Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 156-169) Also available in print.

Thèse (Ph. D.)--Université Laval, 2004. / Bibliogr. Publié aussi en version électronique.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 118 pages. Includes Vita. Includes bibliographical references.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 174-207). Also available in electronic version.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references (leaves 81-90). Also available in electronic version.

Orientador: Lair Zambon / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T08:23:12Z (GMT). No. of bitstreams: 1 Costa_DanielBotelho_D.pdf: 9890444 bytes, checksum: 90e3892529ddea892b184c2ca660ac69 (MD5) Previous issue date: 2008 / Resumo: A maioria dos carcinomas de pulmão não pequenas células (CPNPC) em estádios avançados com mutações ativadoras (deleções do exon 19 ou a mutação L858R do exon 21) do receptor do fator de crescimento epidérmico (EGFR) respondem inicialmente, aos medicamentos gefitinib e erlotinib, que são inibidores da tirosina quinase (TKIs) do EGFR. Porém em uma média de 6-12, meses esses tumores desenvolvem resistência adquirida aos TKIs do EGFR. Dois mecanismos de resistência ao gefitinib/erlotinib explicam porque os CPNPC com mutações do EGFR se tornam resistentes aos TKIs: mutações de resistência secundária e um sistema de "troca de oncogenes". A mutação T790M-EGFR secundária ocorre em 50% dos pacientes com mutação no EGFR com resistência adquirida aos TKIs do EGFR, e em in vitro esta mutação T790M-EGFR inativa a hipersensitividade das mutações ativadoras do EGFR ao gefitnib ou erlotinib. Outras mutações de resistência secundárias (D761Y, L747S, A854T) são raras. Um outro mecanismo de resistência é a amplificação adquirida do oncogene MET, que ocorre em mais ou menos 20% do pacientes resistentes ao gefitinib/erlotinib e, em metade destes casos, em conjunção com T790M. O MET ativa sinais de sinalização que contornam o EGFR inibido, gerando um sistema de "troca de oncogenes" nesses tumores. Esses dados pré-clinicos relevantes aos CPNPCs com o EGFR mutado e resistência ao gefitinib ou erlotinib levaram ao desenvolvimento de experimentos clínicos com novos inibidores do EGFR que inibem "in vitro" a mutação T790M-EGFR (HKI-272, XL-647, BIBW-2992 e PF00299804), e inibidores de MET mais TKIs do EGFR em combinação. Neste trabalho: 1) Agrupamos e resumimos os dados dos experimentos clínicos prospectivos com o gefinitib em pacientes com o EGFR mutado. Mais de 80% dos pacientes com deleções do exon 19 ou a mutação L858R do EGFR tiveram resposta radiográfica, com sobrevivência livre de progressão de 7,7 a 12,9 meses nos estudos identificados, e sobrevivência geral acima de 15 meses; 2) Usamos células CPNPC com mutações do EGFR para identificarmos a molécula pró-apoptótica BIM como o efetor principal da apoptose induzida pelos TKIs do EGFR; 3) Caracterizamos a mutação resistente ao gefinitib EGFR-L858R-L747S, e determinamos que L858R-L747S apresenta um padrão de resistência menos acentuado ao gefitinib do que o observado com L858R-T790M; e 4) Avaliamos os efeitos do erlotinib em pacientes com CPNPC EGFR mutado e resistência ao gefitinib, caracterizando a correlação da resposta radiográfica e clínica com os mecanismos conhecidos de resistência ao TKIs do EGFR (as mutações de resistência secundárias T790M e L747S, e a amplificação do MET). A maioria (mais de 83%) dos pacientes resistentes ao gefitinib tiveram progressões radiográficas nos primeiros 2 a 4 meses de exposição ao erlotinib 150 mg/dia. Isto é consistente com nossas observações pré-clínicas, indicativas de que a maioria dos tumores resistentes ao gefitinib possui predominantemente T790M e/ou amplificações do MET, que são resistentes tanto ao gefitinib quanto erlotinib. Pesquisas pré-clínicas e experimentos clínicos futuros do CPNPC com EGFR mutado têm o potencial de melhorar os resultados do tratamento clínico de pacientes com essas mutações somáticas. / Abstract: Most advanced non-small cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6-12 months) most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and "oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR mutated patients with TKI resistance, and in vitro this mutation negates the hypersensitivity of activating EGFR mutations. Other secondary resistance mutations (D761Y, L747S, A854T) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however in half of the cases with this "oncogene kinase switch" mechanism the T790M is co-existent. The growing pre-clinical data in EGFR mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (HKI-272, XL-647, BIBW-2992 and PF00299804), and MET inhibitors in combination with EGFR TKIs. In this work we: 1) Pooled and summarized data from prospective clinical trials of gefitinib for EGFR mutated patients. More than 80% of patients with exon 19 deletions or the L858R EGFR mutation attained a radiographic response with progression-free survival of 7.7 to 12.9 months in the identified studies, and overall survival exceeding 15 months; 2) Identified the pro-apoptotic molecule BIM as the main effector of EGFR TKI-induced apoptosis using NSCLC cell lines with EGFR mutations; 3) Characterized the L858R-L747S gefitinib-resistant mutation, and demonstrated that L858R-L747S has a partial resistance pattern when compared to L858R-T790M; and 4) Evaluated the effects of erlotinib in EGFR mutated NSCLC with resistance to gefitinib while characterizing the correlation of response and resistance to this approach to the known mechanisms of resistance to EGFR TKIs (the secondary mutations T790M and L747S, and the amplification of MET). Our clinical observation was that the majority (over 83%) of the gefitinib-resistant patients given erlotinib 150 mg/day had radiographic progression within the first 2 to 4 months of exposure. This is consistent with our pre-clinical observations, since we expected gefitinib-resistant tumors to predominantly harbor T790M and/or MET amplification, which are cross-resistant to both gefitinib and erlotinib. Ongoing pre-clinical and clinical research in EGFR mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Les mutations FLT3-ITD et KITD816V sont fréquemment retrouvées dans les leucémies aiguës myéloïdes où elles sont associées à un pronostic défavorable. Ces deux récepteurs à activité tyrosine kinase (RTK) mutés sont des acteurs clés de la leucémogenèse régulant la prolifération, la survie et la différenciation cellulaire. L'objectif de ce travail de thèse a été d'étudier la régulation de l'expression protéique de FLT3 en réponse aux inhibiteurs du protéasome, le rôle de l'autophagie dans les LAM KITD816V et l'impact du 2-deoxy-D-glucose sur la localisation intracellulaire des récepteurs. Les travaux réalisés ont démontré trois manières originales de cibler des cellules portant les oncogènes FLT3-ITD ou KIT en jouant sur leur dégradation, leur localisation intracellulaire et l'autophagie. / FLT3-ITD and KITD816V mutations are recurrently found in acute myeloid leukemia, where they are associated with a poor prognosis. These two Tyrosine Kinase Receptors (TKR) are involved in leukemogenesis, regulating proliferation, survival and cell differentiation. The aim of this thesis was to study the regulation of FLT3 protein expression in response to proteasome inhibitors, the role of autophagy in KITD816V-driven AML and the impact of 2-deoxy-D-glucose (2-DG) on the intracellular localization of TKRs. Our studies investigated three original ways to target cells bearing FLT3-ITD or oncogenic KIT mutations playing on their degradation, intracellular localization and autophagy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21960号 / 医博第4502号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 松原 和夫, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The increasing prevalence of drug resistant cancers to conventional therapies remains a major challenge in oncology, emphasizing the need for further research and treatment development. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) presents as a particularly suitable target for cancer therapy, as this type I transmembrane protein is expressed during embryogenesis and up-regulated in various solid and hematological malignancies, but generally repressed in normal adult tissues. A growing cancer literature has established ROR1 as a contributor to cell metastasis and a survival factor for malignant cells, suggesting the therapeutic potential in targeting ROR1 for cancer therapy. The tumor-selective expression of ROR1 has encouraged investigation of novel ROR1-targeted therapies including monoclonal antibodies, small molecule inhibitors, and chimeric antigen receptor T-cells, and preclinical trials have supported their safety and efficacy in inducing tumor growth suppression. Despite these advances in therapeutics, the role of ROR1 in oncogenic signaling is not yet fully understood. Through a comprehensive examination of ROR1 literature, this review will examine the biology of ROR1 as it relates to tumor progression, and demonstrate the viability of current ROR1-targeted therapies.