A5027337412- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Estrogen and related hormone effects
- Genetic factors in colorectal cancer
- Ovarian cancer diagnosis and treatment
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Cell Adhesion Molecules Research
- PI3K/AKT/mTOR signaling in cancer
- Endometrial and Cervical Cancer Treatments
- Cancer-related gene regulation
- Uterine Myomas and Treatments
- RNA Interference and Gene Delivery
- Reproductive System and Pregnancy
- Multiple Myeloma Research and Treatments
- Cancer-related molecular mechanisms research
- Cancer Research and Treatments
- Immune Cell Function and Interaction
- Angiogenesis and VEGF in Cancer
- Sarcoma Diagnosis and Treatment
- Advanced Breast Cancer Therapies
- Peptidase Inhibition and Analysis
Yale University
2014-2022
Smilow Cancer Hospital
2021-2022
U-M Rogel Cancer Center
2022
University of New Haven
2014-2015
Significance Some cancers, termed carcinosarcomas (CSs), have mixed cell types, with either epithelial or mesenchymal features. Sequencing the genomes of uterine and ovarian CSs demonstrated that these different types derive from a common precursor has many mutations typical cancers. In addition, we find tumors significant burden point amplification histone genes, suggesting potential role in sarcomatous transformation. Consistent this finding, expression specific gene carcinoma cells...
Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while additional 40% 50% express moderate (2+) or low (1+) levels. We investigated efficacy SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed mAb trastuzumab linked highly potent DNA-alkylating agent duocarmycin) in USC. also compared antitumor activity SYD985 head-to-head...
Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of uterus. We analyzed 83 uLMS sample genetics, including 56 Yale and 27 The Cancer Genome Atlas (TCGA). Among them, a total 55 samples two patient-derived xenografts (PDXs) TCGA have whole-exome sequencing (WES) data; 10 RNA-sequencing (RNA-Seq) 11 whole-genome (WGS) data. found recurrent somatic mutations in TP53, MED12, PTEN genes. Top mutated genes included ATRX, PTEN, MEN1 Somatic copy number...
Background Microsatellite instability–high (MSI‐H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter ICIs unclear. This article reports data from prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI‐H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential primary/secondary ICI resistance (NCT02899793). Methods Patients...
Mismatch repair-deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients mutational tumors (6 patients) had higher response rates and longer survival than those epigenetic (18 patients). Mutation burden was compared MMRd; however, within each category MMRd, mutation not correlated ICB response. Pretreatment JAK1 mutations...
Significance Ovarian cancer has the propensity for early dissemination of microscopic metastases, making detection challenging. Development treatments patients with advanced/recurrent chemotherapy-resistant disease remains an unmet need. We sequenced primary, synchronous bilateral ovarian (SBOC), metastatic, and recurrent tumors. found primary metastatic tumors to be remarkably similar SBOC clonally related in all cases, suggesting represent intrinsic feature cancer. c-MYC PIK3CA...
Purpose: Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985 (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine ovarian CS.Experimental Design: Eight CS cell lines were evaluated for surface expression by IHC gene amplification FISH assays....
The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most which harboring Human-Papillomavirus-type-16/18. found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, GNAS) a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) both adenocarcinoma (ACC) squamous carcinomas (SCCs). Somatic copy number variants (CNVs)...
Abstract Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of epithelial solid tumors. We investigated the efficacy sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised humanized anti- Trop-2 antibody, conjugated with active metabolite irinotecan (SN-38), on positive cervical cancer cell lines xenograft model. expression was evaluated 147 primary...
Background Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, active metabolite of irinotecan. This study aimed evaluate Trop-2 expression EOC tissues and preclinical activity SG against primary lines xenografts. Methods was assessed 90 formalin-fixed-paraffin-embedded tumors...
Amplification of c-erbB2 has been reported in over 30% uterine serous carcinoma (USC) and found to confer poor survival because high proliferation increased resistance therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells vitro followed by developing supportive vivo model. Fifteen primary cell lines were assessed immunohistochemistry (IHC) flow...
Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated active metabolite irinotecan (SN-38). We evaluated efficacy SG against biologically aggressive CS.Trop-2 expression was in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry 9 primary cell-lines flow-cytometry. One Trop-2 low/negative (SARARK14) two...
Clinical options for patients harbouring advanced/recurrent uterine serous carcinoma (USC), an aggressive variant of endometrial tumour, are very limited. Next-generation sequencing (NGS) data recently demonstrated that cyclin E1 (CCNE1) gene amplification and pik3ca driver mutations common in USC may therefore represent ideal therapeutic targets. Cyclin expression was evaluated by immunohistochemistry (IHC) on 95 USCs. The efficacy the cyclin-dependent kinase 2/9 inhibitor CYC065 assessed...
We evaluated the role of PIK3CA-mutations as mechanism resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. Fifteen whole-exome-sequenced USC lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four (2-harbouring wild-type-PIK3CA-genes 2-harbouring oncogenic-PIK3CA-mutations) vitro dose-titration-proliferation-assays, cell-viability HER2 S6-protein-phosphorylation after exposure trastuzumab. harbouring wild-type-PIK3CA transfected...
HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, combination two compounds vitro vivo experiments using PIK3CA-mutated wild-type HER2/neu-amplified USC cell lines. Cell viability cell-cycle distribution were assessed flow-cytometry assays. Downstream signaling was by immunoblotting. Preclinical...
Uterine and ovarian carcinosarcomas (CS) are rare but highly aggressive gynecologic tumors which carry an extremely poor prognosis. We evaluated the expression levels of EpCAM in vitro activity solitomab, a bispecific single-chain antibody construct targets epithelial-cell-adhesion-molecule (EpCAM) on tumor cells also contains CD3 binding region, against primary uterine CS cell lines. was by flow cytometry total 5 Sensitivity to solitomab-dependent-cellular-cytotoxicity (ADCC) tested panel...