A typical genome-wide association study is conducted through a single-phenotype analysis of the correlation between each phenotype and genotype one at a time. Alternatively, a multiple-phenotype analysis of the correlation between multiple phenotypes and a genotype often has many advantages over single-phenotype analysis. For example, statistical power in the association test may be increased in a multiple-phenotype analysis and thus may detect small effects that cannot be identified in a single-phenotype analysis. Of the several multiple-phenotype analytical methods that have been proposed, generalized analysis of molecular variance for mixed-model analysis (GAMMA) is used to analyze many phenotypes simultaneously while considering the population structure. This method shows higher accuracy than the other methods. However, GAMMA has not been widely used because no automated and user-friendly software is available; this is also the case with most other multiple-phenotype analysis methods. In addition, the lack of a parallel-processing option, which is essential in a genome-wide-association-studies analysis, is also prevalent in GAMMA. In this study, we propose an easy-to-use R package for GAMMA called GAMMA Renew (GAMMAR) that performs multiple-phenotype analysis using parallel processing. We evaluate GAMMAR using a recently published yeast dataset to locate trans-regulatory hotspots.
Poly (ADP-ribose) polymerase (PARP) inhibitors that are effective against ovarian and breast cancers with breast cancer susceptibility gene (BRCA) mutations have undesirable side effects, such as hematological toxicity. AZD5305, a selective PARP1 inhibitor currently in Phase 1/2 clinical trials, may avoid the side effects caused by PARP2. However, the in vivo pharmacokinetic characteristics of AZD5305 and its bioanalytical methods are unknown. Therefore, a method based on liquid chromatography with tandem mass spectroscopy (LC–MS/MS) was developed and validated to quantify AZD5305 in plasma of mice. Optimal chromatographic separation in terms of peak intensity and symmetry was acquired using a 4-µm Polar-RP 80 Å (2.0 × 150 mm) column with ammonium acetate (5 mM) in distilled water–acetonitrile (50:50, v/v). The retention times of AZD5305 and internal standard (IS; olaparib) were 1.82 min and 1.99 min, respectively. Detection was carried out via triple quadrupole mass spectrometry in positive ion mode employing multiple reaction monitoring transitions at m/z 407.0 → 376.0 for AZD5305 and m/z 435.0 → 281.2 for the IS. The LC–MS/MS method was linear in the range 1–1000 ng/mL with a correlation coefficient ≥ 0.990 and showed acceptable values of major parameters including accuracy, precision, and recovery. Additionally, AZD5305 showed high stability under various conditions. The in vivo and in vitro pharmacokinetics of AZD5305 were successfully characterized by employing the validated LC–MS/MS method. A high level of drug exposure and linear pharmacokinetics were observed after intravenous (IV) bolus and oral administration (PO) of AZD5305 at 0.1–1 mg/kg and 0.1–3 mg/kg, respectively. The bioavailability was close to 100%, and the metabolic stability of AZD5305 in hepatic microsomes of mice and humans was very high. These results may contribute to the improvement of PARP inhibitors that are used to treat malignancies originating from BRCA mutations.
Childhood cancers are rare and clinically diverse. They are typically associated with few driver mutational events than adult cancers, constituting potential targets for patient-specific precision therapy approaches. Here, we evaluated the feasibility of using a patient-derived tumor cell (PDC) based drug screening system and integrated multi-omics data to achieve precision oncology for pediatric patients. We established a PDC library derived from a few passage-cultured tumor cells from surgically resected tumor specimens and conducted chemical screening, which composed of various target agents of major oncogenic pathways (e.g. receptor tyrosine kinase inhibitor, proteasome inhibitor and histone deacetylase etc.). Next Generation Sequencing was performed to characterize the genomic and transcriptomic traits of tumors. Overall, success of establishing PDCs of pediatric cancers was high (80.4%) and comparable to adult cancers. The amount of obtained tissue was an important factor for the success of PDC establishment; the estimated optimal weight for PDC establishment was small (1.14g) and it is noteworthy that a small amount of tumor sample is sufficient to identify the potential hit(s) of parental tumors. The platform provided therapeutic options to pediatric tumors regardless of actionable targets. Our PDC approach identified several potential gene-drug associations, including anti-PI3K/Akt agents for neuroblastomas and anti-SHH agents for sarcomas with EWSR1 fusion. Given that a considerable proportion of pediatric tumors still lack actionable targets with matched treatment options, PDC-based drug screening profiles can be an optimal therapeutic strategy for these cases. Collectively, our analysis confirmed the feasibility of PDC-based in vitro drug screening systems to guide the therapeutic strategy for pediatric patients. This approach will accelerate the preclinical research for pediatric tumors to understand their pathophysiology and investigate the potential therapeutic strategies to fulfill the future precision oncology. Citation Format: Gi Ju Lee, Seung-Won Choi, Seung Ah Choi, Hee-Jin Cho, Robyn Gartrell, Ji Won Lee, Joo Whan Kim, Nam-Gu Her, Raul Rabadan, Ki Woong Sung, Do-Hyun Nam, Seung-Ki Kim. Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4486.
Precision medicine endeavors to match patients to therapies mostly on the basis of the genomic alterations in their tumors. However, it has been shown that ‘genomics only’ approach is often insufficient for best drug selection. Functional precision medicine has been recently emerging as it provides directly translatable information on which drug to choose among available drugs. Traditionally, cancer drugs are tested in cancer cell line models, but cell lines cannot represent individual clinical patients and are too biologically pronounced to be useful for drug screening purposes. Our patient-derived cell (PDC) drug screening system overcomes these points and can generally also correlate with genome changes. AVATAMED and CBmed, together with AimedBio, are collaborating in a Precision Cancer Project, set out next generation drug screening platform to screen Austrian glioma patients for proof-of-concept study. Fresh native tissue from both low- and high-grade glioma are collected. Tumor tissue is used for PDC isolation using mechanical and enzymatic tissue dissociation. To preserve the original tumor similarity, tissue is short term cultured under two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment. We have cultured 65 PDCs from both low- and high-grade glioma. Tissue culture success rate and drug screening success rate was >85% suggesting that specimen logistics and tissue processing are well-established and conducted. PDCs were treated with 79 drugs that are commonly used in clinical setting. In order to evaluate the quality of the results, the screening was conducted at two different sites, AimedBio and CBmed, and the data were compared. Overall, high accuracy and reproducibility were confirmed by low Coefficient of Variation (CV) between replicates and high Z-factor between negative and positive controls. In addition, data generated from both sites showed high correlations. Collectively, our next-generation drug screening platform shows the potential to give the best therapeutic options to glioma patients. To this end, we are moving forward use this platform in clinical study. Citation Format: Nam-Gu Her, Amin El-Heliebi, Gi Ju Lee, San Ha Park, Barbara Prietl, Stephanie S. Ahn, Hong Boon Toh, Thomas R. Pieber, Do-Hyun Nam. Proof of concept study of next generation drug screening platform for glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3411.
Precision medicine refers to the tailoring of individual therapeutics based on each patient’s genetic, phenotypic, and clinical characteristics, therefore seeking the most effective treatment for the patient. With recent advances in genome sequencing technology, it was anticipated that identifying specific genetic alterations would contribute greatly to the realization of precision medicine. However, most cancer patients do not benefit from genomic precision medicine, as shown in recent Next Generation Sequencing (NGS)-driven clinical trials. Functional precision medicine directly uses patient tumor cells to test their ex vivo responses to diverse drugs to predict the most effective drugs. Functional precision medicine is emerging because it provides immediate translatable information to select drugs among clinically available therapeutics. AVATASCAN®, developed by Samsung Medical Center and AimedBio Inc., is a robust and accurate high throughput functional precision medicine platform with more than 1,500 historical sample data. AVATASCAN® has tested more than 1,500 cancer patient samples across 14 different tumor types, including glioblastoma, lung, colorectal, stomach and breast cancers. We achieved a tissue culture success rate and a drug screening success rate of more than 90% in most tumor types. A retrospective analysis of the clinical outcomes of patients given matched drugs demonstrated actual complete/partial response in 85% of AVATASCAN® screening responders. Recognizing its potential for clinical application, AVATASCAN® was selected as one of the datasets referenced by the pediatric tumor board at Seoul National University Hospital for clinical decision-making. Furthermore, AVATASCAN® is now available in Singapore and Thailand as an early-access, premium precision medicine service. Overall, we present compelling evidence that AVATASCAN® is a valuable platform for personalized cancer therapy. Therefore, we are moving forward to adopt and expand this platform in clinical applications. Citation Format: Nam-Gu Her, Gi Ju Lee, Seung Yoon Hyun, San Ha Park, Jae Woo Ahn, Ji Soo Kang, Hong Boon Toh, Do-Hyun Nam. AVATASCAN®, a pioneer of functional precision medicine in guiding clinical decision-making [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3410.
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