Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancer

Eighty-six patients with advanced colorectal, gastric or pancreatic carcinoma and no prior exposure to chemotherapy were treated with brequinar sodium. Brequinar was administered at a median weekly dose of 1200 mg/m 2 intravenously. The toxicity was moderate, with thirty patients (35%) experiencing grade 3 or 4 toxicity. Objective responses were observed in 1/32 evaluable colorectal and 2/29 evaluable gastric carcinoma patients. There were no objective responses in 17 evaluable pancreatic cancer patients. We conclude that, at this dose and schedule, brequinar does not have sufficient activity in these gastrointestinal malignancies to warrant further evaluation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45168/1/10637_2004_Article_BF00873913.pd

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer

PURPOSE: Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. PATIENTS AND METHODS: Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. RESULTS: In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. CONCLUSION: In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed

O valor da patologia na pesquisa de metástase do câncer de mama no linfonodo sentinela:

OBJECTIVES: Recent studies have suggested that sentinel lymph nodes (SLN) are the first nodes that receive drainage from breast cancer. Studies also indicate that SLN biopsy is a safe alternative staging procedure for patients with breast cancer. In this sense, it is necessary to carry out lymphatic mapping in order to identify SLNs and prove that they are reliable predictors of axillary lymph node status, based on the pathologic study of SLN and compared with the results of axillary lymph node dissection (LND).MATERIALS AND METHODS: From April 1999 through August 2000, 50 patients with breast cancer were staged with sentinel lymph node biopsy followed by complete axillary dissection. Three techniques for mapping SLN were used: lymphoscintigraphy with Technetium Tc99m-labeled dextran and, during the transoperative period, detection of radioactivity with gamma probe counter and, simultaneously, blue dye for stained lymphatic ducts or nodes. The study of SLN was carried out using frozen sections and using hematoxilyn and eosin staining (H&amp;E) and cytokeratin immunohistochemical staining (IHC). The LN were studied by standard pathologic H&amp;E.RESULTS: These patients had a mean age of 56.4 years for a median of 57 years; the mean tumor size was 2.3 cm in diameter for a median 2.0 cm. An average 2.2 (range: 1-5) SLN were excised per patient; and 20.6 was the average of axillary lymph nodes excised. H&amp;E identified 20 patients (40%) with SLN metastasis (SLN+) and 30 patients (60%) with metastasis-free SLN (SLN-). IHC in these 30 patients showed an additional 5 SLN positive patients. Thus, the IHC patient-SLN-conversion was of 17% (5/30). The increased rate of SLN+ was correlated with tumors greater than 2.0 cm. The increased incidence in nonsentinel nodes occurred with primary tumors greater than 2.0 cm and patients aged 50 years or less. The prevalence of SLN+ was of 42% according to H&amp;E. Sensitivity was of 95.2%, negative predictive value of 96.6%, and accuracy of 98%.CONCLUSIONS: Results indicated that the method is reliable with 2% false-negatives (1/50) when used together with H&amp;E. IHC indicated an upstaging of 17%, most of which were patients with micrometastasis (tumor less than 2 mm). The accuracy of SLN as a predictor of axillary lymph node was 98%. This suggests that axillary lymph node dissection may not be necessary in patients with metastasis free SLN.OBJETIVOS: Estudos recentes relatam que o câncer de mama drena para o primeiro linfonodo da bacia linfática regional, chamado linfonodo sentinela (LNS), e que a biópsia do LNS é uma alternativa segura para o estadiamento das pacientes com câncer de mama. Para isto, é necessário o mapeamento linfático que possibilita identificar o LNS e provar que ele é preditivo do status axilar, baseado no estudo patológico do LNS e comparado com o resultado da dissecção axilar total (LNT).MATERIAIS E MÉTODOS: De abril de 1999 a agosto de 2000, 50 pacientes com câncer de mama foram estadiadas com a biópsia do LNS, seguida de dissecção dos demais linfonodos axilares. Os autores usaram 3 técnicas para o mapeamento do LNS: linfocintilografia com tecnésio-99 m ligado ao dextran 500 e, no transoperatório, a detecção da radioatividade gama com o aparelho manual Gama Probe e, simultaneamente, o corante linfático Bleu Patent V que cora os ductos aferentes até o LNS. O estudo do LNS foi realizado em secções por congelação e depois em material fixado e embebido em parafina pelas técnicas de coloração com hematoxilina e eosina (H&amp;E) e de imuno-histoquímica (IHQ) para citoqueratina. Os não-LNS foram estudados pela H&amp;E.RESULTADOS: A idade média das pacientes desta amostra foi 56,4 anos e mediana de 57 anos; a média do maior diâmetro tumoral foi 2,3 cm, com mediana 2,0 cm; a média de LNS dissecado foi 2,2 (limites: 1 a 5) e a média de toda axila foi 20,6 linfonodos, com mediana de 20, excisados por paciente. A H&amp;E identificou 20 (40%) pacientes com metástase no LNS (LNS+) e 30 pacientes livres de metástase no LNS (LNS-). Com a IHQ, estas 30 pacientes mostraram um adicional de 5 com LNS+, em uma conversão de 17% (5 / 30). A taxa aumentada de ocorrência de LNS+ se correlacionou com tumores maiores do que 2,0 cm e a incidência aumentada nos nãoLNS ocorreu nos tumores maiores do que 2,0 cm e nas pacientes mais jovens, com idade até 50 anos. A prevalência de LNS+ foi de 42% pela H&amp;E. A sensibilidade do método foi 95,2%, o valor preditivo negativo de 96,6 % e a acuracidade de 98%. CONCLUSÕES: O método se mostrou factível com 2% de falso-negativos, com a H&amp;E, sendo que há um acréscimo de estádio patológico de 17% com a IHQ e a maioria com apenas micrometástase, definida como a presença de tumor com tamanho de até 2 mm. Há previsão de acerto de 98% e isto sugere que a dissecção axilar total, em paciente sem metástase em LNS, deverá brevemente ser abandonada, na dependência da experiência do cirurgião que realiza a biópsia do LN

Selective BRAFV600E Inhibitor PLX4720, Requires TRAIL Assistance to Overcome Oncogenic PIK3CA Resistance

Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAFV600E alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAFV600E mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK) suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKOBRAFV600E/PIK3CAH1047 cells. In contrast, for the same level of apoptosis in HT29BRAFV600E/PIK3CAP449T cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAFV600E. TRAIL dependence on the constitutive activation of BRAFV600E is emphasised through the overexpression of BRAFV600E in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CAMT as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAFV600E mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAFV600E inhibitors in combination with TRAIL in a BRAFV600E mutated background and provided insight for new anti-cancer strategies where the activated PI3KCA mutation oncogene should be suppressed

Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite

Background Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite.[br/] Methods We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage.[br/] Conclusion These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052) now being advanced to phase I trials for the treatment of refractory multiple myeloma will need to be further explored to evaluate the safety profile for its use against malaria