The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 ...pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1-S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16(INK4A)) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become "addicted" to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma.
The combination of inhibitors to BRAF and MEK improved response rates and progression-free survival among patients with metastatic melanoma. Some toxicity was increased, but the incidence of second ...skin cancers was drastically reduced by the combination therapy.
Approximately 50% of metastatic cutaneous melanomas harbor a
BRAF
V600 mutation, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.
1
,
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These discoveries led to the development of agents that specifically target this driver mutation. The BRAF inhibitor vemurafenib (Zelboraf, Genentech) was approved worldwide on the basis of results from a phase 3 trial showing improved progression-free survival and overall survival, as compared with chemotherapy alone; the relative reduction in the risk of death was 63% and in the risk of disease progression was 74%.
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Similar results were also reported for another BRAF inhibitor, dabrafenib,
4
which has also . . .
Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor of low malignant grade characterized by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical ...excision. Wide surgical resection is generally accepted as optimal treatment for DFSP. However, despite optimal surgical management, distant metastases may develop in up to 5% of patients. More than 90% of DFSP are characterized by a reciprocal chromosomal translocation, t(17;22). This rearrangement leads to constitutive activation of the platelet-derived growth factor receptor (PDGFR) as a result of deregulated ligand expression, thus providing a rationale for targeted inhibition of PDGFR as a treatment strategy for patients with unresectable locally advanced or metastatic DFSP.
This article reviews the current understanding of DFSP, with emphasis on molecular-level pathogenetic events and their implications for management, and evidence for the role of tyrosine kinase inhibition in improving the outcomes of patients with unresectable locally advanced or metastatic DFSP.
Surgery with wide margins remains the cornerstone in the management of DFSP. Recently, imatinib, a potent, selective inhibitor of the PDGFR alpha and PDGFR beta protein-tyrosine kinases, has been reported to induce complete or partial remissions in most patients treated for advanced DFSP.
Imatinib is approved for treatment of adult patients with unresectable, recurrent, and/or metastatic DFSP who are not eligible for surgery. Future investigations will determine whether imatinib can also be used in the neoadjuvant setting to reduce tumor volume, thereby allowing resection of very large DFSP that would otherwise not be resectable.
Melanoma is one of the most common cancers in Western countries but has defied the trend of reductions in age-adjusted mortality observed in most other cancers in recent years. Biologically, melanoma ...is characterized by a high propensity to metastasize at low tumor volumes necessitating the need for effective drug therapies to support efforts in prevention and early detection for reducing mortality. Efforts to study the clinical biology of melanoma have led to a new understanding of the disease, with genomic studies identifying several targetable oncogenes, in particular the protein kinases BRAF and KIT. Biologic studies have also identified a variety of immunologic targets, including the programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitory molecules expressed on T lymphocytes. After several decades of clinical trials that failed to demonstrate improvement in overall survival in patients with advanced melanoma, small molecule inhibitors of BRAF or MEK and inhibition of CTLA-4 can improve survival in patients with advanced disease. These early clinical studies have provided a great opportunity to improve mortality in melanoma with the significant potential of combinations of signaling inhibitors or signaling inhibitors combined with immunologic agents, particularly when used in the adjuvant setting, and to transform the care of patients with this most challenging of cancers.
Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that ...rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
► Hematologic cancer cell survival is dependent on activated Pol I transcription ► CX-5461, a selective inhibitor of Pol I, treats hematologic cancers in mice ► CX-5461 selectively kills tumor cells by activating p53-dependent apoptosis ► CX-5461 shows potent antiproliferative capacity in human hematologic tumor cells
Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, ...efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.
This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.
Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8–25), intracranial responses were achieved by 16 (46%; 95% CI 29–63) of 35 patients in cohort A, five (20%; 7–41) of 25 in cohort B, and one (6%; 0–30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.
Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.
Melanoma Institute Australia and Bristol-Myers Squibb.
The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as ...previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.
In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.
Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 95% CI 0·46-0·72, p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 15% in the cobimetinib and vemurafenib group vs 25 10% in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 12% vs one <1%), and alanine transaminase increase (28 11% vs 15 6%). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients 2%) and dehydration (five patients 2%) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.
These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma.
F Hoffmann-La Roche-Genentech.
Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target ...defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein-protein and protein-DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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