Peter Hersey
The University of Sydney, Medicine, Faculty Member
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA... more
The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reprodu...
Research Interests:
Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour... more
Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the...
Research Interests:
3015 Background: We explored baseline tumor size (BTS) as a prognostic factor in addition to standard prognostic variables for overall survival (OS) in pts with metastatic melanoma treated with MK-...
Research Interests:
3005^ Background: MK-3475 demonstrated antitumor activity and acceptable safety in a phase I MEL cohort. We provide updated efficacy data and correlation with tumor PD-L1 expression. Methods: 135 p...
Research Interests:
3000 Background: MK-3475 has shown durable antitumor activity in MEL across multiple doses and schedules. We compared the efficacy and safety of 2 MK-3475 doses in MEL patients (pts). Methods: In s...
Research Interests:
Research Interests:
9503Background: The anti–PD-1 antibody pembro (pembro; MK-3475) prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, and is approved for treating advanced melanoma at a dose of 2 mg/kg every 3 wk (Q3W). Pembro demonstrated superior... more
9503Background: The anti–PD-1 antibody pembro (pembro; MK-3475) prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, and is approved for treating advanced melanoma at a dose of 2 mg/kg every 3 wk (Q3W). Pembro demonstrated superior PFS over chemotherapy for ipilimumab (ipi)-refractory melanoma (KEYNOTE-002) and superior OS and PFS over ipi for advanced melanoma (KEYNOTE-006). We present 3-year OS data for all patients (pts) with melanoma enrolled in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts were enrolled in ipi-naive and ipi-treated cohorts and received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator decision. Clinically stable pts with radiographic progression could remain on pembro until progression was confirmed. Response was assessed by RECIST v1.1 every 12 wk. After pembro discontinuation, pts were contacted to assess survival every 3 mo. OS was estimated using the Kaplan-Meier method. Results: Of the 655 pts enrolled, 24% had ...
Research Interests:
The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant... more
The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free surviva...
Research Interests: Medicine, Population, Humans, Internal Medicine, Placebo, and 15 moreFemale, Melanoma, Male, Placebos, Aged, Middle Aged, Adult, Medicine and Health Sciences, New England Journalof Medicine, Pembrolizumab, Disease Free Survival, Neoplasm staging, Medical and Health Sciences, Intention to treat analysis, and hazard ratio
Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking.... more
Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology an...
Research Interests:
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and... more
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.
Research Interests: Genomics, Cancer, Biology, Cell Cycle, Cell Biology, and 15 moreCancer Research, Landscape, Lung Cancer, Cancer Genomics, Humans, Cell, Aneuploidy, Genome Engineering, Cancer Cell, Cell Proliferation, Chromosomal Instability, Copy Number Alteration, Genome Instability, Chromosome deletion, and Chromosome aberrations
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering... more
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness fe...
Research Interests:
We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study... more
We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study patterns of structural variation, infer tumour evolution, probe the interactions among variants in the germline genome, the tumour genome and the transcriptome, and derive an understanding of how coding and non-coding variations together contribute to driving individual patient's tumours. This work represents the most comprehensive look at cancer whole genomes to date. NOTE TO READERS: This is an incomplete draft of the marker paper for the Pan-Cancer Analysis of Whole Genomes Project, and is intended to provide the background information for a series of in-depth papers that will be posted to BioRixv during the summer of 2017.
Research Interests:
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome... more
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent ...
Research Interests:
Research Interests:
Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1... more
Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical res...
Research Interests:
Research Interests:
We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into... more
We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is ...
Research Interests:
Research Interests:
Introduction L’anticorps humanise IgG4 anti-PD-1, pembrolizumab (pembro ; MK-3475) a demontre des reponses antitumorales durables chez les patients atteints de melanome et de cancer du poumon non a petites cellules metastatiques. Nous... more
Introduction L’anticorps humanise IgG4 anti-PD-1, pembrolizumab (pembro ; MK-3475) a demontre des reponses antitumorales durables chez les patients atteints de melanome et de cancer du poumon non a petites cellules metastatiques. Nous rapportons les resultats obtenus chez 411 patients atteints de melanome metastatique. Patients et methodes Une cohorte non randomisee de patients pre-traites ou non par ipilimumab a ete traitee par pembro 10 mg/kg/2 semaines, 10 mg/kg/3 semaines, ou 2 mg/kg/3 semaines, et une cohorte de patients a ete randomisee en deux bras de traitement : 2 ou 10 mg/3 semaines. Les evaluations etaient effectuees toutes les 12 semaines par les criteres RECIST 1.1 et les criteres d’evaluation immunologiques (irRC). Resultats Cent soixante-deux patients ont ete traites a 2 mg/3 semaines, 192 a 10 mg/3 semaines, et 57 a 10 mg/2 semaines Cent quatre-vingt-dix patients n’avaient pas recu d’ipi et 221 avaient ete traites par ipi anterieurement. Parmi les 365 patients ayant des lesions mesurables avant traitement, le taux de reponse objective etait de 40 % (IC 95 % 32 % > 48 %) chez les patients ipi naifs et de 28 % (IC 95 % 22 % > 35 %) chez les patients traites par ipi. Les reponses etaient durables (88 % encore en reponse au moment de l’analyse avec au moins 6 mois de suivi pour tous les patients). La survie sans progression mediane par RECIST est de 24 semaines chez les ipi-naifs et de 23 semaines chez les ipi-traites. La survie mediane n’est pas atteinte apres un an de survie pour 75 % des patients. Le benefice est observable dans tous les sous-groupes pronostiques (etat clinique, mutation de BRAF, taux de LDH, stade). Douze pour cent des patients ont presente des effets secondaires de grade 3/4 et 4 % ont du interrompre le traitement en raison de la toxicite. Il n’y a pas eu de deces lie au traitement. Conclusion Le pembro est associe a des reponses cliniques durables et une toxicite acceptable a ces differentes doses chez les patients atteints de melanome metastatique.
Research Interests: Medicine and Gynecology
Research Interests:
Research Interests:
Research Interests: Gastroenterology, Medicine, Humans, Internal Medicine, Female, and 15 moreMelanoma, Male, Monoclonal Antibodies, Ipilimumab, Clinical Sciences, Aged, Middle Aged, Adult, New England Journalof Medicine, Antineoplastic Agents, Brain Neoplasms, Skin Neoplasms, Adverse effect, Medical and Health Sciences, and Response evaluation criteria in solid tumors
As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new... more
As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.
Research Interests:
Wild-type p53 is commonly expressed in melanoma but does not appear to be effective in the induction of apoptosis. One explanation is that p53 is targeted for degradation by the E3 ligase MDM2. However, we found in this study that... more
Wild-type p53 is commonly expressed in melanoma but does not appear to be effective in the induction of apoptosis. One explanation is that p53 is targeted for degradation by the E3 ligase MDM2. However, we found in this study that blockade of the interaction of p53 and MDM2 by the MDM2 antagonist nutlin-3 in melanoma cells did not induce apoptosis, even though it upregulated p53 and its proapoptotic targets. Nevertheless, nutlin-3 enhanced TRAIL-induced apoptosis as a result of p53-mediated upregulation of TRAIL-R2. Unexpectedly, nutlin-3 upregulated Mcl-1, which attenuated apoptotic signaling triggered by TRAIL, and inhibited apoptosis induced by the microtubule-targeting drug docetaxel. The increase in Mcl-1 was related to a p53-independent transcriptional mechanism, but stabilization of the Mcl-1 protein played a dominant role, as nutlin-3 upregulated the Mcl-1 protein to a much greater extent than the Mcl-1 mRNA, and this was associated with prolonged half-life time and reduced ...
Research Interests:
Histone acetylation marks have an important role in controlling gene expression and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins and novel inhibitiors of these proteins... more
Histone acetylation marks have an important role in controlling gene expression and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins and novel inhibitiors of these proteins are currently in clinical development. Inhibitors of HDAC and BET proteins have individually been shown to cause apoptosis and reduce growth of melanoma cells. Here we show that combining the HDAC inhibitor LBH589 and BET inhibitor I-BET151 synergistically induce apoptosis of melanoma cells but not of melanocytes. Induction of apoptosis proceeded through the mitochondrial pathway, was caspase dependent and involved upregulation of the BH3 pro-apoptotic protein BIM. Analysis of signal pathways in melanoma cell lines resistant to BRAF inhibitors revealed that treatment with the combination strongly downregulated anti-apoptotic proteins and proteins in the AKT and Hippo/YAP signaling pathways. Xenograft studies showed that the combination of inhibitor...
Research Interests:
LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A... more
LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and &amp;amp;amp;amp;gt;75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]
Research Interests:
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and... more
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique m...
Research Interests:
Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. DERMA... more
Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: fiv...
Most anticancer agents mediate their effects through common pathways which induce apoptosis or in some cases necrosis of cancer cells. The apoptotic pathways are regulated by Bcl-2 family proteins, which include both pro- and... more
Most anticancer agents mediate their effects through common pathways which induce apoptosis or in some cases necrosis of cancer cells. The apoptotic pathways are regulated by Bcl-2 family proteins, which include both pro- and anti-apoptotic members. Much is known about the interactions of these proteins involved in apoptosis and this information is being utilized in the development of new reagents that may be used to treat patients with cancers. The inhibitor of apoptosis family of proteins constitute a second group of proteins which inhibit the effector caspases. Reagents that inhibit their activity are also under development. Resistance of cancer cells to treatment can in many instances be attributed to activation of intracellular signal pathways involved in survival, such as the Ras-Raf-MEK-ERK1/2 or the P13K-Akt pathway. Again, much has been learned about the control of these pathways and their activation of resistance mechanisms. Inhibitors of such pathways are being evaluated ...
Research Interests:
Prior studies have shown that combinations of HDAC and BRAF inhibitors (BRAFi) have synergistic effects in BRAFi resistant melanoma through enhanced apoptosis and inhibition of the cAMP dependent drug resistance pathway. However little is... more
Prior studies have shown that combinations of HDAC and BRAF inhibitors (BRAFi) have synergistic effects in BRAFi resistant melanoma through enhanced apoptosis and inhibition of the cAMP dependent drug resistance pathway. However little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics and patient outcome. The present study extensively profiled class 1 HDAC and their targets/regulators utilising immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status and detailed clinicopatholgical data. HDAC8 was increased in BRAF mutated melanoma (p=0.016), no association between expression of other HDACs and NRAS/BRAF status was identified. There was a positive correlation between HDAC1, HDAC8 expression and phosphorylated NFκb p65 immunoreactivity (p<0.001). Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved...
Research Interests:
Research Interests:
Research Interests:
Two of the hallmark features of melanoma are its development as a result of chronic UV radiation exposure and the limited efficacy of cisplatin in the disease treatment. Both of these DNA-damaging agents result in large helix-distorting... more
Two of the hallmark features of melanoma are its development as a result of chronic UV radiation exposure and the limited efficacy of cisplatin in the disease treatment. Both of these DNA-damaging agents result in large helix-distorting DNA damage that is recognized and repaired by nucleotide excision repair (NER). The aim of this study was to examine the expression of NER gene transcripts, p53, and p21 in melanoma cell lines treated with cisplatin compared with melanocytes. Basal expression of all genes was greater in the melanoma cell lines compared with melanocytes. Global genome repair (GGR) transcripts showed significantly decreased relative expression (RE) in melanoma cell lines 24 hours after cisplatin treatment. The basal RE of p53 was significantly higher in the melanoma cell lines compared with the melanocytes. However, induction of p53 was only significant in the melanocytes at 6 and 24 hours after cisplatin treatment. Inhibition of p53 expression significantly decreased the expression of all the GGR transcripts in melanocytes at 6 and 24 hours after cisplatin treatment. Although the RE levels were lower with p53 inhibition, the induction of the GGR genes was very similar to that in the control melanocytes and increased significantly across the time points. The findings from this study revealed reduced GGR transcript levels in melanoma cells 24 hours after cisplatin treatment. Our findings suggest a possible mechanistic explanation for the limited efficacy of cisplatin treatment and the possible role of UV light in melanoma.
Research Interests:
Research Interests:
Page 1. 125 TF Gajewski and FS Hodi (eds.), Targeted Therapeutics in Melanoma, Current Clinical Oncology, DOI 10.1007/978-1-61779-407-0_9, © Springer Science+Business Media, LLC 2012 Abstract Impairment of cell death is a key property of... more
Page 1. 125 TF Gajewski and FS Hodi (eds.), Targeted Therapeutics in Melanoma, Current Clinical Oncology, DOI 10.1007/978-1-61779-407-0_9, © Springer Science+Business Media, LLC 2012 Abstract Impairment of cell death is a key property of cancer cells. ...