Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond.

Importance Of The Field: Recent discoveries have expanded the understanding of the molecular signaling events critical to melanomagenesis and led to the development of targeted therapeutic agents that are revolutionizing the treatment of patients with advanced melanoma.

Areas Covered In This Review: This article reviews current therapy and its limitations, describes the key pathogenic mechanisms in melanoma for which inhibitors have been tested, and summarizes the results of clinical trials involving molecularly targeted agents in this disease.

What The Reader Will Gain: There has been an explosion of preclinical and clinical research aimed at targeting the key molecular alterations in melanoma for therapeutic benefit.

The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma.

Purpose: Inhibitors of TORC1 have been shown to be active in patients with metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth and survival besides mammalian target of rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more effective than inhibition of TORC1 alone.

Experimental Design: To investigate this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells.

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma.

Objective: To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib.

Patients And Methods: We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables.

Serial monitoring of circulating tumor cells predicts outcome of induction biochemotherapy plus maintenance biotherapy for metastatic melanoma.

Purpose: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT).

Experimental Design: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma.

A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma.

Allovectin-7, a bicistronic plasmid encoding human leukocyte antigen-B7 and beta-2 microglobulin formulated with a cationic lipid system, is an immunotherapeutic agent designed to express allogeneic major histocompatibility complex class I antigen upon intralesional administration. A phase 2 dose-escalation study (VCL-1005-208) was conducted to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy, an Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function.

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy.

Objective: To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy.

Patients And Methods: We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage.

Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery.

Purpose: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma.

Patients And Methods: This was a two-stage phase II trial design.

A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma.

Background: : Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX-2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression.

Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma.

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.

Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases.

PURPOSE: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients. EXPERIMENTAL DESIGN: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.

Targeted therapies: sunitinib in RCC-expanded access equals expanded benefit?

Sunitinib is a standard first-line therapy for patients with advanced or metastatic clear-cell renal cell carcinoma. in an expanded-access study, sunitinib has demonstrated clinical benefit with an acceptable safety profile in a population of patients that is representative of those seen in clinical practice.

Phase II multicenter trial of maintenance biotherapy after induction concurrent Biochemotherapy for patients with metastatic melanoma.

Purpose: Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival.

Patients And Methods: One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers.

Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.

Purpose: There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy.

Methods: Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS.

Resistance to targeted therapy in renal-cell carcinoma.

Therapeutic targeting of integral biological pathways, including those involving vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), has produced robust clinical effects and revolutionised the treatment of metastatic renal-cell carcinoma (RCC). However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. As such, the biological basis for resistance to these targeted therapies and the clinical approach in this setting is of heightened interest.

Rapid development of hypertension by sorafenib: toxicity or target?

Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing. Blood pressure rises on the first day of treatment, facilitating design and interpretation of future trials aiming to correlate blood pressure changes with clinical outcomes.

Results of a multicenter, randomized, double-blind, dose-evaluating phase 2/3 study of lenalidomide in the treatment of metastatic malignant melanoma.

Background: There are currently no systemic treatments for stage IV melanoma, which have been proven in randomized trials to benefit overall survival (OS). Lenalidomide has efficacy against melanoma in animal models and safety in phase 1 trials. The authors reported the results of a phase 2/3 study comparing the safety and efficacy of 2 doses of lenalidomide in patients with relapsed metastatic melanoma disease refractory to previous treatment with dacarbazine, temozolomide, interleukin-2, or interferon-alpha.

Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.

Background: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.

Methods: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle).

Refining indications for contemporary surgical treatment of renal cell carcinoma metastatic to the pancreas.

Background: The pancreas is a rare location for metastatic disease, with only 2-11% of all pancreatic tumours being of non-primary origin. It is also uncommon for renal cell carcinoma (RCC) to metastasize to the pancreas (1-3% of cases) and, when it does, it typically occurs substantially after index nephrectomy. It is not known whether all pancreatic metastases need be resected because today's chemo- and biological therapies are increasingly effective in controlling advanced disease.

Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model?

Purpose: To determine whether arterial spin-labeling (ASL) magnetic resonance (MR) imaging findings at baseline and early during antiangiogenic therapy can predict later resistance to therapy.

Materials And Methods: Protocol was approved by an institutional animal care and use committee. Caki-1, A498, and 786-0 human renal cell carcinoma (RCC) xenografts were implanted in 39 nude mice.

Molecular-targeted therapy in malignant melanoma.

Malignant melanoma is a deadly disease in which standard treatment options have remained remarkably static over the past 30 years. Recent discoveries have expanded the understanding of the molecular processes critical to melanomagenesis. During this same time period, therapeutic agents have been developed that target these processes, leading to an explosion of preclinical research.

Treatment selection for patients with metastatic renal cell carcinoma.

The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin-2 (IL-2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group.

Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference.

The Third Cambridge Conference on Innovations and Challenges in Renal Cancer, a symposium held in Cambridge, Massachusetts, June 27-28, 2008, and chaired by Michael B. Atkins, was convened to discuss the current state of knowledge in the field, critique new data, stimulate communication among those involved in basic and clinical research, and offer recommendations for further study. Four main topics were discussed: genetics and molecular biology of renal cell cancer, staging and prognosis, systemic therapy, and correlative science and biomarkers in stage IV disease.