drugrepocentral.scienceopen.com
Patient-derived lymphoma organoids and repurposed drugs: novel solutions for improved B cell lymphoma treatment
<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d816596e219">B cell lymphomas (BCL) are a heterogenous group of hematologic malignancies, with over 70 identified subtypes. Current first line treatment for all subtypes is rituximab and chemotherapy regimen (R-CHOP); of the treated patients, up to 40-60% relapse or have refractory disease, with typically higher mortality rates. Therefore, more efficient treatment, but also improved <i>ex vivo</i> research models are needed to study the treatment response and resistance. To overcome the expensive and time-consuming process of drug discovery and development, we aim to combat the lymphoma heterogeneity with repurposed drugs, especially focusing on cationic amphiphilic drugs (CADs) that damage cancer cell lysosomes. </p><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d816596e224">Lysosomes are central organelles in nutrient sensing and cellular metabolism. Malignant transformation rewires cellular metabolism to boost growth. In turn, cancer cells increase lysosomal production and activity to meet the metabolic needs. Our current results indicate that targeting the reported cancer cell lysosomal ‘weakness’ with repurposed CADs Ebastine and Penfluridol prevents pro-survival cell signaling, and suppresses long-term tumor outgrowth in B lymphoma cell lines, patient blood B cells, and in patient lymph node-derived organoids. </p><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d816596e226">We have developed a novel patient-derived lymphoma organoid model as an <i>ex vivo</i> drug assay platform from patients’ own cancer tissue. With combining the lymphoma organoid model and repurposed drugs, this study provides a simpler and cost-effective, yet translationally relevant clinical solution for personalized medicine and improved treatment of BCL patients. </p>
