Browsing by Subject "Precision oncology"

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    Genomic Profiling of T-Cell Neoplasms Reveals Frequent JAK1 and JAK3 Mutations With Clonal Evasion From Targeted Therapies
    (American Society of Clinical Oncology, 2018) Greenplate, Allison; Wang, Kai; Tripathi, Rati M.; Palma, Norma; Ali, Siraj M.; Stephens, Phil J.; Miller, Vincent A.; Shyr, Yu; Guo, Yan; Reddy, Nishitha M.; Kozhaya, Lina; Unutmaz, Derya; Chen, Xueyan; Irish, Jonathan M.; Davé, Utpal P.; Medicine, School of Medicine
    Purpose: The promise of precision oncology is that identification of genomic alterations will direct the rational use of molecularly targeted therapy. This approach is particularly applicable to neoplasms that are resistant to standard cytotoxic chemotherapy, like T-cell leukemias and lymphomas. In this study, we tested the feasibility of targeted next-generation sequencing in profiles of diverse T-cell neoplasms and focused on the therapeutic utility of targeting activated JAK1 and JAK3 in an index case. Patients and Methods: Using Foundation One and Foundation One Heme assays, we performed genomic profiling on 91 consecutive T-cell neoplasms for alterations in 405 genes. The samples were sequenced to high uniform coverage with an Illumina HiSeq and averaged a coverage depth of greater than 500× for DNA and more than 8M total pairs for RNA. An index case of T-cell prolymphocytic leukemia (T-PLL), which was analyzed by targeted next-generation sequencing, is presented. T-PLL cells were analyzed by RNA-seq, in vitro drug testing, mass cytometry, and phospho-flow. Results: One third of the samples had genomic aberrations in the JAK-STAT pathway, most often composed of JAK1 and JAK3 gain-of-function mutations. We present an index case of a patient with T-PLL with a clonal JAK1 V658F mutation that responded to ruxolitinib therapy. After relapse developed, an expanded clone that harbored mutant JAK3 M511I and downregulation of the phosphatase, CD45, was identified. We demonstrate that the JAK missense mutations were activating, caused pathway hyperactivation, and conferred cytokine hypersensitivity. Conclusion: These results underscore the utility of profiling occurrences of resistance to standard regimens and support JAK enzymes as rational therapeutic targets for T-cell leukemias and lymphomas.
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    Precision Genomic Practice in Oncology: Pharmacist Role and Experience in an Ambulatory Care Clinic
    (MDPI, 2020-03) Raheem, Farah; Kim, Pauline; Grove, Meagan; Kiel, Patrick J.; Medicine, School of Medicine
    Recent advancements in molecular testing, the availability of cost-effective technology, and novel approaches to clinical trial design have facilitated the implementation of tumor genome sequencing into standard of care oncology practices. Current models of precision oncology practice include specialized clinics or consultation services based on a molecular tumor board (MTB) approach. MTBs are comprised of interprofessional teams of clinicians and scientists who evaluate tumors at the molecular level to guide patient-specific targeted therapy. The practice of precision oncology utilizing MTB-based models is an emerging approach, transforming precision genomics from a novel concept into clinical practice. This rapid shift in practice from cytotoxic therapy to targeted medicine poses challenges, yet brings exciting opportunities to clinical pharmacists practicing in hematology and oncology. Only a few precision genomics programs in the United States have a strong pharmacy presence with oncology pharmacists serving in leadership roles in research, interpreting genomic sequencing, making treatment recommendations, and facilitating off-label drug procurement. This article describes the experience of the precision medicine clinic at the Indiana University Health Simon Cancer Center, with emphasis on the role of the pharmacist in the precision oncology initiative.
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    Targeted treatment of refractory primitive neuroectodermal tumor arising from an immature teratoma with crizotinib leading to a sustained response
    (Wiley, 2023-01-03) Snyder, Benjamin M.; Lion, Alex H.; Helvie, Amy E.; Marshall, Mark S.; Ferguson, Michael J.; Pediatrics, School of Medicine
    Here we present a case of metastatic PNET which arose from an immature teratoma that was refractory to standard Ewing sarcoma chemotherapy. This PNET was determined to have elevated levels of ALK protein via IHC. The patient was treated with crizotinib on a palliative basis with a sustained response.