PubMed Health⌕ Search

Biomedical subjects

Michael B Atkins

Publications and source records attributed to Michael B Atkins.

At least 19 recordsLinked to original sources
PubMed2007

Update on therapy for melanoma: opportunities for patient selection and overcoming tumor resistance.

The incidence of malignant melanoma is rising faster than any other malignancy. Although earlier stage patients can be cured with surgical resection with or without adjuvant therapy, a significant number of patients go on to develop disseminated disease. Currently, limited therapeutic options exist for patients with metastatic melanoma. Recent studies suggest that patient selection is feasible and may enable the restriction of treatment to those most likely to benefit. Additionally, several potential mechanisms of tumor resistance have been identified creating opportunities for circumventing them. This article will review current strategies for patient selection and overcoming therapeutic resistance. These strategies hold the promise of extending the clinical benefits of current therapies as well as facilitating the development of additional and more active treatments.

Antineoplastic Agents↗
PubMed2006

Treatment of patients with metastatic renal cell cancer: a RAND Appropriateness Panel.

BACKGROUND: New developments in the treatment of patients with metastatic renal cell cancer (MRCC) have suggested a need to reevaluate the role of systemic therapies. The authors convened a panel of medical and urologic oncologists to rate the appropriateness of the main options. METHODS: The authors used the RAND/University of California-Los Angeles Appropriateness Method to evaluate systemic therapy options and cytoreductive nephrectomy. After a comprehensive literature review, an expert panel rated the appropriateness of systemic options (108 permutations) and cytoreductive nephrectomy (24 permutations) for patients with MRCC. RESULTS: The appropriateness evaluation indicated that 27.3% of permutations were rated "appropriate," 46.9% were rated "inappropriate," and 25.8% were rated "uncertain." There was a high rate of agreement (95%). Sunitinib and sorafenib were rated appropriate for patients with low-to-moderate risk regardless of prior treatment. Temsirolimus was rated appropriate for first-line therapy for higher risk patients. Interferon-alpha and low-dose interleukin-2 were rated inappropriate or uncertain. In patients who received prior immunotherapy, cytokines were rated inappropriate. In all permutations for evaluating systemic therapy, enrollment into an investigational trial was considered appropriate, treatment with bevacizumab was uncertain, and thalidomide was inappropriate regardless of risk status or prior therapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate in patients who had limited metastatic burden regardless of tumor-related symptoms and in symptomatic patients regardless of metastatic burden. Only the most favorable combination of surgical risk, metastatic burden, and symptoms generated an "appropriate" rating for patients with planned targeted therapy. CONCLUSIONS: The current results begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of MRCC.

Carcinoma, Renal Cell↗
PubMed2006

Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy.

BACKGROUND: Systemic treatment of metastatic melanoma is largely ineffective and alternative approaches are needed. Imatinib mesylate is an oral tyrosine kinase inhibitor that targets bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta, leading to remarkable clinical responses in several cancers. Signal transduction via c-kit, PDGFR-alpha, and PDGFR-beta has been demonstrated in malignant melanoma. METHODS: The primary objective of this Phase II study was to determine the response rate, response duration, and the frequency of 6-month progression-free survival in patients who could receive up to 2 prior therapeutic regimens. Initially, patients received imatinib at at dose of 400 mg twice orally each day. Based on Simon's optimal design, the study allowed entry of 21 patients; if there were > or = 2 objective responses, accrual would then continue to a total of 41 patients. RESULTS: Twenty-six patients were enrolled. Patients experienced 29 episodes of Grade 3 and 2 episodes of Grade 4 toxicity (according to National Cancer Institute common toxicity criteria). No objective clinical responses were noted among the 25 evaluable patients. The median time to progression was 54 days and the median overall survival was 200 days. No patient was free of disease progression at 6 months. Paraffin-embedded tumor specimens from 15 patients were tested for expression of imatinib responsive kinases by immunohistochemistry. Three tumors had moderate and 5 tumors had weak staining for c-kit. Five tumor samples had weak staining for PDGFR-alpha and -beta. CONCLUSIONS: Imatinib is an inactive single agent in metastatic melanoma in a population of predominantely pretreated patients. The levels of c-kit and/or PDGFR-alpha, -beta expression in the current study were lower than previously reported. Alternative treatment strategies remain a priority for patients with advanced melanoma.

Adult↗
PubMed2006

Cytokine-based therapy and biochemotherapy for advanced melanoma.

A variety of immunotherapeutic approaches have shown activity in patients with metastatic melanoma with the best results being observed with interleukin 2 (IL-2). Follow-up data through 2004 confirm the durability of responses produced by the Food and Drug Administration-approved high-dose IL-2 regimen in this patient population. Efforts to develop more tolerable and/or effective IL-2-based treatment regimens by either prolonged administration of lower doses or the combination of IL-2 with other cytokines, monoclonal antibodies, or vaccines have yet to produce results superior to those seen with high-dose IL-2 alone. Recent investigations have suggested that, in some patients, IL-2 may expand regulatory T-cell populations leading to immune tolerance rather than antitumor immunity. Efforts to shift this balance in favor of immune rejection by reducing the confounding effects of regulatory T cells on IL-2 therapy or the use of novel and potentially more purely immunostimulatory cytokines are ongoing. Despite promising phase 2 data, phase 3 studies have failed to show meaningful clinical benefit for the combination of cytokines with cytotoxic chemotherapy, so-called "biochemotherapy." Nonetheless, recent investigations with biochemotherapy followed by maintenance immunotherapy suggest that biochemotherapy may still have a role as a "bridge to immunotherapy" in some patients with rapidly progressive disease. Given the low number of patients achieving durable benefit with cytokine-based immunotherapy, considerable recent effort has focused on identifying predictors of therapeutic response. Investigations suggest that immune responsiveness may be predetermined by a tumor microenvironment conducive to immune recognition and the host propensity to develop autoimmunity. Efforts to understand and further define pretreatment predictors of response through the use of gene expression and proteomic techniques are ongoing and raise the potential for eventually limiting cytokine-based immunotherapy to those most likely to benefit.

Animals↗
PubMed2006

Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma.

The mitogen-activated protein kinase (MAPK; i.e., Ras-Raf-Erk) pathway is an attractive target for therapeutic intervention in melanoma due to its integral role in the regulation of proliferation, invasiveness, and survival and the recent availability of pharmaceutical agents that inhibit the various kinases and GTPases that comprise the pathway. Genetic studies have identified activating mutations in either B-raf or N-ras in most cutaneous melanomas. Other studies have delineated the contribution of autocrine growth factors (e.g., hepatocyte growth factor and fibroblast growth factor) to MAPK activation in melanoma. Still, others have emphasized the consequences of the down-modulation of endogenous raf inhibitors, such as Sprouty family members (e.g., SPRY2) and raf-1 kinase inhibitory protein, in the regulation of the pathway. The diversity of molecular mechanisms used by melanoma cells to ensure the activity of the MAPK pathway attests to its importance in the evolution of the disease and the likelihood that inhibitors of the pathway may prove to be highly effective in melanoma treatment. MAPK inhibition has been shown to result in the dephosphorylation of the proapoptotic Bcl-2 family members Bad and Bim. This process in turn leads to caspase activation and, ultimately, the demise of melanoma cells through the induction of apoptosis. Several recent studies have identified non-mitogen-activated protein/extracellular signal-regulated kinase kinase-binding partners of raf and suggested that the prosurvival effects of raf and the lethality of raf inhibition are mediated through these alternative targets, independent of the MAPK pathway. Other studies have suggested that endothelial cells are the primary targets of raf inhibitors in vivo and that the antitumor effect of these agents are largely attributable to angiogenesis inhibition. This article reviews the genetic and biochemical factors contributing to MAPK activation in melanoma, the mechanisms by which inhibition of the pathway might prove deleterious to tumor cells, and the potential of MAPK inhibitors in the treatment of the disease.

Animals↗
PubMed2006

Innovations and challenges in melanoma: summary statement from the first Cambridge conference.

Innovations and Challenges in Melanoma, chaired by Michael Atkins and cochaired by Ulrich Keilholz, John Kirkwood, and Jeffrey Sosman, was held July 15 to 16, 2005, in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, surgical oncology, anatomic pathology, dermatology, and immunotherapy who wished to advance the field of melanoma treatment by exchanging information and perspectives regarding recent advances and recommendations for further study. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on how genetics, biology, and data information can enhance our understanding of melanoma biology and help inform the use of therapies for this disease.

Humans↗
PubMed2006

The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells.

Mitogen-activated protein kinase (MAPK) is activated in the majority of melanomas, and its activity is essential for cell survival. In this report, we examined the effects of a novel raf inhibitor BAY 43-9006 on melanoma cell viability and intracellular signaling and found that it induces apoptosis through a caspase-independent mechanism. At concentrations that suppress extracellular signal-regulated kinase (ERK) phosphorylation, BAY 43-9006 dephosphorylates Bad on Ser(75) and Ser(99), activates Bak and Bax, and reduces the mitochondrial transmembrane potential. BAY 43-9006 (sorafenib) down-modulates the levels of Bcl-2 and Bcl-X(L) in a MAPK-independent manner in A2058 and SKMEL5 melanoma cells but not in the more resistant A375 cells. Of the three lines tested, only A375 cells were rescued from BAY 43-9006-induced apoptosis by knocking down Bad. BAY 43-9006 induced poly(ADP-ribose) polymerase cleavage and the mitochondrial release of cytochrome c and SMAC. However, the pan-caspase inhibitor Z-VAD-fmk had only a modest protective effect against the drug, suggesting that BAY 43-9006-induced apoptosis is largely caspase independent. BAY 43-9006 but not the MAP/ERK kinase inhibitors PD98059 or U0126 induced the nuclear translocation of apoptosis-inducing factor (AIF) in A2058 and SKMEL5 cells, and the introduction of a small interfering RNA (siRNA) for AIF partially protected these cells from BAY 43-9006-induced apoptosis. The AIF siRNA had little effect in A375 cells, in which drug-induced AIF release was negligible. These data indicate that in sensitive cell lines, BAY 43-9006-induced apoptosis is independent of Bad dephosphorylation and caspase activation and largely mediated through the nuclear translocation of AIF.

Apoptosis↗
PubMed2006

Interleukin-2 therapy of metastatic renal cell carcinoma--predictors of response.

For the past 15 years, immunoreactive cytokines have been the mainstay of treatment for metastatic renal cancer. High-dose bolus interleukin-2 (IL-2) was granted US Food and Drug Administration (FDA) approval in 1992 based on its ability to produce durable complete responses (CRs) in a small number of patients. Unfortunately, the toxicity, expense, and restricted accessibility of high-dose IL-2 make it a poor standard therapy. Regimens involving lower doses of IL-2 either alone or in combination with interferon (IFN) have generally produced fewer tumor regressions and these regressions were of less overall quality. Recent efforts have focused on trying to identify factors predictive of response to IL-2 therapy so that this treatment can be limited to those most likely to benefit. This year, investigators will launch a clinical trial designed to prospectively determine if patients who are more likely to respond to high-dose IL-2 can be identified prior to starting therapy.

Antineoplastic Agents↗
PubMed2006

Interleukin-2 therapy of metastatic renal cell carcinoma: update of phase III trials.

High-dose bolus interleukin-2 (IL-2) was granted Food and Drug Administration approval for the treatment of metastatic renal cell carcinoma based on its ability to produce durable responses in a small number of patients. Results from randomized phase III trials suggest that regimens involving lower doses of IL-2 alone or in combination with interferon produce fewer tumor regressions of decreased overall quality. Because of the toxicity and limited efficacy of this treatment, recent studies have focused on identifying predictors of response (or resistance) to IL-2 therapy. This year, investigators will launch a clinical trial designed to prospectively determine whether patients who are more likely to respond to high-dose IL-2 can be identified before therapy is initiated.

Antineoplastic Agents↗
PubMed2005

Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion.

Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3zeta chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14-, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14- myeloid suppressor cells reestablished T cell proliferation and CD3zeta chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.

Arginase↗
PubMed2005

Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.

PURPOSE: The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Adult↗
PubMed2005

Chemotherapies and immunotherapies for metastatic kidney cancer.

Most patients who develop kidney cancer are effectively treated with a radical nephrectomy; however, for those patients who present with or develop metastatic disease, the therapeutic options are limited. Interferon and interleukin-2 remain the standard therapies. Several studies have identified the optimal doses and schedules of these cytokines and groups of patients most likely to benefit from immunotherapy. Although cytotoxic chemotherapy continues to have a minor role in patients with clear cell renal carcinoma, it may become the treatment of choice for some patients with variant renal cancers. Novel agents targeting the vascular endothelial growth factor, its receptor, and other hypoxia-induced proteins are showing great promise and soon may expand the therapeutic options for patients with advanced kidney cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma.

Immunoreactive cytokines have been the mainstay of treatment of renal cancer for the past 15 years. Most research has focused on interferon alpha (IFN-alpha) and interleukin 2 (IL-2). IFN-alpha has been shown in Phase III studies to produce a modest survival advantage over inactive or non-IFN-containing regimens. Its general tolerability, multiple proposed mechanisms of action, and familiarity have prompted IFN-alpha to be studied in combination with a variety of agents with potential activity against renal cell carcinoma. These various studies may justify an increased role for IFN-alpha in the treatment of renal cancer in the foreseeable future. High-dose bolus IL-2 remains the only treatment for stage IV renal cancer approved by the United States Food and Drug Administration. Food and Drug Administration approval was granted in 1992 based on the ability of this agent to produce durable complete responses in a small number of patients. Unfortunately, the toxicity, expense, and restricted accessibility of high-dose IL-2 make it a poor standard. Regimens involving lower doses of IL-2 either alone or in combination with IFN-alpha have generally produced fewer tumor regressions of less overall quality. Recent efforts have focused on trying to identify factors predictive of response to IL-2 therapy so that this treatment could be limited to those most likely to benefit.

Carcinoma, Renal Cell↗
PubMed2004

Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.

PURPOSE: To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics. RESULTS: CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar. CONCLUSION: In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

Aged↗