Melanoma: Hersey P

Hersey P, Zhang XD. · Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, Newcastle, New South Wales, Australia. · Pigment Cell Melanoma Res. · Pubmed #18476909 No free full text.

Abstract: Primary events in the development of melanoma are gradually being pieced together but a more complete picture of evolution of the disease requires additional understanding of secondary events consequent on initiation of the malignancy. Arguably, the most important driver of secondary events is signals resulting from induction of endoplasmic reticulum (ER) stress for example due to hypoglycaemia and anoxia. This may result in a variety of responses such as apoptosis, autophagy and senescence depending on the initiating event and cell type but most importantly it may result in progression of melanoma due to adaptation and selection of melanoma cells to ER stress. The following reviews what is known about the adaptive responses and how this information may provide new initiatives in treatment of the disease.

Hersey P, Zhuang L, Zhang XD. · Oncology and Immunology Unit, Newcastle Mater Misericordiae Hospital, Newcastle, New South Wales, Australia. · Int Rev Cytol. · Pubmed #16939779 No free full text.

Abstract: 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 in preclinical and clinical studies and are showing promise as a new class of anticancer agents. Much of the progress in future studies will likely depend on the ability to target these new treatments to particular subgroups of patients with tumor characteristics that make them responsive to the agents in question.

Hersey P. · Oncology and Immunology Unit, David Maddison Clinical Sciences Building, Newcastle, New South Wales, Australia. · Curr Opin Oncol. · Pubmed #16462190 No free full text.

Abstract: PURPOSE OF REVIEW: Melanoma has proven resistant to most available chemotherapy and immunotherapy. Despite a range of different biochemical targets, most agents kill cancer cells by induction of apoptosis. RECENT FINDINGS: Investigation of this process has provided insights into the resistance mechanisms in cancer cells and to development of a range of new agents that target apoptosis pathways. These include agents which inhibit antiapoptotic B cell lymphoma-2 family proteins and inhibitor of apoptosis proteins. In addition, a range of signal pathway inhibitors have become available that are able to inhibit signal pathways known to be associated with resistance to apoptosis. SUMMARY: Evaluation of most of these reagents are at a preclinical level but studies on some pathway inhibitors have passed from phase II into phase III studies. Similarly, evaluation of antisense reagents are at an advanced stage. These early trials show much promise and suggest this approach to development of new therapies will lead to much needed advances in treatment of this disease.

Thompson JF, Shaw HM, Hersey P, Scolyer RA. · Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · J Surg Oncol. · Pubmed #15221929 No free full text.

Abstract: The evolution and progressive refinement of an internationally accepted melanoma staging system over the last 50 years has resulted in much greater accuracy and increased utility, but the staging process has become more complex and less intuitive. This raises the question of whether melanoma staging should continue to develop with ever-increasing levels of complexity, or whether attempts should be made to produce an alternative system that is simpler and more intuitive. The current, TNM-based American Joint Committee on Cancer (AJCC) staging system for melanoma incorporates only some of the prognostic factors of proven significance. However, the information that is now available about these and other, well-documented prognostic factors allows accurate prediction of an individual melanoma patient's prognosis using a computer-generated estimate. Thus an alternative staging strategy that could be considered in the future would be to use such an estimate to obtain a numerical score for each patient, based on all available information agreed to be of prognostic relevance. A stage grouping could then be assigned on the basis of that score, according to previously determined score ranges for each stage and substage. The advantages of such a system would be that it would allow more reliable comparison of treatment results within and between institutions, and would provide more equivalent stratification groups for patients entering clinical trials of new therapies and those entering adjuvant therapy trials. A further advantage would be that because there would be a direct link between staging and prognostic estimate, such a system would be more readily able to be understood in an intuitive fashion.

Zhang XD, Gillespie SK, Borrow JM, Hersey P. · Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW 2300, Australia. · Biochem Pharmacol. · Pubmed #14555232 No free full text.

Abstract: TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-X(L) and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.

Hersey P. · Oncology and Immunology Unit, Newcastle Mater Hospital, Newcastle, New South Wales, Australia. · Intern Med J. · Pubmed #12534876 No free full text.

Abstract: Patients with thick, primary melanoma and regional lymph-node metastases are at moderate to high risk of recurrence and death, despite apparent complete surgical removal. Immune responses can be demonstrated against melanoma and this has prompted the conduct of a number of randomized trials of immunotherapy. Several trials have been completed and show minimal benefit in prolonging survival or recurrence from melanoma. Similarly, a large number of trials has been conducted to test the efficacy of alpha-2-interferon (IFN-alpha2) in therapy. Clear benefit in recurrence-free survival was shown in several trials, however there is a lack of convincing evidence of an effect on overall survival. Several trials of vaccine and IFN-alpha2 therapy are still in progress and their results are awaited with great interest. The use of high-dose IFN-alpha2 therapy remains a contentious subject, however available evidence suggests the standard of care remains good surgical management.

Hersey P, Zhang XD. · Immunology and Oncology Unit, Newcastle, New South Wales, Australia. · Nat Rev Cancer. · Pubmed #11905805 No free full text.

Abstract: At the doses used clinically, chemotherapy is believed to kill melanoma by a final common 'mitochondrial' pathway that leads to apoptosis. Similarly, several natural defence mechanisms kill melanoma by the same pathways. A corollary to the latter is that survival of melanoma in the host is due to the development of anti-apoptotic mechanisms in melanoma cells. What are these mechanisms? And how might we bypass them to improve the treatment of melanoma?

Hersey P. · Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW 2300, Australia. · Expert Opin Investig Drugs. · Pubmed #11772323 No free full text.

Abstract: Immune responses appear to play a role in the natural history of melanoma and immunotherapy has therefore been the subject of a number of studies. The results of several large randomised studies using allogeneic melanoma vaccines have shown minimal benefit and Phase I/II studies with gene transfected melanoma cells do not appear particularly encouraging. The majority of current interest now centres on development of vaccines using defined melanoma antigens recognised by T-cells and given as dendritic vaccines or injected directly as melanoma peptides or DNA. It can be expected that the most effective antigens and method of administration will become apparent over the next few years. It is clear, however, that melanoma shows low response rates to immunotherapy, as for chemotherapy. Both forms of therapy appear to kill melanoma by induction of apoptosis, so it is possible that resistance to apoptosis may underlie the low responses to these forms of therapy. Much is already known about agents that may sensitise melanoma to apoptosis and combining these with chemotherapy and/or immunotherapy provides a promising new approach in treatment of melanoma.

Nguyen T, Thomas W, Zhang XD, Gray C, Hersey P. · Oncology and Immunology Unit, Newcastle Mater Hospital, Newcastle, New South Wales, Australia. · Forum (Genova). · Pubmed #11007932 No free full text.

Abstract: Immune responses against human melanoma are common and are believed to influence the natural history of the disease. In particular, CD4 T cell infiltrates are associated with regression of primary melanoma and with responses to treatment with interferon-alpha2 (IFN-alpha2). Our studies have shown that CD4 T cells appear to kill melanoma by means of a member of the tumour necrosis factor (TNF) family expressed on their surface and called TNF related apoptosis inducing ligand (TRAIL). Moreover, sensitivity to TRAIL also predicts responsiveness of melanoma to CD4 T cells. TRAIL is not expressed on resting lymphocytes but is expressed at high levels after exposure to IFN-alpha2 and on activated T cells. Lymphocytes from melanoma patients in early stages of the disease show high levels of expression after exposure to IFN-alpha2 and IFN-gamma but expression was less on lymphocytes from stage IV patients. This may be due to factors from melanoma cells in that supernatants from some melanoma cultures suppressed IFN-alpha2 upregulation of TRAIL. Sensitivity of melanoma cells to TRAIL can be increased by inhibition of the activation of NF-kappaB and anti-apoptotic events downstream of NF-kappaB. These results suggest that TRAIL may be an important mediator of responses against melanoma induced by immunotherapy or by treatment with IFN-alpha2 and interleukin-2. Studies on surgical biopsies of melanoma however show that fresh isolates appear less sensitive to TRAIL-induced apoptosis and effective therapy may involve combinations with other agents.

Serrone L, Hersey P. · I Division of Medical Oncology, Regina Elena Institute, Rome, Italy. · Melanoma Res. · Pubmed #10338334 No free full text.

Abstract: Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.

Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. · University of Kiel, Kiel, Charité Berlin. · J Clin Oncol. · Pubmed #19349552 No free full text.

Abstract: PURPOSE: This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. PATIENTS AND METHODS: A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. RESULTS: The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombocytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP. CONCLUSION: In this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing.

Hersey P, Halliday GM, Farrelly ML, DeSilva C, Lett M, Menzies SW. · Oncology and Immunology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW 2300, Australia. · Cancer Immunol Immunother. · Pubmed #18157724 No free full text.

Abstract: BACKGROUND: In the present study, we have examined whether treatment of patients with metastatic melanoma with matured dendritic cell (DC) vaccines with or without low dose IL-2 may improve treatment outcomes. METHODS: Sixteen patients received DC vaccines (DCs) sensitized with autologous melanoma lysates and 18 patients received DCs sensitized with peptides from gp100, MART-1, tyrosinase, MAGE-3.A2, MAGE-A10 and NA17. IL-2 was given subcutaneously (sc) at 1 MU/m2 on the second day after each injection for 5-14 days in half of each group. DCs were given by intranodal injection. RESULTS: There were 2 partial responses (PR) and 3 with stable disease (SD) in the nine patients receiving DCs + peptides + IL-2, and 1 PR and 1 SD in nine patients treated with DCs + peptides without IL-2. There were only two patients with SD in the group receiving DCs + autologous lysates and no IL-2. Median overall survival for all patients was very good at 18.5 months but this was most probably due to selection of a favourable group of patients for the study. There was no significant difference in survival between the groups by log rank analysis. Treatment was not associated with significant side effects. The quality and yield of the DCs in the preparations were generally good. CONCLUSIONS: We conclude that mature DC preparations may be superior to immature DC preparations for presentation of melanoma peptides and that IL-2 may increase clinical responses to the DCs plus peptides. However, in our view the low response rates do not justify the cost and complexity of this treatment approach.

Millward MJ, Joshua A, Kefford R, Aamdal S, Thomson D, Hersey P, Toner G, Lynch K. · Sydney Cancer Centre & Sydney Melanoma Unit, Royal Prince Alfred Hospital, Sydney, Australia. · Invest New Drugs. · Pubmed #15868382 No free full text.

Abstract: PURPOSE: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content. PATIENTS AND METHODS: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria. RESULTS: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8-12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition. CONCLUSIONS: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.

Byrne CM, Thompson JF, Johnston H, Hersey P, Quinn MJ, Michael Hughes T, McCarthy WH. · The Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown and Discipline of Surgery, The University of Sydney, Sydney, NSW, Australia. · Melanoma Res. · Pubmed #15714120 No free full text.

Abstract: Electroporation therapy (EPT) is a novel treatment modality that uses brief, high-intensity, pulsed electrical currents to enhance the uptake of chemotherapeutic agents, vaccines and genes into cells. This technique is potentially useful for patients with secondary and, possibly, some primary tumours. Nineteen patients with metastatic melanoma were enrolled in a phase two, randomized, open-label study comparing intralesional bleomycin+EPT with intralesional bleomycin alone. Of 18 study lesions, 13 (72%) showed a complete response, one (5%) showed a partial response, three (18%) showed no change and one (5%) showed disease progression over a period of greater than 12 weeks. This represents a 78% objective response rate, which was significantly greater than the 32% response rate observed in the 19 patients with tumours treated with intralesional bleomycin alone (chi=7.94, 1 df, P=0.005). An additional 36 lesions, not enrolled in the study, were also treated with bleomycin+EPT. Of the total of 54 lesions treated with bleomycin+EPT, there was a 72% objective response rate. EPT treatment was well tolerated and was performed on an outpatient basis.

Hersey P, Menzies SW, Coventry B, Nguyen T, Farrelly M, Collins S, Hirst D, Johnson H. · Oncology and Immunology Unit, Room 443, David Maddison Clinical Sciences Building, King & Watt Streets, Newcastle, NSW, 2300, Australia. · Cancer Immunol Immunother. · Pubmed #15449035 No free full text.

Abstract: Previous studies in small groups of patients suggested that immunization of melanoma patients with peptide epitopes recognized by T cells could induce regression of melanoma. This approach was tested in 36 patients with stage IV melanoma. The (MHC class I-restricted) peptides were from gp100, MART-1, tyrosinase, and MAGE-3. The gp100 and MART-1 peptides had been modified to increase their immunogenicity. In half the patients (groups 3 and 4) the peptides were given in the adjuvant Montanide-ISA-720, and half the patients in both groups were given GM-CSF s.c. for 4 days following each injection. Treatment was well tolerated except for two severe erythematous responses to Montanide-ISA-720 and marked inflammatory responses at sites of GM-CSF administration in three patients. There were no objective clinical responses but stabilization of disease for periods from 3 to 12 months were seen in seven patients. Five of these were patients given the peptides in Montanide-ISA-720. Delayed-type hypersensitivity (DTH) skin test responses were also seen mainly in the patients given the peptides in Montanide-ISA-720. GM-CSF did not increase DTH responses in patients in the latter group but may have increased DTH responses in those not given peptides in Montanide-ISA-720. Inflammatory responses around s.c. metastases or regional lymph nodes were observed in two patients. These results suggest that the peptides are more effective when given in the adjuvant Montanide-ISA-720. Nevertheless, results from this study, together with those from a number of comparable studies, indicate that peptide vaccines are currently of minimal benefit to patients and support the need for ongoing development of new strategies in treatment of this disease.

Hersey P, Menzies SW, Halliday GM, Nguyen T, Farrelly ML, DeSilva C, Lett M. · Oncology and Immunology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, 2300, Newcastle, NSW, Australia. · Cancer Immunol Immunother. · Pubmed #14600790 No free full text.

Abstract: Previous studies have suggested that immunotherapy with dendritic cell (DC) vaccines may be effective in treatment of patients with AJCC stage IV melanoma. We examined this treatment in phase I/II studies in 33 patients with good performance status and low volume disease. Nineteen patients received DCs plus autologous lysates and 14 patients DCs plus peptides from the melanoma antigens MAGE-3.A2, tyrosinase, gp100, and MART-1. Keyhole limpet hemocyanin (KLH) was used as a helper protein and influenza peptide was given as a positive control. DCs were produced from adherent cells in blood lymphocytes (monocytic DCs), grown in IL-4 and GM-CSF without a maturation step. The DCs were injected into inguinal lymph nodes at weekly intervals (x4), 2 weeks (x1), and 4-weekly intervals (x2). There were 3 responses (3 partial responses) and 1 mixed response in the 19 patients treated with DCs plus autologous lysates. No responses were seen in the group treated with DCs plus peptides. Stable disease (defined as no progression over a period of 3 months) was seen in 4 patients in group 1 and 5 patients in group 2. Treatment was not associated with significant side effects. We examined whether DTH skin tests or assays of IFN-gamma cytokine production may be useful predictors of clinical responses. Twenty-two of 30 patients had DTH responses to KLH and 12 of 13 patients had DTH responses to the influenza peptide. Five of 15 DTH responses were seen against autologous lysates. This was strongly correlated with clinical responses. Approximately half the patients had responses to MART-1 peptide and a third to the other melanoma peptides. Similarly, cytokine production assays showed responses to influenza in 7 of 13 patients, and approximately one third of patients had responses to the other peptides. No IFN-gamma responses were seen in 5 patients against their autologous lysates. There was no correlation between assays of IFN-gamma production and clinical responses. The present studies suggest that autologous lysates may be more effective than the melanoma peptides used in the study as the source of antigen for DC vaccines. DTH responses to autologous lysates appear useful predictors of clinical responses, but further work is needed to identify other measures associated with clinical responses.

Hersey P, Coates AS, McCarthy WH, Thompson JF, Sillar RW, McLeod R, Gill PG, Coventry BJ, McMullen A, Dillon H, Simes RJ. · Sydney Melanoma Unit, University of Sydney and Royal Prince Alfred Hospital, and the Cancer Council Australia, Sydney. · J Clin Oncol. · Pubmed #12377961 No free full text.

Abstract: PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control versus 151 months in the treated group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.64 to 1.02; P =.068 by stratified univariate Cox analysis). At 5 and 10 years, survival rates for control and treated patients were 54.8% v 60.6% and 41% v 53.4%, respectively. Median RFS was 43 months in the control group compared with 83 months in the treated group (HR, 0.86; 95% CI, 0.7 to 1.07; P =.17). RFS at 5 years was 50.9% for the treated group and 46.8% for the control group. There were no selective benefits from the vaccine for particular subsets of patients. CONCLUSION: Immunotherapy with VMCL was not associated with a statistically significant improvement in OS or RFS, with CIs not ruling out important gains from such treatment.

Hanrahan PF, D'Este CA, Menzies SW, Plummer T, Hersey P. · Oncology & Immunology Unit, Newcastle Mater Misericordiae Hospital, New South Wales, Australia. · J Med Screen. · Pubmed #12370325 No free full text.

Abstract: OBJECTIVES: We have previously shown that photographs assist in detection of change in skin lesions and designed the present randomised population based trial to assess the feasibility of photographs as an aid to management of skin cancers in older men. SETTING: 1899 men over fifty, identified from the electoral roll in two regions in New South Wales (NSW), Australia, were invited by mail to participate. METHODS: A total of 973 of 1037 respondents were photographed and randomised into intervention (participants given their photographs) or control groups (photographs withheld by investigators). At one and two years from the time of photography, all participants were advised to see their primary care practitioner for a skin examination. Those in the intervention group were examined with their photographs and those in the control group without their photographs. RESULTS: The results indicated that the practitioners were more likely to leave suspicious lesions in place for follow up observation (37% v 29%) (p=0.006) and less likely to excise benign non pigmented lesions (20 v 32%). There was little difference in excision rates for benign pigmented lesions (21% v 23%). Lesions excised were more likely to be non-melanoma skin cancer (58% v 42%) from patients who had photographs compared to those without photographs (p=0.005). The use of skin photography resulted in a substantial savings due to the reduced excision of benign lesions. CONCLUSIONS: These results suggest that it would be feasible to conduct a large scale randomised trial to evaluate the value of photography in early detection of melanoma and that such a trial could be cost effective due to the reduced excision of benign skin lesions.

Hanrahan PF, Menzies SW, D'Este CA, Plummer T, Hersey P. · Oncology & Immunology Unit, Newcastle Mater Misericordiae Hospital, New South Wales. · Aust N Z J Public Health. · Pubmed #11215011 No free full text.

Abstract: OBJECTIVE: To examine the acceptability of photography as an aid to skin examinations in men over 50 years of age. METHODS: A randomised trial of men selected from the electoral roll. All participants were photographed, but only half received their photographs. Skin examinations by GPs at years one and two. RESULTS: 55% of men consented to have photographs taken and 51% did so. 86% of respondents had risk factors for melanoma (compared to 68% of non-responders) and 47% had two or more risk factors (compared to 23% of non-responders). At year one, 91% of participants remaining in study regions had been examined. Photographs were lost by only six participants. CONCLUSIONS: Men over 50 years of age respond to personalised health messages about melanoma and respondents include a high proportion of males with risk factors for melanoma. IMPLICATIONS: These initial results suggest that photography may be a logistically acceptable approach for assisting in the early detection of melanoma.

Curry BJ, Myers K, Hersey P. · Oncology and Immunology Unit, Mater Misericordiae Hospital, Newcastle, and Sydney Melanoma Unit, Sydney, New South Wales, Australia. · J Clin Oncol. · Pubmed #10561323 No free full text.

Abstract: PURPOSE: Polymerase chain reaction (PCR) with tyrosinase and with MART-1 permits detection of small numbers of circulating melanoma cells (CMCs) in patients who have undergone surgical resection of localized disease. In a previous study, we showed that PCR with MART-1 had sensitivity and specificity similar to those of PCR with tyrosinase in terms of detection of CMCs but that PCR with MART-1 seemed to identify a different but overlapping subgroup of patients. In the current study, we examined the utility and prognostic significance of PCR with tyrosinase and with MART-1. PATIENTS AND METHODS: We analyzed the prognostic significance of the patterns of expression of tyrosinase and MART-1 in 186 patients followed sequentially before and after surgical removal of American Joint Committee on Cancer stage I, II, or III melanoma. RESULTS: PCR with tyrosinase and with MART-1 in the first 3 months after surgery identified 68.5% of 73 patients who developed recurrence in the 2-year period after surgery. Approximately 35% of patients with positive tests remained disease-free at 2-year follow-up. We found that patients with disseminated recurrence had a significantly lower incidence of MART-1-positive CMCs (16%) than of tyrosinase-positive CMCs (63%). Patients with locoregional metastases had CMCs that expressed tyrosinase and MART-1 at similar rates. These differences in expression of the markers in patients with disseminated recurrence were also associated with a much lower disease-free survival, in those who had CMCs that were positive for tyrosinase but negative for MART-1. The reverse applied in those with locoregional disease. CONCLUSION: These findings suggest that PCR with MART-1 and with tyrosinase identifies subgroups of patients who develop disseminated or locally recurrent metastases. We hypothesize that immune responses against MART-1 may reduce the establishment of disseminated metastases.

Jiang CC, Yang F, Thorne RF, Zhu BK, Hersey P, Zhang XD. · Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, Newcastle, NSW, Australia. · Neoplasia. · Pubmed #19412428 links to  free full text

Abstract: Past studies have shown that melanoma cells have largely adapted to endoplasmic reticulum (ER) stress. In this study, we report that melanoma cells under ER stress are more resistant to apoptosis induced by the microtubule-targeting chemotherapeutic drugs, docetaxel and vincristine, and this is, at least in part, due to activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway mediated by the X-box-binding protein 1 (XBP-1) axis of the unfolded protein response. Treatment with the ER stress-inducer tunicamycin (TM) or thapsigargin before the addition of docetaxel or vincristine reduced the levels of apoptosis induced by the drugs. This was associated with inhibition of mitochondrial release of apoptogenic proteins and activation of Bax and Bak. Induction of ER stress resulted in the rapid activation of the PI3K/Akt pathway that seemed to be important in antagonizing docetaxel and vincristine, in that inhibition of Akt blocked the effect of pretreatment with TM on apoptosis induced by the drugs. Neither docetaxel nor vincristine triggered ER stress in melanoma cells, but the basal activity of XBP-1 signaling seemed to play a role in the protection against the drugs because small interfering RNA knockdown of XBP-1 enhanced docetaxel- and vincristine-induced apoptosis. In addition, inhibition of XBP-1 decreased the constitutive levels of activation of Akt and blocked the activation of Akt induced by TM. Taken together, these results identify activation of the PI3K/Akt pathway by XBP-1-mediated signaling of the unfolded protein response as a resistance mechanism against docetaxel and vincristine in melanoma cells under ER stress.

Watson AJ, Middleton MR, McGown G, Thorncroft M, Ranson M, Hersey P, McArthur G, Davis ID, Thomson D, Beith J, Haydon A, Kefford R, Lorigan P, Mortimer P, Sabharwal A, Hayward O, Margison GP. · Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK. · Br J Cancer. · Pubmed #19367283 No free full text.

Abstract: We evaluated the pharmacodynamic effects of the O(6)-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O(6)-methylguanine (O(6)-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O(6)-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O(6)-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O(6)-meG in PBMC DNA during treatment.

Zhuang L, Scolyer RA, Lee CS, McCarthy SW, Cooper WA, Zhang XD, Thompson JF, Hersey P. · Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Histopathology. · Pubmed #19309398 No free full text.

Abstract: AIMS: Glucose-regulated protein 78 (GRP78) is a protein translated in response to endoplasmic reticulum (ER) stress that has been implicated in the pathogenesis and resistance to therapy of a variety of cancers. The aim of this study was to investigate its expression and role in the development and progression of human melanoma. METHODS AND RESULTS: The immunohistochemical expression of GRP78 in naevi, primary melanoma and melanoma metastases from 171 patients was correlated with clinicopathological factors and patient survival. The GRP78 immunoreactivity score (IRS) was 0.2 in compound naevi, 0.65 in dysplastic naevi, 4.65 in naevi adjacent to primary melanoma, 2.4 in melanoma in situ, 11.2 in thin (</=1.0 mm) and 18.1 in thick (>1.0 mm) primary melanoma. It was 18 and 17.3 in subcutaneous and lymph node metastases, respectively (P < 0.0001). GRP78 expression was positively correlated with increasing tumour thickness (P = 0.001) and with increasing dermal tumour mitotic index (P = 0.0004). Disease-free survival (chi(2) = 8.0703, P = 0.0045) and overall survival (chi(2) = 6.2633, P = 0.0123) in melanoma patients with IRS >25 were significantly lower than in melanoma patients with IRS <25. CONCLUSIONS: GRP78 expression appears to correlate with known correlates of melanoma progression and survival and requires further evaluation as a prognostic biomarker in melanoma.

Mhaidat NM, Thorne R, Zhang XD, Hersey P. · Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan. · Apoptosis. · Pubmed #18989785 No free full text.

Abstract: Our previous studies revealed that Docetaxel-induced apoptosis of melanoma cells is entirely dependent on activation of the JNK signalling pathway. Here, we show that Docetaxel-induced apoptosis is mediated by induction of ER stress. This was shown by Docetaxel-induced activation of proteins involved in ER stress signalling namely GRP78, ATF6, IRE1alpha, and PERK/eIF2alpha. Knockdown of IRE1alpha by siRNA markedly inhibited Docetaxel-induced JNK activation and downstream targets of JNK indicating that activation of IRE1alpha was upstream of activation of the JNK. Co-immunoprecipitation experiments showed that activation of JNK is due to activation of ASK1 through formation of an IRE1alpha-TRAF2-ASK1 complex. ER stress mediated activation of the JNK pathway is downstream of activation of PKCdelta in that downregulation of PKCdelta expression using specific PKCdelta siRNA significantly inhibited Docetaxel-induced activation of IRE1alpha and the JNK pathway. These findings provide new insights to understand the mode of action of taxanes in treatment of human melanoma.

Jiang CC, Mao ZG, Avery-Kiejda KA, Wade M, Hersey P, Zhang XD. · Immunology and Oncology Unit, Newcastle Misericordiae Hospital, David Maddison Clinical Sciences Building, Newcastle, New South Wales, Australia. · Carcinogenesis. · Pubmed #18842681 No free full text.

Abstract: Resistance of melanoma cells to chemotherapeutics remains a major obstacle to successful treatment of melanoma once it has spread beyond locoregional sites. We report in this study that activation of the unfolded protein response (UPR) is involved in resistance of melanoma cells to two chemotherapeutic drugs, cisplatin (CDDP) and adriamycin, and this is associated with glucose-regulated protein 78 (GRP78)-mediated inhibition of activation of caspase-4 and -7. The UPR was constitutively activated in cultured melanoma cell lines and fresh melanoma isolates as evidenced by elevated expression levels of the GRP78 protein and the active form of x-box-binding protein 1 messenger RNA. Treatment with CDDP or adriamycin further increased the levels, indicative of induction of endoplasmic reticulum stress and activation of the UPR by the drugs. Inhibition of GRP78 by small-interference RNA (siRNA)-sensitized melanoma cells to CDDP- and adriamycin-induced apoptosis. This was associated with enhanced caspase-4 and -7 activation as siRNA knockdown of the caspases blocked induction of apoptosis. In contrast, overexpression of GRP78 attenuated activation of caspase-4 and -7 and induction of apoptosis by the drugs. CDDP- and adriamycin-induced activation of caspase-4 and -7 appeared to be mediated by calpain activity in that it was blocked by the calpain inhibitors calpeptin and PD150606 even when GRP78 was inhibited by siRNA. These results provide new insights into resistance mechanisms of melanoma cells to CDDP and adriamycin and identify GRP78 as a potential target for enhancing chemosensitivity in melanoma.