Therapeutic Antibodies in Cancer Treatment in the UK.

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas. As of the date of this review, 37 monoclonal antibody products are approved for use in cancer treatments in the United Kingdom. Currently, the antibody therapeutics market is dominated by monoclonal immunoglobulins (IgGs). New types of recombinant antibody therapeutics developed more recently include bispecific recombinant antibodies and other recombinantly produced functional proteins. This review focuses on the approved therapeutic antibodies used in cancer treatment in the UK today and describes their antigen targets and molecular mechanisms involved. We provide convenient links to the relevant databases and other relevant resources for all antigens and antibodies mentioned. This review provides a comprehensive summary of the different monoclonal antibodies that are currently in clinical use primarily in malignancy, including their function, which is of importance to those in the medical field and allied specialties.

Rational Approach to Finding Genes Encoding Molecular Biomarkers: Focus on Breast Cancer.

Early detection of cancer facilitates treatment and improves patient survival. We hypothesized that molecular biomarkers of cancer could be rationally predicted based on even partial knowledge of transcriptional regulation, functional pathways and gene co-expression networks. To test our data mining approach, we focused on breast cancer, as one of the best-studied models of this disease. We were particularly interested to check whether such a 'guilt by association' approach would lead to pan-cancer markers generally known in the field or whether molecular subtype-specific 'seed' markers will yield subtype-specific extended sets of breast cancer markers. The key challenge of this investigation was to utilize a small number of well-characterized, largely intracellular, breast cancer-related proteins to uncover similarly regulated and functionally related genes and proteins with the view to predicting a much-expanded range of disease markers, especially that of extracellular molecular markers, potentially suitable for the early non-invasive detection of the disease. We selected 23 previously characterized proteins specific to three major molecular subtypes of breast cancer and analyzed their established transcription factor networks, their known metabolic and functional pathways and the existing experimentally derived protein co-expression data. Having started with largely intracellular and transmembrane marker 'seeds' we predicted the existence of as many as 150 novel biomarker genes to be associated with the selected three major molecular sub-types of breast cancer all coding for extracellularly targeted or secreted proteins and therefore being potentially most suitable for molecular diagnosis of the disease. Of the 150 such predicted protein markers, 114 were predicted to be linked through the combination of regulatory networks to basal breast cancer, 48 to luminal and 7 to Her2-positive breast cancer. The reported approach to mining molecular markers is not limited to breast cancer and therefore offers a widely applicable strategy of biomarker mining.

Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer.

Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale 'omics' investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers. Incredibly, the use of a validation marker set of 10 other completely different known CRC markers and the same procedure resulted in a very similar set of 143 predicted markers. Of these, 138 were identical to those found using the training set, confirming our main hypothesis that a much-expanded set of disease markers can be predicted by starting with just a small subset of validated markers. Further to this, we validated the expression of 42 out of 138 top-ranked predicted markers experimentally using qPCR in surgically removed CRC tissues. We showed that 41 out of 42 mRNAs tested have significantly altered levels of mRNA expression in surgically excised CRC tissues. Of the markers tested, 36 have been reported to be associated with aspects of CRC in the past, whilst only limited published evidence exists for another three genes (BCL2, PDGFRB and TSC2), and no published evidence directly linking genes to CRC was found for CCNA1, SHC1 and TGFB3. Whilst we used CRC to test and validate our marker discovery strategy, the reported procedures apply more generally to cancer marker discovery.

Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection.

Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of the most common cancers, few molecular approaches to detect CRC exist. Carcinoembryonic antigen (CEA) is a known serum biomarker that is used in CRC for monitoring disease recurrence or response to treatment. However, it can also be raised in multiple benign conditions, thus having no value in early detection or screening for CRC. Molecular biomarkers play an ever-increasing role in the diagnosis, prognosis, and outcome prediction of disease, however, only a limited number of biomarkers are available and none are suitable for early detection and screening of CRC. A PCR-based Epi proColon® blood plasma test for the detection of methylated SEPT9 has been approved by the USFDA for CRC screening in the USA, alongside a stool test for methylated DNA from CRC cells. However, these are reserved for patients who decline traditional screening methods. There remains an urgent need for the development of non-invasive molecular biomarkers that are highly specific and sensitive to CRC and that can be used routinely for early detection and screening. A molecular approach to the discovery of CRC biomarkers focuses on the analysis of the transcriptome of cancer cells to identify differentially expressed genes and proteins. A systematic search of the literature yielded over 100 differentially expressed CRC molecular markers, of which the vast majority are overexpressed in CRC. In terms of function, they largely belong to biological pathways involved in cell division, regulation of gene expression, or cell proliferation, to name a few. This review evaluates the current methods used for CRC screening, current availability of biomarkers, and new advances within the field of biomarker detection for screening and early diagnosis of CRC.

The use of the faecal immunochemical test during the COVID-19 pandemic to triage urgent colorectal cancer referrals.

AIM: During the first wave of the COVID-19 pandemic in 2020, elective gastrointestinal endoscopy services were abbreviated for fear of viral transmission. However, urgent suspected colorectal cancer (CRC) referrals continued. Serendipitously, a national study suggested that a new faecal immunochemical test (FIT) might be helpful in triaging patients with colorectal alarm symptoms. METHODS: This was a single centre observational study of patients referred using NG12 criteria between March and August 2020. Patients were triaged to the urgent cancer pathway for FIT ≥ 10 µg/g and investigated using the latest National Health Service England guidance. Demographic data, method of investigations, cancer and polyp detection rates were compared to patients referred in the 6 months prior to the use of FIT as a triage tool. RESULTS: In all, 1192 patients (median age 70) were referred using NG12 guidelines during the pandemic period, compared with 1592 patients (median age 72) in the previous 6 months. CRC detection was similar in both groups (n = 45, 2.8% vs. n = 38, 3.5%; P = 0.248). Two patients with a negative FIT (0.36%) had CRC. Using FIT as a triage tool resulted in a significant reduction in the use of endoscopy (n = 477, 43.6% vs. n = 1186, 74.5%; P > 0.001) with a significant increase in CT scanning (n = 696, 63.6% vs. n = 750, 47.1%; P < 0.001). CONCLUSION: The use of FIT in NG12 patients triaged during the first wave of the COVID-19 pandemic reduced endoscopy but not CT scanning and did not compromise CRC detection rates. It is a safe method that aids in reducing the burden on services greatly. A negative FIT test does not absolutely exclude CRC.

Modafinil improves rapid shifts of attention.

RATIONALE: The majority of studies investigating the cognitive effects of modafinil, a wake-promoting compound, demonstrate some improvements in attention. The potential of the drug to selectively benefit distinct components of attention has yet to be fully explored in healthy adults. OBJECTIVE: The present study was conducted to investigate modafinil's effect on specific cognitive tasks that tax components of attention switching. One required the rapid switching of attention between stimuli, and another contained an embedded working memory component on top of the attentional shift requirements. Additionally, prospective memory was examined, which requires the interruption of an ongoing activity to retrieve and act upon a previously formed intention. MATERIALS AND METHODS: Healthy non-smoking volunteers, matched on age, intelligence, and baseline cognitive ability, received either a capsule that contained 200 mg modafinil or placebo. Subjective measures of mood and physiological response were taken throughout the experimental session, and the tasks were completed between 2 and 3 h post-dosing. RESULTS: Two hundred milligrams modafinil improved accuracy without a reaction time trade-off, in both conditions of the attention-shifting task, but only when resources were most challenged. In contrast, the drug afforded no improvement in prospective remembering or in the ongoing task that was interrupted. CONCLUSION: Modafinil appears to promote rapid switching of attention in conditions that are most demanding, whilst it offers no benefits in a task that requires unpredictable and infrequent disengagement of attention from an ongoing task in order to act upon an alternative task.