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Melanoma: HELP
Articles by Scott K. Pruitt
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, Scott Pruitt wrote the following 15 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline Melanoma, version 2.2013: featured updates to the NCCN guidelines. 2013

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Ho, Maria / Anonymous4400755. ·Memorial Sloan-Kettering Cancer Center. ·J Natl Compr Canc Netw · Pubmed #23584343.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

2 Guideline Melanoma. 2012

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dilawari, Raza A / Dimaio, Dominick / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / Anonymous590720. · ·J Natl Compr Canc Netw · Pubmed #22393197.

ABSTRACT: -- No abstract --

3 Review Sentinel node biopsy for head and neck melanoma: a systematic review. 2011

de Rosa, Nicole / Lyman, Gary H / Silbermins, Damian / Valsecchi, Matias E / Pruitt, Scott K / Tyler, Douglas M / Lee, Walter T. ·Duke University, Durham, NC, USA. ·Otolaryngol Head Neck Surg · Pubmed #21540313.

ABSTRACT: OBJECTIVE: This systematic review was conducted to examine the test performance of sentinel node biopsy in head and neck melanoma, including the identification rate and false-negative rate. DATA SOURCES: PubMed, EMBASE, ASCO, and SSO database searches were conducted to identify studies fulfilling the following inclusion criteria: sentinel node biopsy was performed, lesions were located on the head and neck, and recurrence data for both metastatic and nonmetastatic patients were reported. REVIEW METHODS: Dual-blind data extraction was conducted. Primary outcomes included identification rate and test performance based on completion neck dissection or nodal recurrence. RESULTS: A total of 3442 patients from 32 studies published between 1990 and 2009 were reviewed. Seventy-eight percent of studies were retrospective and 22% were prospective. Trials varied from 9 to 755 patients (median 55). Mean Breslow depth was 2.53 mm. Median sentinel node biopsy identification rate was 95.2%. More than 1 basin was reported in 33.1% of patients. A median of 2.56 sentinel nodes per patient were excised. Sentinel node biopsy was positive in 15% of patients. Subsequent completion neck dissection was performed in almost all of these patients and revealed additional positive nodes in 13.67%. Median follow-up was 31 months. Across all studies, predictive value positive for nodal recurrence was 13.1% and posttest probability negative was 5%. Median false-negative rate for nodal recurrence was 20.4%. CONCLUSION: Sentinel node biopsy of head and neck melanoma is associated with an increased false-negative rate compared with studies of non-head and neck lesions. Positive sentinel node status is highly predictive of recurrence.

4 Clinical Trial Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. 2013

Dannull, Jens / Haley, N Rebecca / Archer, Gary / Nair, Smita / Boczkowski, David / Harper, Mark / De Rosa, Nicole / Pickett, Nancy / Mosca, Paul J / Burchette, James / Selim, Maria A / Mitchell, Duane A / Sampson, John / Tyler, Douglas S / Pruitt, Scott K. ·Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA. ·J Clin Invest · Pubmed #23934126.

ABSTRACT: BACKGROUND: Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. METHODS: Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). RESULTS: Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2⁺ subjects, CD8⁺ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. CONCLUSION: These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00672542. FUNDING: Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery.

5 Clinical Trial Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. 2011

Pruitt, Scott K / Boczkowski, David / de Rosa, Nicole / Haley, N Rebecca / Morse, Michael A / Tyler, Douglas S / Dannull, Jens / Nair, Smita. ·Durham VA Medical Center, Durham, NC, USA. scott.pruitt@duke.edu ·Eur J Immunol · Pubmed #22028176.

ABSTRACT: Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.

6 Clinical Trial Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution. 2011

Raymond, Amanda K / Beasley, Georgia M / Broadwater, Gloria / Augustine, Christina K / Padussis, James C / Turley, Ryan / Peterson, Bercedis / Seigler, Hilliard / Pruitt, Scott K / Tyler, Douglas S. ·Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. ·J Am Coll Surg · Pubmed #21493111.

ABSTRACT: BACKGROUND: Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used to manage advanced extremity melanoma, but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. STUDY DESIGN: Using a prospectively maintained database, we reviewed our experience with melphalan-based HILP (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter. RESULTS: Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73-87%), and overall response rate from ILI was 43% (80% CI, 37-49%) for first-time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, and ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR after repeat HILP (50%, n = 10) compared with repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2 of 62) than ILI (0 of 122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25 of 49; 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. CONCLUSIONS: In the largest single-institution regional therapy series reported to date, we found that although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

7 Article Gene Expression Profile of Dendritic Cell-Tumor Cell Hybrids Determined by Microarrays and Its Implications for Cancer Immunotherapy. 2015

Dannull, Jens / Tan, Chunrui / Farrell, Christine / Wang, Cynthia / Pruitt, Scott / Nair, Smita K / Lee, Walter T. ·Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. · Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, NC 27710, USA. · Duke University, Durham, NC 27710, USA. · Duke University School of Medicine, Durham, NC 27710, USA. · Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA ; Division of Experimental Medicine, Merck, Rahway, NJ 07065, USA. · Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, NC 27710, USA ; Duke University School of Medicine, Durham, NC 27710, USA ; Durham VA Medical Center, Section of Otolaryngology-Head and Neck Surgery, Durham, NC 27705, USA. ·J Immunol Res · Pubmed #26605345.

ABSTRACT: BACKGROUND: Dendritic cell- (DC-) tumor fusion cells stimulate effective in vivo antitumor responses. However, therapeutic approaches are dependent upon the coadministration of exogenous 3rd signals. The purpose of this study was to determine the mechanisms for inadequate 3rd signaling by electrofused DC-tumor cell hybrids. METHODS: Murine melanoma cells were fused with DCs derived from C57BL/6 mice. Quantitative real-time PCR (qPCR) was used to determine relative changes in Th (T helper) 1 and Th2 cytokine gene expression. In addition, changes in gene expression of fusion cells were determined by microarray. Last, cytokine secretion by fusion cells upon inhibition of signaling pathways was analyzed by ELISA. RESULTS: qPCR analyses revealed that fusion cells exhibited a downregulation of Th1 associated cytokines IL-12 and IL-15 and an upregulation of the Th2 cytokine IL-4. Microarray studies further showed that the expression of chemokines, costimulatory molecules, and matrix-metalloproteinases was deregulated in fusion cells. Lastly, inhibitor studies demonstrate that inhibition of the PI3K/Akt/mTOR signaling pathway could restore the secretion of bioactive IL-12p70 by fusion cells. CONCLUSION: Our results suggest that combining fusion cell-based vaccination with administration of inhibitors of the PI3K/Akt/mTOR signaling pathway may enhance antitumor responses in patients.

8 Article Whole blood cells loaded with messenger RNA as an anti-tumor vaccine. 2014

Phua, Kyle K L / Boczkowski, David / Dannull, Jens / Pruitt, Scott / Leong, Kam W / Nair, Smita K. ·Department of Chemical & Biomolecular Engineering, National University of Singapore, Singapore, 117576; Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. ·Adv Healthc Mater · Pubmed #24339387.

ABSTRACT: The use of a cell-based vaccine composed of autologous whole blood cells loaded with mRNA is described. Mice immunized with whole blood cells loaded with mRNA encoding antigen develop anti-tumor immunity comparable to DC-RNA immunization. This approach offers a simple and affordable alternative to RNA-based cellular therapy by circumventing complex, laborious and expensive ex vivo manipulations required for DC-based immunizations.

9 Article Local secretion of IL-12 augments the therapeutic impact of dendritic cell-tumor cell fusion vaccination. 2013

Tan, Chunrui / Dannull, Jens / Nair, Smita K / Ding, Enyu / Tyler, Douglas S / Pruitt, Scott K / Lee, Walter T. ·Division of Otolaryngology, Duke University Medical Center, Durham, North Carolina. ·J Surg Res · Pubmed #23891424.

ABSTRACT: BACKGROUND: The development of dendritic cell (DC)-tumor fusion vaccines is a promising approach in cancer immunotherapy. Using fusion vaccines allows a broad spectrum of known and unidentified tumor-associated antigens to be presented in the context of MHC class I and class II molecules, with potent co-stimulation provided by the DCs. Although DC-tumor fusion cells are immunogenic, murine studies have shown that effective immunotherapy requires a third signal, which can be provided by exogenous interleukin 12 (IL-12). Unfortunately, systemic administration of IL-12 induces severe toxicity in cancer patients, potentially precluding clinical use of this cytokine to augment fusion vaccine efficacy. To overcome this limitation, we developed a novel approach in which DC-tumor fusion cells locally secrete IL-12, then evaluated the effectiveness of this approach in a murine B16 melanoma model. MATERIALS AND METHODS: Tumor cells were stably transduced to secrete murine IL-12p70. These tumor cells were then electrofused to DC to form DC-tumor heterokaryons. These cells were used to treat established B16 pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon rank sum test. Interferon γ enzyme-linked immunosorbent spot assay was performed on splenocytes from treated mice. RESULTS: We show that vaccination with DCs fused to syngeneic melanoma cells that stably express murine IL-12p70 significantly reduces counts of established lung metastases in treated animals when compared with DC-tumor alone (P = 0.029). Interferon γ enzyme-linked immunosorbent spot assays suggest that this antitumor response is mediated by CD4(+) T cells, in the absence of a tumor-specific CD8(+) T cell response, and that the concomitant induction of antitumor CD4(+) and CD8(+) T cell responses required exogenous IL-12. CONCLUSIONS: This study is, to the best of our knowledge, the first report that investigates the impact of local secretion of IL-12 on antitumor immunity induced by a DC-tumor fusion cell vaccine in a melanoma model and may aid the rational design of future clinical trials.

10 Article Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model. 2013

Tan, Chunrui / Reddy, Varun / Dannull, Jens / Ding, Enyu / Nair, Smita K / Tyler, Douglas S / Pruitt, Scott K / Lee, Walter T. ·Division of Otolaryngology, Duke University Medical Center, Durham, NC, USA. ·J Transl Med · Pubmed #23768240.

ABSTRACT: BACKGROUND: A promising cancer vaccine involves the fusion of tumor cells with dendritic cells (DCs). As such, a broad spectrum of both known and unidentified tumor antigens is presented to the immune system in the context of the potent immunostimulatory capacity of DCs. Murine studies have demonstrated the efficacy of fusion immunotherapy. However the clinical impact of DC/tumor fusion vaccines has been limited, suggesting that the immunosuppresive milieu found in patients with malignancies may blunt the efficacy of cancer vaccination. Thus, novel strategies to enhance fusion vaccine efficacy are needed. Regulatory T cells (Tregs) are known to suppress anti-tumor immunity, and depletion or functional inactivation of these cells improves immunotherapy in both animal models and clinical trials. In this study, we sought to investigate whether functional inactivation of CD4+CD25+FoxP3+ Treg with anti-CD25 monoclonal antibody (mAb) PC61 prior to DC/tumor vaccination would significantly improve immunotherapy in the murine B16 melanoma model. METHODS: Treg blockade was achieved with systemic PC61 administration. This blockage was done in conjunction with DC/tumor fusion vaccine administration to treat established melanoma pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon Rank Sum Test. IFN-gamma ELISPOT assay was performed on splenocytes from treated mice. RESULTS: We demonstrate that treatment of mice with established disease using mAb PC61 and DC/tumor fusion significantly reduced counts of pulmonary metastases compared to treatment with PC61 alone (p=0.002) or treatment with control antibody plus fusion vaccine (p=0.0397). Furthermore, IFN-gamma ELISPOT analyses reveal that the increase in cancer immunity was mediated by anti-tumor specific CD4+ T-helper cells, without concomitant induction of CD8+ cytotoxic T cells. Lastly, our data provide proof of principle that combination treatment with mAb PC61 and systemic IL-12 can lower the dose of IL-12 necessary to obtain maximal therapeutic efficacy. CONCLUSIONS: To our knowledge, this is the first report investigating the effects of anti-CD25 mAb administration on DC/tumor-fusion vaccine efficacy in a murine melanoma model, and our results may aide the design of future clinical trials with enhanced therapeutic impact.

11 Article Hazard-rate analysis and patterns of recurrence in early stage melanoma: moving towards a rationally designed surveillance strategy. 2013

Salama, April K S / de Rosa, Nicole / Scheri, Randall P / Pruitt, Scott K / Herndon, James E / Marcello, Jennifer / Tyler, Douglas S / Abernethy, Amy P. ·Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. ·PLoS One · Pubmed #23516415.

ABSTRACT: BACKGROUND: While curable at early stages, few treatment options exist for advanced melanoma. Currently, no consensus exists regarding the optimal surveillance strategy for patients after resection. The objectives of this study were to identify patterns of metastatic recurrence, to determine the influence of metastatic site on survival, and to identify high-risk periods for recurrence. METHODS: A retrospective review of the Duke Melanoma Database from 1970 to 2004 was conducted that focused on patients who were initially diagnosed without metastatic disease. The time to first recurrence was computed from the date of diagnosis, and the associated hazard function was examined to determine the peak risk period of recurrence. Metastatic sites were coded by the American Joint Committee on Cancer (AJCC) system including local skin, distant skin and nodes (M1a), lung (M1b), and other distant (M1c). RESULTS: Of 11,615 patients initially diagnosed without metastatic disease, 4616 (40%) had at least one recurrence. Overall the risk of initial recurrence peaked at 12 months. The risk of initial recurrence at the local skin, distant skin, and nodes peaked at 8 months, and the risk at lung and other distant sites peaked at 24 months. Patients with a cutaneous or nodal recurrence had improved survival compared to other recurrence types. CONCLUSIONS: The risk of developing recurrent melanoma peaked at one year, and the site of first recurrence had a significant impact on survival. Defining the timing and expected patterns of recurrence will be important in creating an optimized surveillance strategy for this patient population.

12 Article Plasma cytokine analysis in patients with advanced extremity melanoma undergoing isolated limb infusion. 2013

Shetty, Gina / Beasley, Georgia M / Sparks, Sara / Barfield, Michael / Masoud, Melanie / Mosca, Paul J / Pruitt, Scott K / Salama, April K S / Chan, Cliburn / Tyler, Douglas S / Weinhold, Kent J. ·Department of Immunology, Duke University, Durham, NC, USA. ·Ann Surg Oncol · Pubmed #23456379.

ABSTRACT: BACKGROUND: Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma. METHODS: Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated. RESULTS: Of 180 ILIs performed, 28 % (95 % confidence interval 22-35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients. CONCLUSIONS: Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.

13 Article The effect of metastatic site and decade of diagnosis on the individual burden of metastatic melanoma: contemporary estimates of average years of life lost. 2012

Salama, April K S / Rosa, Nicole de / Scheri, Randall P / Herndon, James E / Tyler, Douglas S / Marcello, Jennifer / Pruitt, Scott K / Abernethy, Amy P. ·Duke Comprehensive Cancer Center, Duke University Medical Center (DUMC), Durham, North Carolina 27710, USA. ·Cancer Invest · Pubmed #23020583.

ABSTRACT: OBJECTIVES: Metastatic melanoma (MM) is a leading cause of years of life lost due to malignancy. This study aimed to identify the average years of life lost (AYLL) in MM patients. METHODS: MM patients were identified from a prospectively maintained database, and a linear model predicting AYLL was developed. RESULTS: Between 1970 and 1999, 4,774 patients diagnosed with MM died. The AYLL was 23.2 years. AYLL remained stable across three decades. CONCLUSIONS: AYLL for MM is greater than 20 years, and has not improved. This burden underscores the need for continued research and access to funding for this disease.

14 Article Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. 2010

Augustine, Christina K / Toshimitsu, Hiroaki / Jung, Sin-Ho / Zipfel, Patricia A / Yoo, Jin S / Yoshimoto, Yasunori / Selim, M Angelica / Burchette, James / Beasley, Georgia M / McMahon, Nicole / Padussis, James / Pruitt, Scott K / Ali-Osman, Francis / Tyler, Douglas S. ·Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA. Christi.augustine@duke.edu ·Mol Cancer Ther · Pubmed #20571072.

ABSTRACT: Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

15 Article Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma. 2010

Toshimitsu, Hiroaki / Yoshimoto, Yasunori / Augustine, Christina K / Padussis, James C / Yoo, Jin S / Angelica Selim, M / Pruitt, Scott K / Friedman, Henry S / Ali-Osman, Francis / Tyler, Douglas S. ·Department of Surgery, Duke University Medical Center, Durham, NC, USA. ·Ann Surg Oncol · Pubmed #20182810.

ABSTRACT: BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. MATERIALS AND METHODS: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. RESULTS: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P < .04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. CONCLUSION: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.