Leleesha Samaraweera
Bronx, New York, United States
2K followers
500+ connections
About
• Extensive experience in leading and developing publication strategies and plans…
Activity
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We have a new opening for a TT Assistant Professor position in Ecology and Evolutionary Biology. A focal point of the position is the opportunity to…
We have a new opening for a TT Assistant Professor position in Ecology and Evolutionary Biology. A focal point of the position is the opportunity to…
Liked by Leleesha Samaraweera
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What an incredible and insightful event at the mRNA-Based Therapeutics Summit! We were delighted to have our Chief Business Officer, Thaminda…
What an incredible and insightful event at the mRNA-Based Therapeutics Summit! We were delighted to have our Chief Business Officer, Thaminda…
Liked by Leleesha Samaraweera
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To the Infinite and Beyond! Sky is the limit!
To the Infinite and Beyond! Sky is the limit!
Liked by Leleesha Samaraweera
Experience
Education
Publications
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A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC.
Nature Publications
Abstract
Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence…Abstract
Panobinostat (pano) is an FDA-approved histone deacetylase inhibitor. There is interest in evaluating alternate dosing schedules and novel combinations of pano for the treatment of upper aerodigestive and lung malignancies; thus we evaluated it in combination with Taxol, a chemotherapeutic with activity in both diseases. Dose-dependent synergy was observed in Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines and was due to senescence rather than potentiation of cell death. Senescence occurred following cisplatin- or Taxol-treatment in cell lines from both cancer types and was associated with decreased histone 3 (H3) acetylation and increased Bcl-xL expression: the latter a biomarker of senescence and target of anti-senescence therapeutics, or senolytics. Since H3 acetylation and Bcl-xL expression were altered in senescence, we subsequently evaluated pano as a senolytic in chemotherapy-treated cancer cells enriched for senescent cells. Pano caused cell death at significantly higher rates compared to repeat dosing with chemotherapy. This was associated with decreased expression of Bcl-xL and increased acetylated H3, reversing the expression patterns observed in senescence. These data support evaluating pano as a post-chemotherapy senolytic with the potential to kill persistent senescent cells that accumulate during standard chemotherapy in NSCLC and HNSCC.Other authors -
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Exploiting MEK inhibitor-mediated activation of ERα for therapeutic intervention in ER-positive ovarian carcinoma.
PLoS One
bstract
While the clinical benefit of MEK inhibitor (MEKi)-based therapy is well established in Raf mutant malignancies, its utility as a suppressor of hyperactive MAPK signaling in the absence of mutated Raf or Ras, is an area of ongoing research. MAPK activation is associated with loss of ERα expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ERα overexpression, phosphorylation and transcriptional…bstract
While the clinical benefit of MEK inhibitor (MEKi)-based therapy is well established in Raf mutant malignancies, its utility as a suppressor of hyperactive MAPK signaling in the absence of mutated Raf or Ras, is an area of ongoing research. MAPK activation is associated with loss of ERα expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ERα overexpression, phosphorylation and transcriptional activation of ER-regulated genes. Mechanistically, MEKi-mediated ERα overexpression is largely independent of erbB2 and AKT feedback activation, but is ERK-dependent. We subsequently exploit this phenomenon therapeutically by combining the ER-antagonist, fulvestrant with MEKi. This results in synergistic suppression of tumor growth, in vitro and potentiation of single agent activity in vivo in nude mice bearing xenografts. Thus, we demonstrate that exploiting adaptive feedback after MEKi can be used to sensitize ERα-positive tumors to hormonal therapy, and propose that this strategy may have broader clinical utility in ERα-positive ovarian carcinoma. -
MicroRNAs define distinct human neuroblastoma cell phenotypes and regulate their differentiation and tumorigenicity.
BMC Cancer
Unsupervised hierarchical clustering of miRNA microarray data segregated neuroblastic and non-neuronal cell lines and showed that specific miRNAs define each phenotype. qRT-PCR validation confirmed that increased levels of miR-21, miR-221 and miR-335 are associated with the non-neuronal phenotype, whereas increased levels of miR-124 and miR-375 are exclusive to neuroblastic cells. Downregulation of miR-335 in non-neuronal cells modulates expression levels of HAND1 and JAG1, known modulators of…
Unsupervised hierarchical clustering of miRNA microarray data segregated neuroblastic and non-neuronal cell lines and showed that specific miRNAs define each phenotype. qRT-PCR validation confirmed that increased levels of miR-21, miR-221 and miR-335 are associated with the non-neuronal phenotype, whereas increased levels of miR-124 and miR-375 are exclusive to neuroblastic cells. Downregulation of miR-335 in non-neuronal cells modulates expression levels of HAND1 and JAG1, known modulators of neuronal differentiation. Overexpression of miR-124 in stem cells induces terminal neuronal differentiation with reduced malignancy. Expression of miR-375 is exclusive for N-myc-expressing neuroblastic cells and is regulated by N-myc. Moreover, miR-375 downregulates expression of the neuronal-specific RNA binding protein HuD.
CONCLUSIONS:
Thus, miRNAs define distinct NB cell phenotypes. Increased levels of miR-21, miR-221 and miR-335 characterize the non-neuronal, non-malignant phenotype and miR-335 maintains the non-neuronal features possibly by blocking neuronal differentiation. miR-124 induces terminal neuronal differentiation with reduction in malignancy. Data suggest N-myc inhibits neuronal differentiation of neuroblastic cells possibly by upregulating miR-375 which, in turn, suppresses HuD. As tumor differentiation state is highly predictive of patient survival, the involvement of these miRNAs with NB differentiation and tumorigenic state could be exploited in the development of novel therapeutic strategies for this enigmatic childhood cancer. -
Reciprocal antagonistic regulation of N-myc mRNA by miR‑17 and the neuronal-specific RNA-binding protein HuD
Spandidos Publications
Abstract
Neuroblastoma is a childhood cancer originating from embryonic neural crest cells. Amplification of the proto‑oncogene N-myc, seen in ~30% of neuroblastoma tumors, is a marker for poor prognosis. Recently discovered small regulatory RNAs, microRNAs (miRNAs), are implicated in cancers, including neuroblastoma. miRNAs downregulate the expression of genes by binding to the 3'-untranslated regions (3'-UTRs), thereby inhibiting translation or inducing degradation of cognate mRNAs. Our…Abstract
Neuroblastoma is a childhood cancer originating from embryonic neural crest cells. Amplification of the proto‑oncogene N-myc, seen in ~30% of neuroblastoma tumors, is a marker for poor prognosis. Recently discovered small regulatory RNAs, microRNAs (miRNAs), are implicated in cancers, including neuroblastoma. miRNAs downregulate the expression of genes by binding to the 3'-untranslated regions (3'-UTRs), thereby inhibiting translation or inducing degradation of cognate mRNAs. Our study sought to identify miRNAs that regulate N-myc expression and thereby malignancy in neuroblastoma. miRNAs whose expression negatively correlates with N-myc expression were identified from a miRNA microarray of 4 N-myc-amplified neuroblastoma cell lines. Three of these miRNAs (miR-17, miR-20a and miR-18a) belong to the miR-17-92 cluster, previously shown to be upregulated by N-myc. qPCR validation of these miRNAs in a larger panel of cell lines revealed that levels of miR-17 were inversely proportional to N-myc mRNA amounts in the N-myc-amplified cell lines. Notably, miR-17 also downregulated N-myc protein synthesis in the N-myc-amplified cells, thereby generating a negative feedback regulatory loop between the proto-oncogene and this miRNA. Moreover, the neuronal-specific RNA-binding protein HuD (ELAVL4), which regulates the processing/stability of N-myc mRNA, competes with miR-17 for a binding site in the 3'-UTR of N-myc. Thus, N-myc levels appear to be modulated by the antagonistic interactions of both miR-17, as a negative regulator, and HuD, as a positive regulator, providing further evidence of the complex cellular control mechanisms of this oncogene in N-myc-amplified neuroblastoma cells.
Languages
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English
Native or bilingual proficiency
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Sinhalese
Native or bilingual proficiency
Organizations
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AACR
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- Present
More activity by Leleesha
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I’m looking forward to presenting at the 4th mRNA-Based Therapeutics Summit this July. See my session details in the event program here:…
I’m looking forward to presenting at the 4th mRNA-Based Therapeutics Summit this July. See my session details in the event program here:…
Liked by Leleesha Samaraweera
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It was really fun teaching peptide NMR and mass spectrometry to a group of very enthusiastic and engaging PhD students who are part of the ULLA…
It was really fun teaching peptide NMR and mass spectrometry to a group of very enthusiastic and engaging PhD students who are part of the ULLA…
Liked by Leleesha Samaraweera
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Thaminda Ramanayake Appointed as Chief Business Officer at CureVac Dr. Sunil Singh Smita Singh Subscribe to HR TODAY - A Truly International…
Thaminda Ramanayake Appointed as Chief Business Officer at CureVac Dr. Sunil Singh Smita Singh Subscribe to HR TODAY - A Truly International…
Liked by Leleesha Samaraweera
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The energy and excitement at @ASCO is contagious. It's also a good time to connect with friends and colleagues to share how we are progressing in…
The energy and excitement at @ASCO is contagious. It's also a good time to connect with friends and colleagues to share how we are progressing in…
Liked by Leleesha Samaraweera
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Hanging the Akeso #ASCO24 poster #4095 - The Safety and Efficacy of Ivonescimab in Combination With Chemotherapy as First-Line Treatment for Advanced…
Hanging the Akeso #ASCO24 poster #4095 - The Safety and Efficacy of Ivonescimab in Combination With Chemotherapy as First-Line Treatment for Advanced…
Liked by Leleesha Samaraweera
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Congratulations to all Fordham CSTEP scholars! Your village celebrates you! Onward and upward! Mike Molina, Michelle Santana, MSEd, Shantay Owens,…
Congratulations to all Fordham CSTEP scholars! Your village celebrates you! Onward and upward! Mike Molina, Michelle Santana, MSEd, Shantay Owens,…
Liked by Leleesha Samaraweera
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