A5081147586- Protein Degradation and Inhibitors
- Click Chemistry and Applications
- Cell Adhesion Molecules Research
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- Renal cell carcinoma treatment
- Renal and related cancers
- PI3K/AKT/mTOR signaling in cancer
- CRISPR and Genetic Engineering
- CAR-T cell therapy research
- Cellular Mechanics and Interactions
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Histone Deacetylase Inhibitors Research
- Synthesis and biological activity
- Advanced Breast Cancer Therapies
- Virus-based gene therapy research
- Angiogenesis and VEGF in Cancer
- Autophagy in Disease and Therapy
- Cancer therapeutics and mechanisms
- Cutaneous Melanoma Detection and Management
- melanin and skin pigmentation
- Redox biology and oxidative stress
- Cardiovascular and Diving-Related Complications
- Chronic Lymphocytic Leukemia Research
Huntsman Cancer Institute
2019-2025
University of Utah
2016-2025
Weber State University
2024-2025
Abstract Alterations in the PI3K/AKT pathway occur up to 70% of melanomas and are associated with disease progression. The three AKT paralogs highly conserved but data suggest they have distinct functions. Activating mutations AKT1 AKT3 human melanoma their role formation metastasis remains unclear. Using an established mouse model, we evaluated E17K, E40K, Q79K AKT1, AKT2, show that mice harboring tumors expressing AKT1E17K had highest incidence brain lowest mean survival. Tumors displayed...
Abstract An area of particular interest in FLASH is the potential influence immune microenvironment sparing normal tissue. After finding loss effect via survival studies immunocompromised SCID mice, we examined proteomic analyses performed upon skin BALB/c mice for classifiers that may be involved response. Intriguingly, one our top hits was a known regulator, mTOR (mammalian target rapamycin). Here have validated and further explored role FLASH. For these exposed pelvic region 6-7-week-old...
This study addresses the urgent need for effective therapies patients with brain metastases from cutaneous melanoma, a major cause of treatment failure despite recent therapeutic advances. Utilizing mouse models that mimic human melanoma metastases, this investigates necessity focal adhesion kinase (FAK) in development distant and its potential as target. Pharmacological inhibition FAK demonstrates significant efficacy reducing preclinical models. Importantly, provides insight into crosstalk...
NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or lung (MLE-12) cells is sufficient to promote rapidly growing tumors mice. Both tumor models exquisitely sensitive targeted inhibition with entrectinib, a tropomyosin-related A (TRKA) inhibitor. Initial regression NTRK1-driven driven by induced BIM, such BIM silencing leads diminished...
Abstract Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 3 (AKT1–3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition AKT1–3 melanoma cells. Although pharmacological was without effect, silencing all three paralogs significantly...
<p>Supplementary Figure S2 shows the classification of MTG001 and MTG004. Immunoblotting MTG004 PDX-derived cell lines showed similar levels P-AKT (Ser473), total AKT, P-ERK (Thr202/Tyr204), ERK1/2, P-Ribosomal S6 Kinase (Ser235/236), Kinase. GAPDH was used as a loading control. The cells exhibited higher PTEN. Analysis RNA sequencing data demonstrated that both express wildtype PTEN.</p>
<p>Supplementary Figure S1 shows that pharmacological inhibition of AKT has little effect on melanoma cells. Cell confluency assay under inhibition. A375, HT144, SK-MEL28, WM793, MTG001, and MTG004 cells were largely resistant to inhibitors MK2206 (2.5 µM) GDC0068 (1µM) while SK-MEL 28 MTG001 sensitive PI3Kα by GDC0941 (P < 0.001). Error bars indicate standard error the mean triplicate wells.</p>
<p>Supplementary Figure S2 shows the classification of MTG001 and MTG004. Immunoblotting MTG004 PDX-derived cell lines showed similar levels P-AKT (Ser473), total AKT, P-ERK (Thr202/Tyr204), ERK1/2, P-Ribosomal S6 Kinase (Ser235/236), Kinase. GAPDH was used as a loading control. The cells exhibited higher PTEN. Analysis RNA sequencing data demonstrated that both express wildtype PTEN.</p>
<p>Supplementary Figure S4 demonstrates that siAKT1-3 is specific for human AKT. A, The cell confluency assay of YUMM1.1 mouse melanoma cells under genetic inhibition demonstrated no effect on death with siAKT1, siAKT2, siAKT3, or any combination. Error bars indicate standard error the mean triplicate wells. B, Immunoblotting treated siCtrl vs siAKT1-3. No knockdown P-AKT (Ser473) P-PRAS40 (T246) indicated specificity siRNAs AKT.</p>
<p>Supplementary Figure S7 shows chemical structures of all pharmacological agents utilized in study, including MK2206, GSK2141795, GDC-0941, BYL719, RapaLink-1, GSK650394, GDC-0068, GDC-0084, and INY-03-041.</p>
<p>Supplementary Figure S3 shows confirmation of AKT expression and knockdown in additional cell lines. A, Immunoblotting analysis WM793 HT144 cells treated with each siRNA alone or combination showed effective individual paralogs using antibodies against total AKT1, AKT2, AKT3. B, Expression paralog MTG001 MTG004 RT-PCR.</p>
<p>Supplementary Figure S7 shows chemical structures of all pharmacological agents utilized in study, including MK2206, GSK2141795, GDC-0941, BYL719, RapaLink-1, GSK650394, GDC-0068, GDC-0084, and INY-03-041.</p>
<p>Supplementary Figure S6 shows that INY-03-041 leads to a substantial effect on melanoma cell proliferation but it is not as potent siAKT1-3. A, Cell confluency assay of MTG001 and MTG004 lines treated with DMSO control, GDC0068 (1µM), GDC0941 Lenalidomide or siAKT1-3 (50nM). Treatment led decreased (P < 0.0001 in each line), did lead death, similar MTG004. Lenalidomide, recruiter the E3 ubiquitin ligase Cereblon, conjugated form INY-03-041, was used negative control for...
<p>Supplementary Figure S1 shows that pharmacological inhibition of AKT has little effect on melanoma cells. Cell confluency assay under inhibition. A375, HT144, SK-MEL28, WM793, MTG001, and MTG004 cells were largely resistant to inhibitors MK2206 (2.5 µM) GDC0068 (1µM) while SK-MEL 28 MTG001 sensitive PI3Kα by GDC0941 (P < 0.001). Error bars indicate standard error the mean triplicate wells.</p>
<div>Abstract<p>Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 3 (AKT1–3) are <i>bona fide</i> oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition AKT1–3 melanoma cells. Although pharmacological was without effect,...
<p>Supplementary Figure S3 shows confirmation of AKT expression and knockdown in additional cell lines. A, Immunoblotting analysis WM793 HT144 cells treated with each siRNA alone or combination showed effective individual paralogs using antibodies against total AKT1, AKT2, AKT3. B, Expression paralog MTG001 MTG004 RT-PCR.</p>
<p>Supplemental Figure 5 shows that caspase 3 and 8 inhibition protects melanoma cells from siAKT1-3-mediated apoptosis. A, Cell confluency assay upon treatment with siAKT1-3 versus co-treatment inhibitors. Co-treatment of A375 MTG004 Z-VAD-FMK, Z-DEVD-FMK, Z-IETD-FMK inhibitors protected against cell death. B, Incuycte® Cytotox Red comparing siCtrl, siAKT1-3, siCtrl + each inhibitor, C, Caspase 3/7 The percentage dead stained red reagents increased only in the group, indicating...
<p>Supplementary Figure S6 shows that INY-03-041 leads to a substantial effect on melanoma cell proliferation but it is not as potent siAKT1-3. A, Cell confluency assay of MTG001 and MTG004 lines treated with DMSO control, GDC0068 (1µM), GDC0941 Lenalidomide or siAKT1-3 (50nM). Treatment led decreased (P < 0.0001 in each line), did lead death, similar MTG004. Lenalidomide, recruiter the E3 ubiquitin ligase Cereblon, conjugated form INY-03-041, was used negative control for...
<p>Supplemental Figure 5 shows that caspase 3 and 8 inhibition protects melanoma cells from siAKT1-3-mediated apoptosis. A, Cell confluency assay upon treatment with siAKT1-3 versus co-treatment inhibitors. Co-treatment of A375 MTG004 Z-VAD-FMK, Z-DEVD-FMK, Z-IETD-FMK inhibitors protected against cell death. B, Incuycte® Cytotox Red comparing siCtrl, siAKT1-3, siCtrl + each inhibitor, C, Caspase 3/7 The percentage dead stained red reagents increased only in the group, indicating...
<div>Abstract<p>Aberrant activation of the PI3K–AKT pathway is common in many cancers, including melanoma, and AKT1, 2 3 (AKT1–3) are <i>bona fide</i> oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition AKT1–3 melanoma cells. Although pharmacological was without effect,...
<p>Supplementary Figure S4 demonstrates that siAKT1-3 is specific for human AKT. A, The cell confluency assay of YUMM1.1 mouse melanoma cells under genetic inhibition demonstrated no effect on death with siAKT1, siAKT2, siAKT3, or any combination. Error bars indicate standard error the mean triplicate wells. B, Immunoblotting treated siCtrl vs siAKT1-3. No knockdown P-AKT (Ser473) P-PRAS40 (T246) indicated specificity siRNAs AKT.</p>
Abstract Despite promising results from recent FDA-approved therapies, many advanced melanoma patients develop resistance to both immunotherapy and targeted therapy. A common mechanism therapy is upregulation of the PI3K/AKT signaling pathway, which has also been shown promote development brain metastases. Historically, AKT inhibitors have failed in clinic due their limited efficacy or intolerable toxicity. Proteomic analysis comparing non-metastatic vs metastatic primary tumors mice...