Targeting Cytosolic Phospholipase A2 alpha (cPLA2α) in Hematological Cancers and Inflammation
Doctoral thesis
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Date
2023Metadata
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- Institutt for biologi [2596]
Abstract
Cytosolic phospholipase A2 alpha (cPLA2α) is an enzyme that plays a crucial role in regulating the balance between cellular growth and death by releasing the unsaturated fatty acid arachidonic acid from membrane lipids. The arachidonic acid acts as a precursor for the synthesis of very potent hormones. While the enzyme's relation to inflammation is well-established, its role in cancer is less clear. This doctoral thesis focused on investigating the biologic understanding of cPLA2α, particularly in relation to inflammation and cancer, with a specific focus on skin diseases like psoriasis and hematological cancers such as multiple myeloma and T cell acute lymphoblastic leukemia (T-ALL).
The research explored the impact of a cPLA2α inhibitor (AVX001) on psoriatic skin, revealing that inhibiting cPLA2α can prevent the release of inflammatory substances and inhibit abnormal cell growth in the skin. Another aspect investigated the response of cPLA2α inhibition (AVX002, AVX420) in hematological cancer cells, particularly multiple myeloma. The findings suggested that cPLA2α inhibitors could reduce the viability of these cancer cells, potentially through inducing programmed cell death. In another hematological cancer, AVX420, demonstrated potent efficacy in reducing inflammatory substances with high sensitivity in T-ALL cells. Further analysis revealed that AVX420 induced programmed cell death in T-ALL cells through various mechanisms, making it a promising candidate for treating this specific cancer type.
Overall, the research supports the concept that cPLA2α inhibitors have potential anti-inflammatory and anti-cancer properties. The promising safety profiles observed in psoriasis clinical trials suggest further exploration in hematological cancers, with the hope of developing a clinically approved cPLA2α inhibitor as a novel, therapeutic strategy for these malignancies.