Precision Phenomics to Personalized Drug Therapy (P3DT)
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ABSTRACT:
PROVIDER: PRJNA595707 | ENA |
REPOSITORIES: ENA
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Project description:Precision Phenomics to Personalized Drug Therapy (P3DT)
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Project description:Purpose: Advanced high-grade gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) are highly aggressive and heterogeneous epithelial malignancies with poor clinical outcomes. No therapeutic predictive biomarkers exist and representative preclinical models to study their biology are missing. Patient-derived (PD) tumoroids may enable fast ex vivo pharmacotyping and provide subsidiary biological information for more personalized therapy strategies in individual patients. Experimental Design: PD tumoroids were established from rare biobanked surgical resections of advanced high-grade GEP-NEN patients. Using targeted in vitro pharmacotyping and next-generation sequencing of patient samples and matching PD tumoroids, we profiled individual patients and compared treatment-induced molecular stress response and in vitro drug sensitivity to the clinical therapy response. Results: We demonstrate high success rates in culturing PD tumoroids of high-grade GEP-NENs within clinically meaningful timespans. PD tumoroids recapitulate biological key features of high-grade GEP-NEN and mimic clinical response to cisplatin and temozolomide in vitro. Moreover, investigating treatment-induced molecular stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A (KDM5A) and interferon-beta (IFNB1) as two vulnerabilities that act synergistically in combination with cisplatin and may present novel therapeutic options in high-grade GEP-NENs. Conclusion: Patient-derived tumoroids from high-grade GEP-NENs represent a relevant model to screen drug sensitivities of individual patients within clinically relevant timespans and provide novel functional insights into drug-induced stress responses. Clinical patient response to standard-of-care chemotherapeutics matches with drug sensitivities of PD tumoroids. Together, our findings provide a functional precision oncology approach for gathering patient-centered subsidiary treatment information that will potentially increase therapeutic opportunities in the framework of personalized medicine.
2024-03-01 | GSE213504 | GEO
Project description:Personalized therapy of rheumatoid arthritis (RA) based on traditional Chinese medicine cold and hot syndromes is selection of the best treatment for an individual patient. Wutou Decoction (WTD) is one of the classic Chinese herbal formulae which achieve favorable therapeutic response in treating RA-cold syndrome. Microarray analysis based on the adjuvant induced arthritis model combined with characteristics of RA and cold/hot syndromes was performed to screen RA-cold and RA-hot-syndrome-related genes, as well as WTD effect genes.
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Project description:The potential of eccrine sweat as a bio-fluid of interest for diagnosis and personalized therapy has not yet been fully evaluated, due to the lack of in-depth sweat characterization studies. Thanks to recent developments in the field of omics together with the availability of accredited eccrine sweat collection methods, the analysis of human sweat may now be envisioned as a standardized, non-invasive test for individualized monitoring and personalized medicine. Here, we characterized individual sweat samples, collected from 28 healthy adult volunteers under the most standardized sampling methodology, by applying an optimized Shotgun proteomic analysis. This deep characterization of the sweat proteome allowed the identification of about 1000 unique proteins from which 347 were identified across all samples. Annotation-wise, the study of the sweat proteome unveiled the over-representation of newly addressed Actin dynamics, oxidative stress and proteasome-related functions, in addition to well-described proteolysis and anti-microbial immunity. The sweat proteome composition appeared to be correlated to the inter-individual variability of sweat secretion parameters (water and solute losses). Besides, both gender-exclusive proteins and gender-specific protein abundances were highlighted in spite of the high similarity between human female and male sweat proteomes. In conclusion, standardized sample collection coupled to optimized shotgun proteomics significantly improved the depth of sweat proteome coverage, far beyond previous similar studies. The identified proteins were involved in many diverse biological processes and molecular functions indicating the potential of this bio-fluid as a valuable biological matrix for further studies. Addressing sweat variability, our results prove the proteomic profiling of sweat to be a promising bio-fluid for individualized, non-invasive monitoring and personalized medicine.
2021-11-03 | PXD025899 | Pride
Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
2023-12-01 | GSE248401 | GEO
Project description:Optimizing Personalized Therapy for Rheumatoid Arthritis Using a Novel Drug Combination of Bioactive Chemical Constituents Derived from a Classic Chinese Herbal Formula
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Project description:“Direct to Drug” screening as a precision medicine tool in multiple myeloma
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