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THE IMPACT OF INTER- AND INTRA-TUMORAL HETEROGENEITY ON THE TREATMENT OF CANCER

Gopal, Priyanka
http://rave.ohiolink.edu/etdc/view?acc_num=case1554485746538973

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Genetic diversity in solid tumors have critical consequences for tailoring personalized patient care. Treatments using chemo and/or radiation therapy has rendered the “one size fits all” model ineffective. Recent large-scale sequencing studies in cancers have shown that the overall mutational landscapes and tumor microenvironments can be distinct. These same studies have not largely focused on intra-tumoral heterogeneity. This expansive heterogeneity poses a major obstacle towards the personalization of treatment. Central to our approach in studying heterogeneity is the use of patient-derived xenograft (PDX). Our models, described herein, are poised to predict response to drug and radiation treatments in both individual and groups of patients with particular genetic constitutions. Our approach also combined mathematical and experimental models to study intratumoral diversity and evolution. We show that tumors genetic compositions can drift and under some circumstances, like the application of a selective pressure, can dramatically shift. Thus, the sampling of a tumor for genomic analyses in a fixed time and space offers only a geographically and temporally restricted view of its genetic composition. Our study on clonal evolution in cancers with BRAF mutations elucidates some of these principals. Namely, those that govern evolutionary dynamics of tumor subclones that we predict can confer resistance to our treatments. We describe our results on the subclonal architecture of non-small cell lung cancer (NSCLC) tumors containing cells with variants of the BRAF gene. We show that these distinct classes of tumor architecture have significant implications for targeted and genotoxic therapies. In an effort to expand our explanatory models beyond the genome, we show that distinct differentiation/epigenetic states within individual tumors contribute to substantial phenotypic variability. We use small cell lung cancer (SCLC), a tumor of neuroectodermal origin or the “primitive” epithelium, as our model. SCLC is an aggressive lung malignancy that often has initial dramatic responses to therapies but and almost invariably resists and rebounds after first-line treatments. Our approach involved the use of large transcriptomic datasets to identify new taxonomies regulating SCLC phenotypes which marked both tumoral and intratumoral heterogeneity. Taken together, these studies begin to elucidate the inter-tumor and intra-tumoral landscape of some cancers and the impact of this heterogeneity on therapeutic resistance in cancer.
Mohamed Abazeed (Advisor)
Donna Driscoll (Committee Chair)
Daniel Lindner (Committee Member)
Nathan Pennell (Committee Member)
Bioinformatics; Cellular Biology
Heterogeneity; subclones; intratumoral; phenotypic

Recommended Citations

Citations

  • Gopal, P. (2019). THE IMPACT OF INTER- AND INTRA-TUMORAL HETEROGENEITY ON THE TREATMENT OF CANCER [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1554485746538973

    APA Style (7th edition)

  • Gopal, Priyanka. THE IMPACT OF INTER- AND INTRA-TUMORAL HETEROGENEITY ON THE TREATMENT OF CANCER. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1554485746538973.

    MLA Style (8th edition)

  • Gopal, Priyanka. "THE IMPACT OF INTER- AND INTRA-TUMORAL HETEROGENEITY ON THE TREATMENT OF CANCER." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554485746538973

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.