A5017406323- Advanced Breast Cancer Therapies
- Neuroblastoma Research and Treatments
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Multiple Myeloma Research and Treatments
- Cancer Genomics and Diagnostics
- Neurofibromatosis and Schwannoma Cases
- CAR-T cell therapy research
- Protein Degradation and Inhibitors
- Colorectal Cancer Treatments and Studies
- Protein Tyrosine Phosphatases
- Monoclonal and Polyclonal Antibodies Research
- Glioma Diagnosis and Treatment
- Radiomics and Machine Learning in Medical Imaging
- Cancer Immunotherapy and Biomarkers
- Phagocytosis and Immune Regulation
- Sarcoma Diagnosis and Treatment
- interferon and immune responses
- Pancreatic and Hepatic Oncology Research
- Pancreatic function and diabetes
- Cell Adhesion Molecules Research
- Proteoglycans and glycosaminoglycans research
- Platelet Disorders and Treatments
- Ocular Oncology and Treatments
- Metabolism, Diabetes, and Cancer
University of Iowa
2020-2025
Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options clinical outcomes have improved in past decades, most patients will die of metastatic disease. New systemic therapies needed.
Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss CDK-inhibitory proteins such as p27(Kip1). RABL6A an inhibitor RB1 whose role in MPNSTs unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling CDK inhibitor-based therapy MPNSTs.We...
Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding factors regulating and PNET pathogenesis needed to improve current therapies. We discovered that RABL6A, new oncogenic driver proliferation, required for AKT activity. Silencing RABL6A caused cell-cycle arrest coincided with selective loss AKT-S473 (not T308) phosphorylation...
Abstract Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme serotonin biosynthesis. Patients with level may develop carcinoid syndrome, can be treated somatostatin analogues Tph1 inhibitor telotristat ethyl (TE) severe cases. Although active drug TE efficiently reduce levels, its effect on tumor growth is unclear. This study...
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,...
Schwann cells are normally quiescent, myelinating glia of the peripheral nervous system. Their aberrant proliferation and transformation underlie development benign tumors (neurofibromas) as well deadly malignant nerve sheath (MPNSTs). We discovered a new driver MPNSTs, an oncogenic GTPase named RABL6A, that functions in part by inhibiting RB1 tumor suppressor. is key mediator cellular senescence, permanent withdrawal from cell cycle protects against immortalization transformation. Based on...
Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with complex molecular and genetic alterations. Powerful tumor suppressors CDKN2A TP53 commonly disrupted along NF1, a gene that encodes negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding critical drivers MPNSTs is needed to guide more informed targeted therapies for patients. RABL6A newly identified driver cell survival...
Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, highly expressed in patient pNETs required cell proliferation survival vitro. Here, we investigated the role RABL6A progression vivo using well-established model disease. RIP-Tag2 (RT2) mice develop functional (insulinomas) due SV40 large T-antigen...
Inflammation is present in many diseases and identification of immune cell infiltration a common assessment. CD138 (syndecan-1) recommended immunohistochemical marker for human plasmacytes although it also expressed various epithelia tumors. Similarly, murine plasmacytes, but its tissue immunostaining not well-defined. Endogenous expression an important confounding factor when evaluating plasmacyte infiltration. We studied two markers (CD138 Kappa light chains) endogenous five organs one...
Abstract Pancreatic neuroendocrine neoplasms (pNENs) are slow growing cancers of increasing incidence that lack effective treatments once they become metastatic. Unfortunately, nearly half pNEN patients present with metastatic liver tumors at diagnosis and current therapies fail to improve overall survival. Pre-clinical models metastasis needed advance our understanding the mechanisms driving process for development novel, targeted therapeutic interventions. To model dissemination tumor...
Abstract Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, highly expressed in patient pNETs required cell proliferation survival vitro . Here, we investigated the role RABL6A progression vivo using well-established model disease. RIP-Tag2 (RT2) mice develop functional (insulinomas) due SV40 large...
<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>