Panitumumab and inhibition of the epidermal growth factor receptor signaling in the treatment of metastatic colorectal cancer

Panitumumab is a human monoclonal antibody that targets epidermal growth factor receptor (EGFR) approved for the treatment of patients with metastatic colorectal cancer (mCRC). The current use of panitumumab is, however, restricted to the management of patients who have failed chemotherapy with irinotecan and oxaliplatin. The results of a phase III studies published in 2010 made it possible to demonstrate clinical benefit from using panitumumab in combination with first- or second-line chemotherapy in mCRC, at the same time confirming in prospective setting the benefits of using anti-EGFR treatments only in the group of patients without the KRAS mutation. We present the results of these studies and discuss selected communications from ASCO 2010 and WCGI 2010 related to anti-EGFR treatment in mCRC. Onkol. Prak. Klin. 2010; 6, 6: 290–300Panitumumab jest ludzkim przeciwciałem monoklonalnym nakierowanym na receptor naskórkowego czynnika wzrostu (EGFR), zarejestrowanym do stosowania u pacjentów z przerzutowym rakiem jelita grubego. Obecnie stosowanie panitumumabu ogranicza się do leczenia chorych po niepowodzeniu chemioterapii z wykorzystaniem irynotekanu i oksaliplatyny. Wyniki opublikowanych w 2010 badań III fazy pozwoliły na wykazanie korzyści klinicznych ze stosowania panitumumabu w połączeniu z chemioterapią w pierwszej i drugiej linii leczenia raka jelita grubego z przerzutami, jednocześnie potwierdzając w badaniach prospektywnych korzyść z leczenia anty-EGFR wyłącznie w grupie pacjentów, u których nie występuje mutacja w obrębie KRAS. W niniejszym artykule przedstawiono wyniki tych badań, a także omówiono wybrane doniesienia z konferencji ASCO 2010 i WCGI 2010 dotyczące problematyki leczenia anty-EGFR w przerzutowym raku jelita grubego. Onkol. Prak. Klin. 2010; 6, 6: 290–30

ShapeGTB: the role of local DNA shape in prioritization of functional variants in human promoters with machine learning

Motivation The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional single nucleotide polymorphisms within promoter regions—ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (average precision 0.93 vs. 0.47–0.55). On the external validation set based on ClinVar database it displayed worse performance but was still competitive with other methods (average precision 0.47 vs. 0.23–0.42). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future

Capecitabine in the treatment of advanced gastric cancer

Leczenie zaawansowanego raka żołądka ewoluowało w ciągu ostatnich 20 lat od leczenia wspomagającego do chemioterapii wielolekowej, co wiąże się z poprawą mediany przeżycia całkowitego z 3 do 11 miesięcy. W praktyce klinicznej, ale także w zaleceniach ekspertów, w dalszym ciągu brakuje konsensusu odnośnie wskazań do leczenia paliatywnego, składu chemioterapii, a także złożoności programów chemioterapii (programy dwu- czy trójlekowe) oraz zasadności leczenia kolejnych linii. Klasyczne programy chemioterapii paliatywnej raka żołądka opierają się na przedłużonym wielodobowym stosowaniu 5-fluorouracylu (5-FU). W tym zakresie istotną odmianę wprowadziło zastosowanie kapecytabiny — doustnej fluoropirymidyny mającej charakter proleku, która dzięki postaci farmaceutycznej i metabolizmowi w tkankach guza nowotworowego pozwala na uzyskanie wysokiej aktywności przeciwnowotworowej. W badaniach III fazy REAL-2 i ML17032 wykazano, że w połączeniu z pochodnymi platyny jest ona nie mniej skuteczna od 5-FU w analogicznych schematach leczenia u chorych z zaawansowanym rakiem żołądka. Dodatkowo metaanaliza powyższych badań wykazała, iż stosowanie kapecytabiny zamiast 5-FU istotnie wydłuża przeżycie całkowite, nie wpływając znacznie na profil toksyczności i czas do progresji. W pracy przedstawiono aktualny stan wiedzy na temat miejsca kapecytabiny w leczeniu raka żołądka w kontekście badań rejestracyjnych oraz pozarejestracyjnych, zidentyfikowanych w ramach przeglądu systematycznego literatury. Onkol. Prak. Klin. 2011; 7, 3: 119–126Treatment of advanced gastric cancer has evolved over the past 20 years and includes adjuvant treatment as well as multidrug chemotherapy. Such treatments are associated with improved median overall survival rates between 3 and 11 months. In clinical practice, and also according to expert opinion, there is still no consensus regarding: the indications for the use of palliative treatment; the composition of chemotherapy; the complexity of chemotherapy programs (double- or triple-drug combinations); and the merits of second line treatments. Classical programs of palliative chemotherapy of gastric cancer are based on an extended multiday use of 5-fluorouracil (5-FU). In this respect, a significant change was brought about with the use of capecitabine, which is an orally-available prodrug form of fluoropyrimidine. The active metabolites of capecitabine display high anticancer activity. In Phase III of REAL-2 and ML17032 it was demonstrated that, in combination with platinum derivatives, capecitabine is not less effective than 5-FU in the same regimens when used for patients with advanced gastric cancer. A meta-analysis of these studies showed that the use of capecitabine, in place of 5-FU, significantly extended overall survival. Furthermore, the toxicity profile and time to progression appeared the same when the two drugs were compared. The paper presents the current state of knowledge relating to the use of capecitabine in the treatment of gastric cancer. To this end, both pre-registration and post-registration clinical studies were identified in the systematic review of the literature. Onkol. Prak. Klin. 2011; 7, 3: 119–12

Efficacy, safety, and pharmacokinetics of the anti-programmed cell death receptor-1 (PD-1) monoclonal antibody, tislelizumab (BGB-A317) in a phase 2, open-label, multicenter study to investigate in patients with unresectable hepatocellular carcinoma - Trial in progress.

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Distant homologs of anti-apoptotic factor HAX1 encode parvalbumin-like calcium binding proteins

<p>Abstract</p> <p>Background</p> <p>Apoptosis is a highly ordered and orchestrated multiphase process controlled by the numerous cellular and extra-cellular signals, which executes the programmed cell death <it>via </it>release of cytochrome c alterations in calcium signaling, caspase-dependent limited proteolysis and DNA fragmentation. Besides the general modifiers of apoptosis, several tissue-specific regulators of this process were identified including HAX1 (HS-1 associated protein X-1) - an anti-apoptotic factor active in myeloid cells. Although HAX1 was the subject of various experimental studies, the mechanisms of its action and a functional link connected with the regulation of apoptosis still remains highly speculative.</p> <p>Findings</p> <p>Here we provide the data which suggests that HAX1 may act as a regulator or as a sensor of calcium. On the basis of iterative similarity searches, we identified a set of distant homologs of HAX1 in insects. The applied fold recognition protocol gives us strong evidence that the distant insects' homologs of HAX1 are novel parvalbumin-like calcium binding proteins. Although the whole three EF-hands fold is not preserved in vertebrate our analysis suggests that there is an existence of a potential single EF-hand calcium binding site in HAX1. The molecular mechanism of its action remains to be identified, but the risen hypothesis easily translates into previously reported lines of various data on the HAX1 biology as well as, provides us a direct link to the regulation of apoptosis. Moreover, we also report that other family of myeloid specific apoptosis regulators - myeloid leukemia factors (MLF1, MLF2) share the homologous C-terminal domain and taxonomic distribution with HAX1.</p> <p>Conclusions</p> <p>Performed structural and active sites analyses gave new insights into mechanisms of HAX1 and MLF families in apoptosis process and suggested possible role of HAX1 in calcium-binding, still the analyses require further experimental verification.</p

Functional features of gene expression profiles differentiating gastrointestinal stromal tumours according to KIT mutations and expression

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal stromal tumours (GISTs) represent a heterogeneous group of tumours of mesenchymal origin characterized by gain-of-function mutations in <it>KIT </it>or <it>PDGFRA </it>of the type III receptor tyrosine kinase family. Although mutations in either receptor are thought to drive an early oncogenic event through similar pathways, two previous studies reported the mutation-specific gene expression profiles. However, their further conclusions were rather discordant. To clarify the molecular characteristics of differentially expressed genes according to GIST receptor mutations, we combined microarray-based analysis with detailed functional annotations.</p> <p>Methods</p> <p>Total RNA was isolated from 29 frozen gastric GISTs and processed for hybridization on GENECHIP^®HG-U133 Plus 2.0 microarrays (Affymetrix). <it>KIT </it>and <it>PDGFRA </it>were analyzed by sequencing, while related mRNA levels were analyzed by quantitative RT-PCR.</p> <p>Results</p> <p>Fifteen and eleven tumours possessed mutations in <it>KIT </it>and <it>PDGFRA</it>, respectively; no mutation was found in three tumours. Gene expression analysis identified no discriminative profiles associated with clinical or pathological parameters, even though expression of hundreds of genes differentiated tumour receptor mutation and expression status. Functional features of genes differentially expressed between the two groups of GISTs suggested alterations in angiogenesis and G-protein-related and calcium signalling.</p> <p>Conclusion</p> <p>Our study has identified novel molecular elements likely to be involved in receptor-dependent GIST development and allowed confirmation of previously published results. These elements may be potential therapeutic targets and novel markers of <it>KIT </it>mutation status.</p