Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2000 breast tumors (777 estrogen receptor-negative, ER-) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy.Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK expression is an independent biomarker of poor prognosis in postmenopausal ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause