A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Genome Medicine

Mariano J. Alvarez¹  Farhad Forouhar²  Mahesh M. Mansukhani³  Peter L. Nagy³  Stuart J. Andrews³  Andrew T. Turk³  Chelsey M. Mitchell⁴  Julia L. Glade Bender⁴  Darrell J. Yamashiro⁴  Lianna J. Marks⁴  Beata Modzelewski⁵  Filemon S. Dela Cruz⁵  Andrew L. Kung⁵  Allison R. Rainey⁵  Daniel Diolaiti⁵  Andrea Califano⁶  Alberto Ambesi-Impiombato⁶ 

[1] Darwin Health Inc.;Department of Biological Sciences, Columbia University;Department of Pathology and Cell Biology, Columbia University Medical Center;Department of Pediatrics, Columbia University Medical Center;Department of Pediatrics, Memorial Sloan Kettering Cancer Center;Department of Systems Biology, Columbia University Medical Center;

关键词: Poorly differentiated carcinoma (PDC);    Patient-derived xenograft (PDX) models;    Precision medicine;    MAX;    mTOR;    BRAF;   

DOI  :  10.1186/s13073-016-0366-0

来源: DOAJ

【 摘 要 】

Abstract Background Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. Methods We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. Results WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. Conclusions This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.

【 授权许可】

Unknown