Honors & Awards
Member, Phi Beta Kappa Honor Society (2010)
Education & Certifications
BS, University of Denver, Molecular Biology (2010)
I am currently pursuing my PhD in the labs of Dr. Max Diehn (MD/PhD) and Dr. Ash Alizadeh (MD/PhD) at Stanford’s School of Medicine. I am broadly interested in translational cancer research and bioinformatics, with a focus on using cancer genomics to inform more personalized treatment strategies for cancer patients. My lab uses cell free DNA (cfDNA), which is accessible via the circulation, as a non-invasive biomarker to detect and characterize how the genetic landscape of cancer patient’s tumors change over time. To do this, my lab has developed Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), which enables the ultra-sensitive detection of circulating tumor DNA (ctDNA) that is broadly applicable to human cancers. My research in focused on the mechanisms underlying acquired resistance to genotype-targeted therapies in patients with Non-Small Cell Lung Cancer (NSCLC).
Beyond these research focuses, I am also very interested in business and entrepreneurship, specifically in the commercialization of biomedical research and the industries of biotechnology and molecular diagnostics. I worked for two biotech companies while I was an undergraduate at the University of Denver and since completing my B.S. in 2010 I have taken graduate level coursework as a part of a certificate program in “Bioinnovation and Entrepreneurship” administered by the University of Colorado Medical School. This coursework has exposed me to subject matter such as the fundamentals of entrepreneurship and entity formation, intellectual property law and technology transfer, FDA regulatory compliance, and reimbursement strategy.
In my free time I enjoy doing most anything outdoors, and love hiking, fishing, rafting, and skiing.
Worked as a professional research assistant at the University of Colorado Denver School of Medicine in the department of Pulmonary Sciences and Critical Care Medicine in the lab of Dr. Rubin Tuder. I worked with Dr. Brian Graham and the primary focus of our research is to investigate pulmonary arterial hypertension (PAH) caused by the parasite Schistosoma Mansoni. S. mansoni infection causes Schistosomiasis, the third most common parasitic disease worldwide and one of the most common causes of PAH. Our goal was to identify and characterize signaling pathways relevant to the development of pathogenic inflammation and pulmonary vascular remodeling in Schistosomiasis-associated PAH. We utilize multiple different knock-out mouse lines as well as small molecule inhibitors and pharmacological interventions in order to investigate the pathways underlying the development of this disease.
I worked in a research laboratory for 2.5 years at the University of Denver under Dr. Nancy Lorenzon. I obtained a summer research grant in 2008 funding my research and continued to work in the lab on my thesis until I graduated in June 2010. The purpose of my thesis was to use immunocytochemisty, confocal microscopy, and calcium imaging techniques to 1) investigate the subcellular localization of the calcium release channel protein RyR1 in Purkinje cells, 2) compare Purkinje cell morphology and expression of RyR1 in wild type and mutant mice (human malignant hyperthermia disease mutation), and 3) compare basal intracellular calcium levels and calcium release levels in response to the RyR agonist caffeine in cells dissociated from wild type and mutant mice. The work I did to address these research objectives culminated in the presentation of two posters, and a written thesis project which I passed as a part of the requirements of the University Honors Program, as well as to graduate with departmental distinction in the Biological Sciences.
My work with Evolve primarily consisted of assembling a market analysis for a technology that the firm was considering assisting the inventors with commercializing. This market analysis assessed the costs/feasibility associated with commercialization as well as the market for the product and the competitive environment within that market. This analysis was the precursor which aided the firm in determining whether they should put resources into applying for SBIR/STTR (or other non-dilutive grant funding) for the technology as well as assisting the inventors in writing a business plan.
Interned under the Director of Corporate Strategy for SomaLogic during the summer of 2009. Worked on many projects but the primary focus of my internship was a project in which I synthesized corporate analyses of multiple possible partners for the company..
I have been a USA Hockey certified Ice Hockey official since 2004. I officiate all levels of ice hockey from youth to NCAA sanctioned college leagues to adult leagues, and I have been of level 4 certification since 2010.
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
View details for DOI 10.1038/ncomms11815
View details for Web of Science ID 000378007200001
View details for PubMedID 27283993
High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.
View details for DOI 10.1038/nbt.3520
View details for Web of Science ID 000375735000036
View details for PubMedID 27018799
The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-β signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-β-dependent vascular remodeling.Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-β activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.Combined IL-4 and IL-13 deficiency is required for protection against TGF-β-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.
View details for DOI 10.1164/rccm.201410-1820OC
View details for Web of Science ID 000363359400015
View details for PubMedID 26192556
The mechanistic target of rapamycin (mTOR) is a central regulator of cellular responses to environmental stress. mTOR (and its primary complex mTORC1) is, therefore, ideally positioned to regulate lung inflammatory responses to an environmental insult, a function directly relevant to disease states such as the acute respiratory distress syndrome. Our previous work in cigarette smoke-induced emphysema identified a novel protective role of pulmonary mTORC1 signaling. However, studies of the impact of mTORC1 on the development of acute lung injury are conflicting. We hypothesized that Rtp801, an endogenous inhibitor of mTORC1, which is predominantly expressed in alveolar type II epithelial cells, is activated during endotoxin-induced lung injury and functions to suppress anti-inflammatory epithelial mTORC1 responses. We administered intratracheal lipopolysaccharide to wild-type mice and observed a significant increase in lung Rtp801 mRNA. In lipopolysaccharide-treated Rtp801(-/-) mice, epithelial mTORC1 activation significantly increased and was associated with an attenuation of lung inflammation. We reversed the anti-inflammatory phenotype of Rtp801(-/-) mice with the mTORC1 inhibitor, rapamycin, reassuring against mTORC1-independent effects of Rtp801. We confirmed the proinflammatory effects of Rtp801 by generating a transgenic Rtp801 overexpressing mouse, which displayed augmented inflammatory responses to intratracheal endotoxin. These data suggest that epithelial mTORC1 activity plays a protective role against lung injury, and its inhibition by Rtp801 exacerbates alveolar injury caused by endotoxin.
View details for DOI 10.1016/j.ajpath.2014.06.002
View details for PubMedID 25016184
There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model.
View details for DOI 10.1086/675992
View details for PubMedID 25006448
The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries.Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
View details for DOI 10.1161/CIRCULATIONAHA.113.003072
View details for Web of Science ID 000324477900020
View details for PubMedID 23958565
Rationale: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease by whole-lung transcriptome analysis. Methods: Wildtype mice were experimentally exposed to S. mansoni ova by intraperitoneal sensitization followed by tail vein augmentation, and the phenotype assessed by right ventricular catheterization and tissue histology, RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, the latter analyzed using 2 bioinformatic methods. Functional testing of the candidate IL-6 pathway was determined using IL6-knockout mice and the STAT3 inhibitor STI-201. Results: Wild-type mice exposed to S. mansoni had increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole lung transcriptome analysis identified the IL6-STAT3-NFATc2 pathway as being upregulated, which was confirmed by PCR and immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL6 or treated with STI-201 developed pulmonary hypertension associated with significant intima remodeling after exposure to S. mansoni. Conclusions: Whole lung transcriptome analysis identified upregulation of the IL6-STAT3-NFATc2 pathway, and IL6 signaling was found to be protective against Schistosoma-induced intimal remodeling.
View details for PubMedID 23815102
It remains unclear whether basophils and mast cells are derived from a common progenitor. Furthermore, how basophil versus mast cell fate is specified has not been investigated. Here, we have identified a population of granulocyte-macrophage progenitors (GMPs) that were highly enriched in the capacity to differentiate into basophils and mast cells while retaining a limited capacity to differentiate into myeloid cells. We have designated these progenitor cells "pre-basophil and mast cell progenitors" (pre-BMPs). STAT5 signaling was required for the differentiation of pre-BMPs into both basophils and mast cells and was critical for inducing two downstream molecules: C/EBP? and MITF. We have identified C/EBP? as the critical basophil transcription factor for specifying basophil cell fate and MITF as the crucial transcription factor for specifying mast cell fate. C/EBP? and MITF silenced each other's transcription in a directly antagonistic fashion. Our study reveals how basophil and mast cell fate is specified.
View details for PubMedID 23871207
Schistosomiasis-associated pulmonary arterial hypertension (PAH) is one of the most common causes of pulmonary hypertension worldwide. A potential contributing mechanism to the pathogenesis of this disease is a localized immune reaction to retained and persistent parasite-derived antigens. We sought to identify Schistosoma-derived egg antigens present in the lungs of individuals who died of the disease. We obtained 18 lung samples collected at autopsy from individuals who died of schistosomiasis-associated PAH in Brazil. A rabbit polyclonal antibody was created to known Schistosoma mansoni-soluble egg antigen (SEA). Histologic assessment and immunostaining of the human tissue was performed, along with immunostaining and immunoblotting of lung tissue from mice experimentally infected with S. mansoni. All 18 lung samples had evidence of pulmonary vascular remodeling with plexiform lesions and arterial medial thickening, but no visible eggs were seen. The anti-SEA antibody detected S. mansoni egg antigens in visible eggs in mouse lung and human intestine specimens, but did not identify a significant amount of egg antigen in the human lung specimens. In mouse granulomas containing degraded eggs, we observed colocalization of egg antigens and macrophage lysosomes. In conclusion, there is unlikely to be a significant amount of persistent parasite-derived antigens within the lungs of individuals who die of schistosomiasis-associated PAH. This suggests that retained and persistent parasite proteins are not contributing to a localized immune response in the pathogenesis of this disease.
View details for DOI 10.4103/2045-8932.93544
View details for PubMedID 22530100