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Targeting the Lysosomal Acid Lipase A to "Stress Out" Ovarian Cancer


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Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. The overall survival for metastatic OCa is dismal (<20 percent 5-year survival) and has not changed significantly for decades. Intratumoral and intertumoral heterogeneity of OCa drives tumor resistance to standard therapies and represents a significant clinical challenge. We had identified a small molecule, ERX-41, that consistently enhances endoplasmic reticulum stress (ERS) and apoptosis in OCa cells. Our overarching hypothesis is that the high basal ERS in OCa represents a critical and targetable vulnerability. First-year experiments employing numerous established and primary ovarian cancer cells revealed that treatment with ERX-41 reduced cell viability, decreased colony formation, and increased apoptosis of OCa cells. The expression of LIPA is necessary for ERX-41's action because activity of ERX-41 was rendered inactive by LIPA knockout. Treatment of OCa cells with ERX-41 promoted ERS, as seen by increased sXBP1 splicing and increased ATF4 expression. Additionally, RT-qPCR analyses supported the activation of genes related to each of the three main UPR response stress pathways. Ongoing studies further examined mechanisms and validate the utility using preclinical models. Overall, the first-year data support the use of ERX-41 as a novel targeted therapy that specifically targets the ERS vulnerability in ovarian cancer.



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