ABSTRACT
Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Lactones/therapeutic use , Melanoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/drug therapy , Aged, 80 and over , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Brain/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/secondary , Cell Line, Tumor , Female , Gene Expression Profiling , Humans , Lactones/blood , Lactones/pharmacokinetics , Male , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Mice, Knockout , Mutation , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Treatment Outcome , Exome SequencingABSTRACT
Specific clinical diagnostic criteria have established a consensus for defining patients with lumbar discogenic pain. However, if conservative medical management fails, these patients have few treatment options short of surgery involving discectomy often coupled with fusion or arthroplasty. There is a rapidly-emerging research effort to fill this treatment gap with intradiscal therapies that can be delivered minimally-invasively via fluoroscopically guided injection without altering the normal anatomy of the affected vertebral motion segment. Viable candidate products to date have included mesenchymal stromal cells, platelet-rich plasma, nucleus pulposus structural allograft, and other cell-based compositions. The objective of these products is to repair, supplement, and restore the damaged intervertebral disc as well as retard further degeneration. In doing so, the intervention is meant to eliminate the source of discogenic pain and avoid surgery. Methodologically rigorous studies are rare, however, and based on the best clinical evidence, the safety as well as the magnitude and duration of clinical efficacy remain difficult to estimate. Further, we summarize the US Food and Drug Administration's (FDA) guidance regarding the interpretation of the minimal manipulation and homologous use criteria, which is central to designating these products as a tissue or as a drug/device/biologic. We also provide perspectives on the core evidence and knowledge gaps associated with intradiscal therapies, propose imperatives for evaluating effectiveness of these treatments and highlight several new technologies on the horizon.
ABSTRACT
OBJECTIVE: Impairment of the thrombomodulin-protein C anticoagulant pathway has been implicated in pathological thrombosis associated with malignancy. Patients who receive proteasome inhibitors as part of their chemotherapeutic regimen appear to be at decreased risk for thromboembolic events. We investigated the effects of proteasome inhibitors on endothelial thrombomodulin expression and function. METHODS AND RESULTS: Proteasome inhibitors as a class markedly induced the expression of thrombomodulin and enhanced the protein C activating capacity of endothelial cells. Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. These effects were confirmed in vivo, where systemic administration of a proteasome inhibitor enhanced thrombomodulin expression that was paralleled by changes in the expression of KLF2 and KLF4. CONCLUSIONS: These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects.
Subject(s)
Boronic Acids/pharmacology , Endothelial Cells/drug effects , Kruppel-Like Transcription Factors/physiology , Protease Inhibitors/pharmacology , Proteasome Inhibitors , Pyrazines/pharmacology , Thrombomodulin/genetics , Animals , Bortezomib , Cells, Cultured , Endothelial Cells/metabolism , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/genetics , Male , Mice , Mice, Inbred C3H , NF-kappa B/antagonists & inhibitors , Protein C/physiology , Thrombomodulin/physiologyABSTRACT
PURPOSE: Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC. METHODS AND MATERIALS: Eligible patients received cisplatin once weekly at 30 mg/m(2) per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m(2) and escalation levels of 1.0 and 1.3 mg/m(2). Dose escalation was performed only after assessment to rule out any dose-limiting toxicity. RESULTS: We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m(2) (7 patients), 1.0 mg/m(2) (10 patients), and 1.3 mg/m(2) (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients). CONCLUSION: Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m(2) in patients previously treated for HNC and 1.3 mg/m(2) in radiation-naive patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/methods , Head and Neck Neoplasms/therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Chemoradiotherapy/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Pyrazines/administration & dosage , Pyrazines/adverse effects , Radiotherapy Dosage , TherapeuticsABSTRACT
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a recently described paraneoplastic syndrome with prominent neuropsychiatric symptoms. We report a case of NMDA receptor encephalitis in a 15-year-old female related to the development of NMDA receptor autoantibodies triggered by an ovarian teratoma. Removal of the mature teratoma proved curative with eventual resolution of the paraneoplastic disease process and associated psychiatric symptoms. Increasingly, reports of anti-NMDA receptor encephalitis associated with ovarian teratomas in pediatric patients, as well as a novel assay to measure these antibodies, suggest an etiology for this disease process that may be amenable to prompt surgical excision. The clinical presentation, diagnosis, and surgical management of the disease, as well as a review of the literature, are included.
Subject(s)
Autoimmune Diseases of the Nervous System/etiology , Encephalitis/etiology , Ovarian Neoplasms/etiology , Paraneoplastic Syndromes, Nervous System/etiology , Receptors, N-Methyl-D-Aspartate/immunology , Teratoma/etiology , Adolescent , Autoimmune Diseases of the Nervous System/diagnosis , Encephalitis/diagnosis , Female , Humans , Ovarian Neoplasms/diagnosis , Paraneoplastic Syndromes, Nervous System/diagnosis , Teratoma/diagnosisABSTRACT
PURPOSE: We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM). PATIENTS AND METHODS: A cycle of therapy consisted of bortezomib 1.3 mg/m(2) intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m(2) on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment. RESULTS: Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade < or = 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy. CONCLUSION: The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.