A5038104452- Protein Degradation and Inhibitors
- Melanoma and MAPK Pathways
- Genomics and Chromatin Dynamics
- RNA regulation and disease
- RNA Research and Splicing
- melanin and skin pigmentation
- Cutaneous Melanoma Detection and Management
- Cell Adhesion Molecules Research
- Circular RNAs in diseases
- Estrogen and related hormone effects
- Chromatin Remodeling and Cancer
- Cancer, Lipids, and Metabolism
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Cancer Treatment and Pharmacology
- Ubiquitin and proteasome pathways
- Cancer-related molecular mechanisms research
- PI3K/AKT/mTOR signaling in cancer
- Nanoplatforms for cancer theranostics
- Anodic Oxide Films and Nanostructures
- Silk-based biomaterials and applications
- MicroRNA in disease regulation
- Click Chemistry and Applications
- Lipid metabolism and biosynthesis
- Immunotherapy and Immune Responses
Boston University
2020-2025
GTx (United States)
2023
Wake Forest University
2017-2020
Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown be altered in therapy-resistant melanomas and other cancers, a specific targetable mechanism has not been validated. Here, we evaluated corepressor for element 1-silencing transcription factor (CoREST) repressor complex recently developed bivalent inhibitor corin within context of phenotype plasticity therapeutic resistance....
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery the primary treatment for localized MPNST 61.9% overall survival rate, metastatic disease often fatal due to resistance systemic therapies which underscores urgent need effective treatments. MPNSTs frequently harbor inactivating driver mutations PRC2 epigenetic repressor complex suggesting represent specific...
<p>This figure illustrates the acetylation sites in SOX10 and how protein but not mRNA levels decrease with p300 inhibition.</p>
<p>This figure illustrates the correlation between p300 inhibition and subsequent downregulation of gene expression in SOX10-activated genes</p>
<p>This figure illustrates the melanocytic cluster of genes located at human chromosome 22q13.1 and 22q13.2</p>
<p>This figure illustrates the effects of A-485 on SOX10 protein expression without gene expression.</p>
<p>This figure illustrates how A-485 leads to inhibition of expression genes involved in melanoma cell invasion</p>
<p>This figure shows the correlation between EP300 and SOX10 gene copy numbers versus protein expression in melanoma cell lines as well associations PAK1 GAB2 that do not correlate with or lines.</p>
<p>This figure shows the correlation of EP300 and SOX10 gene copy numbers in acral melanoma datasets.</p>
Objective and Impact Statement . Molecular signatures are needed for early diagnosis improved treatment of metastatic melanoma. By high-resolution multimodal chemical imaging human melanoma samples, we identify a metabolic reprogramming from pigmentation to lipid droplet (LD) accumulation in Introduction Metabolic plasticity promotes cancer survival metastasis, which promises serve as prognostic marker and/or therapeutic target. However, identifying alterations has been challenged by...
Abstract SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth; on the other hand, loss-of-function drives emergence of therapy-resistant, invasive phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in proliferation while preventing concomitant increase cell invasion. In this study, we report that lysine acetyltransferase (KAT) EP300 and gene loci chromosome 22 are frequently co-amplified melanomas, including...
Abstract Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery the primary treatment for localized MPNST 61.9% overall survival rate, metastatic disease often fatal due to resistance systemic therapies which underscores urgent need effective treatments. MPNSTs frequently harbor inactivating driver mutations PRC2 epigenetic repressor complex suggesting represent...
Triple-negative breast cancer (TNBC) is an aggressive subtype of that tends to affect young women and has a high propensity metastasize. No targeted treatments are available for this type due lack estrogen or progesterone receptors overexpression human epidermal growth factor receptor 2 overexpression. Currently, patients have no therapeutic options once standard care complete, indicating need safe effective therapies slow prevent the progression TNBC metastatic disease. Studies showed...
The goal of this study was to determine if a proprietary muscadine grape seed and skin extract (MGE) inhibits triple negative breast cancer (TNBC) metastasis alters the gut microbiota. 4T1 TNBC cells were injected into mammary fat pad 6-week-old female Balb/c mice. After 2 weeks, tumors surgically removed mice placed control group (n = 8) or treatment that received 0.1 mg/mL total phenolics MGE (Piedmont R&D) in drinking water 8). Mice sacrificed after 4 weeks; tissues fecal samples...
Abstract SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while loss-of-function drives the emergence of therapy-resistant, invasive phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in proliferation, preventing concomitant increase cell invasion. Here, we report that lysine acetyltransferase (KAT) EP300 and gene loci on Chromosome 22 are frequently co-amplified melanomas, including UV-associated acral tumors....
Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain in infants, and more than 60% of children with ATRT die from their tumor. associated mutational inactivation/deletion SMARCB1 , a member SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play critical role development progression. Moreover, disruption allows unopposed activity repressors, which contribute to tumorigenicity. We therefore explored CoREST repressor complex ATRT....
Abstract Hyperpigmentation disorders are commonly diagnosed dermatologic conditions that can be cosmetically distressing for patients and cause negative psychosocial impacts. There is a need to better understand the underlying pathophysiology of pigmentary as well develop improvements in management these disorders. Here, we evaluated p300 (CBP/p300) histone acetyltransferase (HAT) inhibitor, A-485, determine if epigenetically targeting melanogenesis could therapeutic value. We find A-485...
Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are deadly infantile brain tumors, primarily arising from a single recurring biallelic loss-of-function mutation in SMARCB1 which is member of the SWI-SNF chromatin remodeling complex. The partially functional complex (without SMARCB1) able to inhibit EZH2 at most locations genome except gene promoter regions where co-localizes with REST This results hypermethylation and subsequent repression genes coding for neuronal differentiation tumor...
Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are deadly infantile brain driven by a loss-of-function mutation of SMARCB1, critical component the SWI-SNF chromatin remodeling complex. However, residual activity inhibits EZH2 at all loci except where CoREST colocalizes with these complexes, specifically contributing to ATRT pathogenesis. This results in hypermethylation and subsequent repression genes coding for neuronal differentiation tumor suppressors, accounting ATRTs’...
<p>p300 KAT activity is essential for the activation of SOX10-repressed EMT markers. <b>A,</b> Diagram depicting hypothesis that p300 expression SOX10-activated genes, but genes may also require their activation. <b>B,</b> Volcano plots differentially expressed due to A-485 treatment IPC-298, CO79, and A375 cells (DEGs defined as FC > |2| <i>P</i> < 0.05). <b>C,</b> are enriched involved in EMT, similar invasion-related pathways...