tumorigenic processes, highlighting the potential of GnRHR antagonists combined with Src or FAK inhibitors as a promising strategy to develop new drugs that interfere with the ability of breast tumor progression.

We applied a novel model mimicking the most intense 5‐min game periods to investigate muscle metabolic and fatigue responses to peak‐intensity exercise occurring early and late in a simulated soccer game. Eleven well‐trained male players completed a modified simulated soccer game (the Copenhagen Soccer Test) with 5‐min peak‐intensity period simulations inserted early (PP1; 10–15 min) and late (PP2; 85–90 min) in the game. Muscle biopsies and blood samples were obtained before and after each peak period. Muscle glycogen decreased during both peak periods (p < 0.001) by 62 ± 46 mmol kg−1 dw in PP1 and by 25 ± 37 mmol kg−1 dw in PP2, without a statistically significant difference in the glycogen breakdown in PP1 vs. PP2, despite a numerical trend (p = 0.115). Muscle lactate increased during both peak periods (p < 0.001) to 47 ± 25 mmol kg−1 dw and 32 ± 12 mmol kg−1 dw, with no clear difference in the increase (p = 0.108), despite blood lactate levels rising more in PP1 vs. PP2 (p = 0.031), reaching higher post PP1 levels (13.9 ± 3.6 mmol L−1 vs. 9.8 ± 2.4 mmol L−1, p = 0.003). Muscle ATP decreased by 4% (p = 0.004) and phosphocreatine by ~50% (p < 0.001) following both peak periods. RPE was higher during PP2 (10.0 ± 0.0 AU vs. 9.2 ± 0.8 AU, p = 0.023), while 10‐m sprint performance declined by ~10% (p < 0.001), with no differences between PP1 and PP2 (p = 0.280). In conclusion, a 5‐min peak period occurring early in a simulated game elicited a high anaerobic energy turnover, with marked muscle glycogen reductions, lactate accumulation, and PCr depletion. While high‐energy phosphate metabolism remained similar during the late peak period, glycogenolytic rate appeared attenuated, accompanied by aggravated perceived exertion but similar sprint performance deteriorations.