Ex Vivo Drug Sensitivity Testing and Mutation Profiling
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PROVIDER: PRJEB71008 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND:Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in treatment decisions. The use of ex vivo drug sensitivity screens has the potential to improve the treatment of patients with platinum-resistant ovarian cancer by providing personalized treatment plans and thus reducing toxicity from unproductive therapy attempts. MATERIALS AND METHODS:We evaluated the treatment responses of a set of six early-passage patient-derived ovarian cancer cell lines towards a set of 30 Food and Drug Administration-approved chemotherapy drugs using drug-sensitivity testing. RESULTS:We observed a wide range of treatment responses of the cell lines. While most compounds displayed vastly different treatment responses between cell lines, we found that some compounds such as docetaxel and cephalomannine reduced cell survival of all cell lines. CONCLUSION:We propose that ex vivo drug-sensitivity screening holds the potential to greatly improve patient outcomes, especially in a population where multiple continuous treatments are not an option due to advanced disease, rapid disease progression, age or poor overall health. This approach may also be useful to identify potential novel therapeutics for patients with ovarian cancer.
| S-EPMC7323502 | biostudies-literature
Project description:ObjectiveTo describe the frequency of use of tumor genomic profiling and functional ex vivo drug sensitivity testing in pediatric patients with hematologic malignancies at our institution, and to determine how the results affected treatment selection.MethodsA retrospective chart review was conducted to analyze the frequency of tumor genomic profiling and functional drug sensitivity screening in our institution in pediatric patients with hematologic malignancies and to ask if the results were used to direct treatment. A case series of patients for whom these testing recommendations resulted in therapeutic interventions is reported.ResultsThirty-three patients underwent tumor genomic profiling assays, functional ex vivo testing, or both. Nineteen patients (58%) had genomic profiling assays performed alone, 3 (9%) had functional ex vivo testing performed alone, and 11 (33%) had both tests performed. Twenty-one (64%) patients had potentially actionable mutations detected by the genomic profiling assay. Seven (21%) patients received at least 1 chemotherapeutic agent in accordance with the tumor genomic profiling or functional ex vivo drug sensitivity testing results. Three (43%) of the 7 patients who were treated with testing directed therapy had a favorable treatment response (PR or CR) to treatments selected based upon results of genomic or functional ex vivo testing.ConclusionsThis retrospective case series demonstrates that precision medicine techniques such as genomic profiling and drug sensitivity testing can positively inform treatment selection in pediatric patients with relapsed or refractory leukemia and lymphoma.
| S-EPMC8837212 | biostudies-literature
Project description:BackgroundEsophageal cancer remains one of the hardest cancers to treat with rising incidence rates, low overall survival and high levels of treatment resistance. The lack of clinically available biomarkers hinder diagnosis and treatment stratification. While large scale sequencing approaches have uncovered a number of molecular makers, little has translated in the routine treatment of esophageal cancer patients.Material and methodsWe evaluate the treatment response towards a panel of 215 FDA-approved and 163 epigenetic compounds of 4 established and 2 patient-derived esophageal cancer cell lines. Cell viability was evaluated after 72h of treatment using cell titer glow. The drug sensitivity testing results for gemcitabine and cisplatin were validated using clonogenic assays.ResultsThe tested cell lines display different drug sensitivity profiles, although we found compounds that display efficacy in all of the tested established or patient-derived cell lines. Clonogenic assays confirmed the validity of the drug sensitivity testing results. Using the epigenetic library, we observed high sensitivity towards a number of epigenetic modifiers.DiscussionEx vivo drug sensitivity testing may present a viable option for the treatment stratification of esophageal cancer patients and holds the potential to greatly improve patient outcome while reducing treatment toxicity.
| S-EPMC6136712 | biostudies-literature
Project description:Current treatment selection for acute myeloid leukemia (AML) patients depends on risk stratification based on cytogenetic and genomic markers. However, the forecasting accuracy of treatment response remains modest, with most patients receiving intensive chemotherapy. Recently, ex vivo drug screening has gained traction in personalized treatment selection and as a tool for mapping patient groups based on relevant cancer dependencies. Here, we systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show that ex vivo drug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion, ex vivo drug profiling can assess risk for individual AML patients and may guide clinical decision-making.
| S-EPMC10753296 | biostudies-literature
Project description:Genomic profiling of relapsed and refractory childhood cancers
| PRJNA661354 | ENA
Project description:Genomic profiling of relapsed and refractory childhood cancers
| PRJNA661355 | ENA
Project description:In South Africa, leukemia remains a major health concern, posing significant challenges in treatment due to its varied subtypes. There is an unmet need for a testing pipeline that can identify drug effects on patient samples in an ex-vivo setting. Using the pilot study with South African patient samples, this paper reports the development of a drug-sensitivity testing pipeline for studying the drug effects in leukemia patient-derived cells. Forty-one (41) patients with Acute myeloid leukemia (AML) (n = 7), Chronic myelogenous leukemia (CML) (n = 30), and Chronic lymphocytic leukemia (CLL) (n = 4) were recruited for this study. Thirty (30) FDA-approved drugs were utilized for single drug sensitivity screening (DSS) on leukemia patient-derived cells with drug concentrations (1-1000 nM). The single DSS showed a distinct sensitivity pattern with different profiles among patients of the same subtype, confirming the need for precision therapy. This study observed irinotecan, used in solid tumour treatment, demonstrated efficacy in PBMCs in many patient samples compared to conventional leukemia drugs such as nilotinib. For drug combination studies, ten clinically relevant drugs were selected and tested based on the results of single drug sensitivity tests. This pilot study marks a crucial stride towards revolutionizing leukemia treatment in South Africa through an innovative ex vivo drug sensitivity testing platform. This pioneering initiative forms the basis for tailored and effective treatment options holding promise for more personalized treatment. Further exploration and validation of these findings could significantly contribute to cancer precision medicine efforts in South Africa.
| S-EPMC11914478 | biostudies-literature
Project description:Background chemotherapy is part of most breast cancer (BC) treatment schedules. However, a substantial fraction of BC tumors does not respond to the treatment. Unfortunately, no standard biomarkers exist for response prediction. Therefore, we aim to develop ex vivo sensitivity assays for two types of commonly used cytostatics (i.e., platinum derivates and taxanes) on organotypic BC tissue slices.MethodsEx vivo cisplatin sensitivity assays were established using organotypic tissue slices derived from the surgical resection material of 13 primary BCs and 20 fresh histological biopsies obtained from various metastatic sites. Furthermore, tissue slices of 10 primary BCs were used to establish a docetaxel ex vivo sensitivity assay.ResultsCisplatin sensitivity was assessed by tissue morphology, proliferation and apoptosis, while the relative increase in the mitotic index was discriminative for docetaxel sensitivity. Based on these read-outs, a scoring system was proposed to discriminate sensitive from resistant tumors for each cytostatic. We successful completed the cisplatin sensitivity assay on 12/16 (75%) biopsies as well.ConclusionsWe developed an ex vivo cisplatin and docetaxel assay on BC slices. We also adapted the assay for biopsy-sized specimens as the next step towards the correlation of ex vivo test results and in vivo responses.
| S-EPMC8909506 | biostudies-literature
Project description:Ex vivo assay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-term in vitro culture and ex vivo antimalarial susceptibility assays are relatively cumbersome, relying on in vivo passage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stage Plasmodium berghei, P. yoelii, and P. vinckei vinckei using a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.
| S-EPMC5075096 | biostudies-literature
Project description:The management of multiple myeloma (MM) is challenging: An assortment of available drug combinations adds complexity to treatment selection, and treatment resistance frequently develops. Given the heterogeneous nature of MM, personalized testing tools are required to identify drug sensitivities. To identify drug sensitivities in MM cells, we established a drug testing pipeline to examine ex vivo drug responses. MM cells from 44 patients were screened against 30 clinically relevant single agents and 44 double- and triple-drug combinations. We observed variability in responses across samples. The presence of gain(1q21) was associated with low sensitivity to venetoclax, and decreased ex vivo responses to dexamethasone reflected the drug resistance observed in patients. Less heterogeneity and higher efficacy was detected with many combinations compared to the corresponding single agents. We identified new synergistic effects of melflufen plus panobinostat using low concentrations (0.1-10 nm and 8 nm, respectively). In agreement with clinical studies, clinically approved combinations, such as triple combination of selinexor plus bortezomib plus dexamethasone, acted synergistically, and synergies required low drug concentrations (0.1 nm bortezomib, 10 nm selinexor and 4 nm dexamethasone). In summary, our drug screening provided results within a clinically actionable 5-day time frame and identified synergistic drug efficacies in patient-derived MM cells that may aid future therapy choices.
| S-EPMC8936517 | biostudies-literature