A5102744882- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Cancer Risks and Factors
- Estrogen and related hormone effects
- HER2/EGFR in Cancer Research
- Breast Cancer Treatment Studies
- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- Gene expression and cancer classification
- Cancer Treatment and Pharmacology
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- Medical Imaging Techniques and Applications
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Monoclonal and Polyclonal Antibodies Research
- Lung Cancer Treatments and Mutations
- Advanced Biosensing Techniques and Applications
- Chronic Lymphocytic Leukemia Research
- Radiomics and Machine Learning in Medical Imaging
- Retinoids in leukemia and cellular processes
- Lung Cancer Research Studies
- Nanoplatforms for cancer theranostics
- Protein Tyrosine Phosphatases
Vanderbilt-Ingram Cancer Center
2011-2017
Vanderbilt University
2011-2017
Vanderbilt University Medical Center
2012-2017
Huntsman Cancer Institute
2014
Cornell University
2014
The University of Texas MD Anderson Cancer Center
2011-2013
Breast Cancer Care
2013
University of California, San Francisco
2013
Foundation Medicine (United States)
2013
Dana-Farber Cancer Institute
2012-2013
Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In lacking pCR, NAC selects subpopulation chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive analyses on residual disease 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) 20 matched pretreatment biopsies. Combined NGS and...
We examined the effects of an inhibitor PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment XL147 resulted in dose-dependent inhibition growth and levels pAKT pS6, signal transducers PI3K/AKT/TOR pathway. In HER2-overexpressing cells, was followed by up-regulation expression phosphorylation multiple receptor tyrosine kinases, including HER3. Knockdown FoxO1 FoxO3a transcription factors suppressed induction HER3, InsR, IGF1R, FGFR2 mRNAs upon PI3K....
Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an role for ER the CDK4/Rb/E2F transcriptional axis in hormone-independent growth of cancer cells. downregulation with fulvestrant or small interfering RNA (siRNA) inhibited growth. Chromatin immunoprecipitation genomic binding activity estrogen-deprived cells primary tumors treated aromatase inhibitors. Gene expression profiling...
Human epidermal growth factor receptor 2 ( HER2 ; ERBB2 ) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha PIK3CA mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response HER2-directed therapies. We generated mouse model HER2-overexpressing (HER2 + ), H1047R -mutant Mice expressing both human mutant mammary epithelium developed tumors...
Purpose Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, preliminary in patients metastatic ER-positive refractory to Patients Methods received letrozole two different administration schedules. Outcomes were assessed by standard...
Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant antiestrogens. In this study, we sought identify kinases essential for growth of ER(+) cancer cells long-term estrogen (LTED). A kinome-wide siRNA screen showed that the insulin (InsR) is required MCF-7/LTED cells. Knockdown InsR and/or insulin-like factor-I (IGF-IR) inhibited 3 4 LTED cell lines. Inhibition IGF-IR with dual tyrosine kinase inhibitor OSI-906 prevented emergence...
Abstract Purpose: Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive treatment response not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin paclitaxel would provide synergistic antitumor effects in TNBC. Methods: Patients stage II/III TNBC were enrolled a randomized phase II trial preoperative weekly cisplatin, daily or placebo for 12 weeks,...
Genomic profiling of ER + /HER2 − breast tumors after short-term estrogen deprivation revealed alterations associated with intrinsic resistance and provided mechanistic insights.
Abstract Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response chemotherapy. This study aimed evaluate genes as individual predictive biomarkers in cancer. Experimental Design: mRNA microarray data from cancer cell lines were used identify bimodal genes—those with highest potential for robust high/low classification clinical assays. Metabolic function was evaluated vitro the scoring gene, lactate...
Abstract Introduction Estrogen receptor α-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance antiestrogen therapies. Upon acquisition of independence, ER+ cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined effects AKT inhibition its compensatory upregulation insulin-like growth factor (IGF)-I/InsR signaling in with acquired estrogen deprivation. Methods Inhibition using catalytic inhibitor AZD5363 was...
Aberrant regulation of the erythroblastosis oncogene B (ErbB) family receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 required luminal mammary epithelial cells (MECs) for growth survival. Since breast cancer phenotypes may reflect biological traits MECs from which they originate, we tested hypothesis that drives growth. We found higher ERBB3 expression more frequent gene copy gains A/B cancers compared with other subtypes. In cell culture, increased cells....
Abstract The HER2 oncogene is amplified in 20-25% of breast cancers and associated with poor patient outcome. Mutational activation PIK3CA, the gene encoding p110α catalytic subunit PI3K, occurs ∼30% cancers. amplification PIK3CA mutations often co-occur cancer, suggesting that these two oncogenes cooperate to promote tumor growth. Whether mutant PI3K enhances HER2-induced tumorigenesis cancer progression vivo has not yet been examined. In addition, aberrant pathway implicated resistance...
Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole identified a D189Y mutation in inhibitory SH2 domain of SRC family kinase (SFK) LYN. Evaluation 463 The Cancer Genome Atlas revealed four LYN mutations, two which affected domain. In addition, was upregulated multiple cancer lines...
Abstract Mutations in PIK3CA, the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding mutant via p85 phosphorylated YXXM motifs activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator PI3K, is required for PIK3CA-mediated transformation MECs. Conditional loss ErbB3 epithelium resulted...
Neonatal meningitis is a rare but devastating condition. Multi-drug resistant (MDR) bacteria represent substantial global health risk. This study reports on an aggressive case of lethal neonatal due to MDR Escherichia coli (serotype O75:H5:K1). Serotyping, pattern and phylogenetic typing revealed that this strain emergent highly virulent E. isolate. The isolate was both ampicillin gentamicin; antibiotics currently used for empiric sepsis treatment. also positive multiple virulence genes...
510 Background: Mutations in PIK3CA, the gene encoding p110a subunit of PI3K, have been associated with antiestrogen resistance ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment ER+/PI3K mutant BC should include PI3K inhibitors plus antiestrogens. Methods: We conducted a phase Ib trial letrozole (2.5 mg/d) pan-PI3K inhibitor BKM120 post-menopausal patients (pts) ER+/HER2 MBC. (100 was given continuously (Arm A) or...
We describe herein a patient presenting with bilateral estrogen-receptor-positive (ER+) breast tumors who was enrolled in clinical trial exploring molecular aberrations associated hormone-refractory tumor cell proliferation. Short-term (two week) hormonal therapy the aromatase inhibitor letrozole substantially reduced proliferation as measured by Ki67 immunohistochemistry one tumor, whereas second essentially unchanged. Extensive and genetic work-up of two yielded divergent lesions tumors:...
// Katherine E. Hutchinson 1 , Douglas B. Johnson 2 Adam S. 3 Violeta Sanchez Maria Kuba Pengcheng Lu 4 Xi Chen Mark C. Kelley 5 Qingguo Wang 6 Zhongming Zhao 1, Kris 7 Michael F. Berger 8, 9 Jeffrey A. Sosman William Pao 2, 10 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Medicine/Division Hematology-Oncology, Pathology, Microbiology & Immunology, Biostatistics, Surgery, Division Surgical Oncology and Endocrine Biomedical Informatics,...
Objectives: Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in literature. Here we present clinical and histopathologic findings primary arising left horseshoe kidney 61-year-old female patient. Materials Methods: Pathologic features were evaluated standard hematoxylin eosin sections immunohistochemical studies. A literature review was performed to place our case context previous reports. Results: The associated intestinal metaplasia high-grade...
1024 Background: Tumor cell proliferation measured by Ki67 in the surgically removed tumor after neoadjuvant chemotherapy (NAC) has been shown to predict patient outcome breast cancer. It is unclear from these studies if cancer subtype may account part for predictive ability of Ki67. Thus, we tested whether score surgically-resected residual (RT) NAC predicted a cohort triple negative (TNBC). Gene expression profiling was performed identify molecular and test association with gene modules...
8 Background: Mutations in PIK3CA are the most common somatic alterations breast cancer and represent a potentially useful therapeutic target. As more PI3K pathway inhibitors enter clinical arena, it is important to understand characteristics of patients harboring mutations. This study seeks identify clinico/pathological mutant cancers evaluated at Vanderbilt University Medical Center. Methods: Molecular profiling (SNaPShot) was used detect mutations three genes (PIK3CA, PTEN, AKT1)....
Abstract Lacking human epithelial growth factor receptor 2 (HER2) amplification as well estrogen and progesterone receptors, TNBC is a heterogeneous collection of biologically diverse cancers that likely contributes to variable clinical outcomes for patients suffering from this disease. Since lacks well-defined molecular targets, we recently performed gene expression (GE) analyses identified six distinct subtypes with unique biologies. To further decipher the contribution tumor epithelium...
Abstract The HER2 (ERBB2) oncogene is amplified in 20-25% of breast cancers and associated with poor patient outcome. Mutational activation PIK3CA, the gene encoding p110α catalytic subunit phosphatidylinositol 3-kinase (PI3K), occurs ~30% cancers. amplification PIK3CA mutations often co-occur cancer. Aberrant PI3K pathway has been shown to correlate a diminished response HER2-directed therapies. We sought directly determine whether mutant enhances HER2-induced tumor progression promotes...