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ECE Colloquium Series – Dr. George Vasmatzis
March 5 @ 4:00 pm - 5:00 pm
As part of the *Eleanore Hale Wilson Lecture Series, ECE is proud to present:
Analytical and Functional Models of Advanced Cancer: a Path to Alternative Combinatorial Treatments
Dr. George Vasmatzis
Host: Prof. Marc Riedel
Radical improvement in cancer care can be accomplished by individualizing patient management via the application of genomics and functional model systems into clinical practice. Recent breakthroughs in immunotherapy (i.e. checkpoint inhibitors) and targeted therapies (i.e. NTRK inhibitors) have shown that therapy of advanced cancers might become agnostic to the organ of origin, arguing for a more individualized approach to patient care. Emerging genomics technologies, data integration and visualization platforms are powerful tools to determine the state of the individual’s tumor and point to tailored treatments. Furthermore, an efficient combination of comprehensive genomics with 3D microcancer functional model systems can further refine treatment decisions. However, applying such disruptive technologies in clinical practice is not trivial. Regulatory, financial and clinical barriers will be discussed. An introduction to genomics technologies, data integration and visualization platforms will first be presented followed by demonstrative translational examples of tests that are clinically being used. A complete process will be described that combines comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3D ex vivo models for drug screening, to assess response to therapeutic agents targeting specific genomic alterations. The process was applied to a breast cancer patient with widely metastatic, weakly hormone receptor positive, HER2 nonamplified, infiltrating lobular breast cancer refractory to standard therapy. Clinical testing of liver metastasis identified BRIP1, NF1, CDH1, RB1, and TP53 mutations pointing to potential therapies including PARP, MEK/RAF, and CDK inhibitors. The comprehensive genomic analysis identified 395 mutations and several structural rearrangements that resulted in loss of function of 36 genes. Metaanalysis revealed biallelic inactivation of TP53, CDH1, FOXA1, and NIN whereas only one allele of NF1 and BRIP1 was mutated. A novel ERBB2 somatic mutation of undetermined significance (P702L), high expression of both mutated and wild-type ERBB2 transcripts, high expression of ERBB3, and a LITAF-BCAR4 fusion resulting in BCAR4 over-expression, pointed towards ERBB related therapies. Ex vivo analysis validated the ERBB related therapies and invalidated therapies targeting mutations in BRIP1 and NF1. Systemic patient therapy with afatinib, a HER1/HER2/HER4 small molecule inhibitor, resulted in a near complete radiographic response by 3 months. Unlike clinical testing, the combination of tumor profiling, data integration, and functional validation, accurately assessed driver alterations and predicted effective treatment.
*Established in 2009, the Eleanore Hale Wilson Fund supports engineering field leaders for travel to Minnesota to share their expertise and discoveries with University of Minnesota graduate students, faculty, and alumni. The fund also supports the receptions held in honor of each speaker.