A5076345776- Advanced Breast Cancer Therapies
- Neurofibromatosis and Schwannoma Cases
- Neuroblastoma Research and Treatments
- Multiple Myeloma Research and Treatments
- Cancer Genomics and Diagnostics
- Sarcoma Diagnosis and Treatment
- CAR-T cell therapy research
- Nerve injury and regeneration
- Cancer Mechanisms and Therapy
- Protein Tyrosine Phosphatases
- Phagocytosis and Immune Regulation
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Lung Cancer Research Studies
- Colorectal Cancer Treatments and Studies
- Radiomics and Machine Learning in Medical Imaging
- Monoclonal and Polyclonal Antibodies Research
- Glioma Diagnosis and Treatment
- interferon and immune responses
- Neuroendocrine Tumor Research Advances
- Cancer Treatment and Pharmacology
- Microtubule and mitosis dynamics
- Adrenal and Paraganglionic Tumors
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
Johns Hopkins University
2020-2024
Johns Hopkins Medicine
2020-2024
Sidney Kimmel Comprehensive Cancer Center
2020-2023
University of Baltimore
2021-2023
Abstract Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target these tumors have been investigated, without clinical success date. A potential strategy inhibit oncogenic activity is the disruption prenylation, an obligate step for membrane localization effector pathway signaling, through inhibition farnesyltransferase (FTase). Of major family members, HRAS uniquely dependent on FTase whereas NRAS KRAS can...
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies desperately needed. We observe antiproliferative potency of genetic depletion PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into signaling response to SHP2i reveal that resistance TNO155 is partially mediated by reduced RB function, we therefore test addition a CDK4/6 (CDK4/6i) enhance...
Abstract Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival relapsed disease remains poor, thus novel therapeutic approaches needed. NF1 is essential for negative regulation RAS activity altered about 90% malignant (MPNST). A complex interplay upstream signaling parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, inhibiting more than one effector pathway...
Abstract Background Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics MPNST, we aimed to establish an ex vivo 3D platform accurately captured genomic diversity of MPNST and could be utilized a medium-throughput manner drug screening studies validated using patient-derived xenografts (PDX). Methods Genomic analysis was performed on all...
Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. Experimental Design: Patient-matched MPNSTs precursor lesions were examined by FISH, RNA sequencing, IHC, Connectivity-Map analyses. Antitumor activity CDK4/6 MEK inhibitors was measured cell lines,...
Abstract Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform (PNF), atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP), and malignant (MPNST). The successful advancement therapeutic for NF1-associated PNST necessitates systematic acquisition analysis human tumor specimens their corresponding model systems. RNA...
Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients MPNST have remained stagnant most succumb to their disease; thus, novel therapeutic approaches needed. A better understanding immune ecosystem will aid development strategies activate system against tumor. Herein, we profile tumor microenvironment (TIME)...
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into signaling response to SHP2i reveal that resistance TNO155 is partially mediated by reduced RB function, we therefore test addition a CDK4/6...
<p>Supplementary Figure S3. Tumor growth kinetics of individual de novo MPNSTs during therapy</p>
<p>Supplementary Figure S8. Additional MPNST analyses for CDK4/6-MEK inhibition plus anti-PD-L1 therapy study.</p>
<p>Supplementary Figure S6. Analysis of helper (CD4) and pan (CD3) T cells in combination therapysensitive versus therapy-resistant MPNSTs</p>
<p>Supplementary Figure S5. Evaluation of differentially expressed genes (DEGs) and tumor infiltrating immune cells (plasma B cells) in drug-treated de novo MPNSTs.</p>
<p>Supplementary Figure S7. Analyses of p-RB1, Ki67, and PD-L1 in combination therapy-sensitive - resistant MPNSTs NF1 patient tumors.</p>
<p>Supplementary Figure S1. Combination therapy co-targeting CDK4/6 and MEK acts synergistically against MPNST cells in vitro</p>
<p>Supplementary Figure S4. Predicted immune cell composition of human PNFs, ANNUBPs, and MPNSTs based on CIBERSORT analyses.</p>
<p>Supplementary Figure S2. Dual CDK4/6-MEK inhibition synergistically suppresses the growth of some, but not all, MPNST PDXs in immune deficient mice</p>
<p>Supplementary Figure S6. Analysis of helper (CD4) and pan (CD3) T cells in combination therapysensitive versus therapy-resistant MPNSTs</p>
<p>Supplementary Figure S4. Predicted immune cell composition of human PNFs, ANNUBPs, and MPNSTs based on CIBERSORT analyses.</p>
<p>Supplementary Figure S8. Additional MPNST analyses for CDK4/6-MEK inhibition plus anti-PD-L1 therapy study.</p>
<p>Supplementary Figure S2. Dual CDK4/6-MEK inhibition synergistically suppresses the growth of some, but not all, MPNST PDXs in immune deficient mice</p>
<p>Supplementary Figure S3. Tumor growth kinetics of individual de novo MPNSTs during therapy</p>
<p>Supplementary Figure S5. Evaluation of differentially expressed genes (DEGs) and tumor infiltrating immune cells (plasma B cells) in drug-treated de novo MPNSTs.</p>