Identifying Novel Targetable Genes and Pathways in Cancer by Integrating Diverse Omics Data.

Omics technologies for high-throughput profiling of human genome, transcriptome and proteome are revolutionizing cancer research and driving a paradigm shift in clinical care, from “one size” fits all treatments to molecularly informed therapies. The success of this new precision medicine paradigm will depend on our ability to combine diverse omics-based measurements to distill clinically relevant information that can be acted upon. This thesis developed bioinformatics approaches to integrate multi-omics datasets and applied these approaches in three distinct studies that identified novel actionable genes and pathways in cancer. In the first study, we aim at finding alternative targetable proteins in non-small cell lung cancers (NSCLC) with activating mutations in KRAS, a well-know but undruggable oncogene, by profiling their transcriptome, proteome and phosphoproteome. By reconstructing targetable networks associated with KRAS dependency, we nominate lymphocyte-specific protein tyrosine kinase (LCK) as a critical gene for cell proliferation in these samples, suggesting LCK as a novel druggable protein in KRAS-dependent NSCLC. In the second study, we aim at identifying oncogenic gene fusions in NSCLC patients of unknown driver gene. By characterizing the highly heterogeneous fusion’s landscape in NSCLC, we show that gene fusions incidence is an independent prognostic factor for poor outcome and discover novel Neurorregulin 1 (NRG1) fusions present exclusively in patients of unknown driver; resembling previously reported kinase fusions. This warrants further studies of the therapeutic opportunities for patients with NRG1 rearrangements. Finally in the third study, we aim at characterizing cancer-related genes that overlap and could be regulated by natural antisense transcripts. By determining the extent of antisense gene expression across human cancers and comparing with well-documented sense-antisense pairs, our results raise the possibility that antisense transcripts could modulate the expression of well-known tumor suppressors and oncogenes. This study provides a resource, oncoNATdb, a catalogue of cancer related genes with significant antisense transcription, which will enable researchers to investigate the mechanisms of sense-antisense regulation and their role in cancer. We anticipate that the computational methods developed and the results found in this thesis would assist others with similar tasks and inspire further studies of the therapeutic opportunities provided by these novel targets.PHDBioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107215/1/oabalbin_1.pd

ceritinib plus nivolumab in patients with advanced alk rearranged non small cell lung cancer results of an open label multicenter phase 1b study

Abstract Introduction Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. Methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. Results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. Conclusion Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent

Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).</p

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Purpose: To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss. Methods: This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded. Results: 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug–drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%). Conclusion: The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. Trial registration: NCT01870726

Calidad de vida en niños asmaticos en el Hospital Nacional Hipolito Unanue, 2018

Introducción: Para determinar un tratamiento adecuado es fundamental poder determinar la calidad de vida en pacientes que padecen asma sobre todo en edad pediátrica. Objetivo: El objetivo del presente trabajo es poder conocer la calidad de vida que presentan los niños que padecen de asma y sus cuidadores. Metodología: Se desarrollaron dos cuestionarios de calidad de vida en asma de Juniper. El cuestionario de calidad de vida para pacientes pediátricos con asma (PAQLQ) fue desarrollado por 202 niños asmáticos persistentes de 8 a 15 años de edad del Hospital Nacional Hipólito Unanue. El cuestionario de calidad de vida para la persona encargada del cuidado del niño con asma (PACQLQ) fue contestado por sus respectivos cuidadores o tutores de cada niño asmático. Se tomó en consideración un promedio menor de 5 puntos como alteración significativa de calidad de vida. Se estudió el impacto de la severidad y duración del asma en la calidad de vida del niño que padece de asma y su cuidador. Para el análisis estadístico se utilizó Chi cuadrado considerando como valor significativo un p < 0,05. Resultados: El promedio de calidad de vida global menor de 5 fue de 39,6% para los niños asmáticos y 68,6% para los cuidadores. En los subgrupos de limitación de actividades y de función emocional se encontró mayor proporción de puntaje < 5 puntos en cuidadores que en niños asmáticos. Se evidencio una alteración de la calidad de vida global con respecto a la duración del asma (p = 0,0057), la de la dimensión de limitación de actividades (p = 0,00003) y la de la dimensión de la función emocional (p = 0,018) del cuidador. La calidad de vida global (p = 0,035) y de la dimensión limitación de actividades (p = 0,0037) del cuidador fueron alterados por la severidad del asma. Conclusiones: En el presente estudio resalta un porcentaje significativo de pacientes que presentan alguna alteración de la calidad de vida, con una mayor proporción en cuidadores que en niños asmáticos. La severidad y duración del asma presenta una mayor alteración en la calidad de vida del cuidador más no afecta significativamente al niño asmático

Calidad de vida en niños asmaticos en el Hospital Nacional Hipolito Unanue, 2018

TesisIntroducción: Para determinar un tratamiento adecuado es fundamental poder determinar la calidad de vida en pacientes que padecen asma sobre todo en edad pediátrica. Objetivo: El objetivo del presente trabajo es poder conocer la calidad de vida que presentan los niños que padecen de asma y sus cuidadores. Metodología: Se desarrollaron dos cuestionarios de calidad de vida en asma de Juniper. El cuestionario de calidad de vida para pacientes pediátricos con asma (PAQLQ) fue desarrollado por 202 niños asmáticos persistentes de 8 a 15 años de edad del Hospital Nacional Hipólito Unanue. El cuestionario de calidad de vida para la persona encargada del cuidado del niño con asma (PACQLQ) fue contestado por sus respectivos cuidadores o tutores de cada niño asmático. Se tomó en consideración un promedio menor de 5 puntos como alteración significativa de calidad de vida. Se estudió el impacto de la severidad y duración del asma en la calidad de vida del niño que padece de asma y su cuidador. Para el análisis estadístico se utilizó Chi cuadrado considerando como valor significativo un p < 0,05. Resultados: El promedio de calidad de vida global menor de 5 fue de 39,6% para los niños asmáticos y 68,6% para los cuidadores. En los subgrupos de limitación de actividades y de función emocional se encontró mayor proporción de puntaje < 5 puntos en cuidadores que en niños asmáticos. Se evidencio una alteración de la calidad de vida global con respecto a la duración del asma (p = 0,0057), la de la dimensión de limitación de actividades (p = 0,00003) y la de la dimensión de la función emocional (p = 0,018) del cuidador. La calidad de vida global (p = 0,035) y de la dimensión limitación de actividades (p = 0,0037) del cuidador fueron alterados por la severidad del asma. Conclusiones: En el presente estudio resalta un porcentaje significativo de pacientes que presentan alguna alteración de la calidad de vida, con una mayor proporción en cuidadores que en niños asmáticos. La severidad y duración del asma presenta una mayor alteración en la calidad de vida del cuidador más no afecta significativamente al niño asmático

Temporal competition between differentiation programs determines cell fate choice

Multipotent differentiation, where cells adopt one of several possible fates, occurs in diverse systems ranging from bacteria to mammals. This decision-making process is driven by multiple differentiation programs that operate simultaneously in the cell. How these programs interact to govern cell fate choice is poorly understood. To investigate this issue, we simultaneously measured activities of the competing sporulation and competence programs in single Bacillus subtilis cells. This approach revealed that these competing differentiation programs progress independently without cross-regulation before the decision point. Cells seem to arrive at a fate choice through differences in the relative timing between the two programs. To test this proposed dynamic mechanism, we altered the relative timing by engineering artificial cross-regulation between the sporulation and competence circuits. Results suggest a simple model that does not require a checkpoint or intricate cross-regulation before cellular decision-making. Rather, cell fate choice appears to be the outcome of a 'molecular race' between differentiation programs that compete in time, providing a simple dynamic mechanism for decision-making