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Publications (142)
Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell-intrinsic changes or by changes in the microenv...
Infiltration into the brain tissue is one of the main features of diffuse midline gliomas (DMG), also characterized by the histone mutation H3K27M and overall survival of 12-15 months from diagnosis. To study which genes are critical for H3K27M-DMG tumor cell migration in the brain, we established a novel two-step pooled whole genome CRISPR-Migrati...
KRAS mutations are common in non-small cell lung cancer (NSCLC) and often co-occur with TP53 mutations. Although the KRAS oncogene was once considered ‘undruggable,’ FDA approval of KRASG12C inhibitors and promising pre-clinical data from KRASG12D inhibitors highlight the potential for targeted therapies. The tumor microenvironment (TME) of NSCLC c...
Background:
Chronic obstructive pulmonary disease (COPD) exhibits considerable progression heterogeneity. We hypothesized that elastic principal graph analysis (EPGA) would identify distinct clinical phenotypes and their longitudinal relationships.
Methods:
Cross-sectional data from 8,972 tobacco-exposed COPDGene participants, with and without C...
Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal midline brain tissue, hindering surgical resection and contributing to overall morbidity and mortality. We established a novel two-step pooled whole genome CRISPR-Migration screen by using serum-free conditions and laminin-dependent cell attachment, mimic...
Mechanisms of resistance to inhibitors against mutant KRAS are linked to the remodeling of the tumor microenvironment (TME). Understanding this remodeling process during intervention and tumor recurrence will likely guide the development of future therapeutic treatment paradigms with long-term responses. 56% of never-smokers with non-small cell lun...
Background
Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet t...
Withdrawal Statement
This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert...
Despite advancements in targeted therapy and immunotherapy, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide, with an estimated 2.2 million deaths each year. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas and lung squamous cell carcinoma. Mutatio...
Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control...
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognos...
Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control...
Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood–brain barrier and lead to long-term control...
Rationale and objectives:
Small airways disease (SAD) and emphysema are significant components of chronic obstructive pulmonary disease (COPD), a heterogenous disease where predicting progression is difficult. SAD, a principal cause of airflow obstruction in mild COPD, has been identified as a precursor to emphysema. Parametric Response Mapping (P...
Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG biopsies. We hypothesized that ALDH-mediated stemness and resistance may in part be driven by the...
Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. IPF patients have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses fo...
Rationale and Objectives: Small airways disease (SAD) and emphysema are significant components of COPD, a heterogenous disease where predicting progression is difficult. SAD, a principal cause of airflow obstruction in mild COPD, has been identified as a precursor to emphysema. Parametric Response Mapping (PRM) of chest computed tomography (CT) can...
Purpose: Small airways disease (SAD), a major cause of airflow obstruction in COPD patients, has been identified as a precursor to emphysema. Nevertheless, there is a lack of clinical techniques that can quantify the progression of SAD. We aim to determine if our Parametric Response Mapping (PRM) method to quantify SAD offers insight into lung prog...
Early detection of lung cancer is critical for improvement of patient survival. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMM) have become integral in identifying and evaluating the molecular underpinnings of this complex disease that may be exploited as therapeutic targets. Assessment of GEMM tu...
Despite advancements in targeted therapy and immunotherapy, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide, with an estimated 2.2 million deaths each year. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas and lung squamous cell carcinoma. Mutatio...
Diffuse midline glioma (DMG) is the leading cause of brain tumor-related deaths in children. DMG typically presents with variable neurologic symptoms between ages 3 and 10. Currently, radiation remains the standard therapy for DMG to halt progression and reduce tumor bulk to minimize symptoms. However, tumors recur in almost 100% of patients and th...
Background: Assessment and selection of donor lungs remains largely subjective and experience based. Criteria to accept or decline lungs are poorly standardized and are not compliant with the current donor pool. Using ex vivo CT images, we investigated the use of a CT-based machine learning algorithm for screening donor lungs prior to transplantati...
Mitochondrial glutamate-oxaloacetate (GOT2) is part of the malate-aspartate shuttle (MAS), a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the lo...
Diffuse Intrinsic Pontine Glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome of this devastating disease. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CS...
Therapeutic resistance remains a major obstacle in the successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor arising in the brain stem. Currently available therapies do not prevent tumor recurrence in nearly all patients diagnosed with this devastating disease. Innovative combinatorial therapies tha...
Purpose
Parametric response mapping (PRM) of high-resolution inspiration/expiration CT scans is a promising imaging technique that is currently utilized in diagnostic applications and offers the ability to characterize and quantify certain pulmonary pathologies on a patient-specific basis. As one of the first studies to implement such a technique i...
In chronic obstructive pulmonary disease (COPD) functional small airways disease (fSAD) has been identified as a transitional state between healthy lung and irremediable emphysema. Topological analysis of the CT-based parametric response map (PRM) spatially quantifies distribution and arrangement of fSAD and emphysema. We present a cross sectional...
Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has b...
Early detection of lung cancer is critical for improvement of patient survival. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMM) have become integral in identifying and evaluating the molecular underpinnings of this complex disease that may be exploited as therapeutic targets. Assessment of GEMM tu...
Chronic obstructive pulmonary disease (COPD) presents significant clinical heterogeneity and non-trivial progression trajectories resulting in a wide range of patient outcomes. Clinical trajectory analysis (ClinTrajAn) is a powerful tool based on elastic principal graphs for the discovery and evaluation of trajectories in large cross-sectional clin...
Background
Radiologic evidence of air trapping (AT) on expiratory computed tomography (CT) scans is associated with early pulmonary dysfunction in patients with cystic fibrosis (CF). However, standard techniques for quantitative assessment of AT are highly variable, resulting in limited efficacy for monitoring disease progression.
Objective
To inv...
Purpose: Lung cancer has been the leading cause of cancer-related deaths worldwide. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMMs) have become integral in identifying and evaluating unique pathways that may be exploited as therapeutic targets. Assessment of GEMM tumor burden on histopathological...
Background
Radiologic evidence of air trapping (AT) on expiratory CT scans is associated with early pulmonary dysfunction in patients with cystic fibrosis (CF). However, standard techniques for quantitative assessment of AT are highly variable, resulting in limited efficacy for monitoring disease progression.
Objective
To investigate the effective...
Understanding the cancer stem cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient-derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characteriza...
Lung cancer remains the leading cause of cancer-related deaths worldwide, with an estimated 1.6 million deaths each year. Non-small cell lung cancer (NSCLC) is with 85% by far the most common subtype of lung cancer, comprising adenocarcinomas and lung squamous cell carcinoma. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal...
Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain cancer with a five-year survival rate of less than 1%. This is reflective of a 100% tumor reoccurrence emphasizing the need for efficacious therapies. Previous studies have identified Aldehyde dehydrogenase expression (ALDH) as a marker for stemness and an indicator of tumor aggres...
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and consequently nutrient and oxygen access and drug delivery. Redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that t...
An inexpensive, accurate focused ultrasound stereotactic targeting method guided by pretreatment magnetic resonance imaging (MRI) images for murine brain models is presented. An uncertainty of each sub-component of the stereotactic system was analyzed. The entire system was calibrated using clot phantoms. The targeting accuracy of the system was de...
We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell-synchronization an...
Parametric response mapping (PRM) is a novel computed tomography (CT) technology which has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of the current study was to evaluate if variations in image acquisition under real world conditions affect the PRM m...
PDA is characterized by an extensive fibroinflammatory stroma. This fibroinflammatory stroma is mainly composed of fibroblasts and tumor-infiltrating immune cells. The most abundant infiltrating immune cells are myeloid cells. Myeloid cells including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and granulocytes are require...
Diffuse intrinsic pontine glioma (DIPG) is a rare, but lethal childhood cancer with a 5-year survival less than 1 %. Genetic profiling of DIPG biopsies and post-mortem tissue have recently identified mutations in PI3KCA, PTEN, TP53, ATM/MPL, histones and PDGF receptor overexpression. PI3KCA and PTEN mutations as well as PDGF receptor overexpression...
The Ras-ERK and PI3K/mTOR signaling pathways have profound effects on cancer cell survival, differentiation, proliferation, metabolism and motility. Due to the importance of these pathways, a myriad of compounds has been developed to inhibit key signaling nodes including MEK, PI3K and PI3K/mTOR inhibitors. Evidence has shown that extensive cross-ta...
Metastatic prostate cancer to bone remains incurable, driving efforts to develop individualized, targeted therapies to improve clinical outcomes while limiting adverse side-effects. Due to the complexity in cellular signaling pathways and the interaction between cancer and its microenvironment, multiparametric imaging approaches for treatment respo...
Purpose:
ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles...
Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancre...
Responses to targeted therapies frequently are brief with patients relapsing with drug resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy o...
The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168) which displays improved MEK1 and PI3K isoform inhibition is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8, 2.7, 23 and 2.5-fold improved inhibition towards the PI3K α, PI3K β, PI3Kδ and PI3Kγ isoforms, respectively, as...
Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRMfSAD has...
Brain tumor biopsies that are routinely performed in clinical settings significantly aid in diagnosis and staging. The aim of this study is to develop and evaluate a methodological image-guided approach that would allow for routine sampling of glioma tissue from orthotopic mouse brain tumor models. A magnetic resonance imaging-guided biopsy method...
Management of glioblastoma multiforme remains a challenging problem despite recent advances in targeted therapies. Timely assessment of therapeutic agents is hindered by the lack of standard quantitative imaging protocols for determining targeted response. Clinical response assessment for brain tumors is determined by volumetric changes assessed at...
The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) <...
Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitor...
Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment l...
Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. Increased abundance of phosphorylated FADD in p...
Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Acti-vating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. Increased abundance of phosphorylated FADD in...
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Lung cancer accounts for 27% of all cancer deaths worldwide. 80% of these deaths are due to a specific subtype Non-small cell lung cancer (NSCLC). Almost half of all NSCLC patients carry gatekeeper mutations in the EGFR/KRAS pathway. Although KRAS mutations are the most prevalen...
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Purposes: Large molecules like antibodies cannot penetrate the intact blood-brain barrier (BBB) in adequate amounts to deploy efficacy. Brain shuttle antibodies for enhanced BBB crossing are considered to overcome this obstacle. Thus, we established a non-invasive technology tha...
High grade gliomas often possess an impaired blood-brain barrier (BBB) which allows delivery of large molecules to brain tumors. However, achieving optimal drug concentrations in brain tumors remains a significant hurdle for treating patients successfully. Thus, detailed investigations of drug activities in gliomas are needed. To investigate BBB pe...
Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. r...
Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation p...
Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO sho...