Cancer is a group of multifactorial diseases with complex genesis and progression. Irrespective of the type, all tumour cells are characterised by their ability to grow, invade and metastasise in an unregulated manner. According to statistics, around 9.6 million people around the world lost their battle against cancer in 2018. Not only that, 1 out of 3 people diagnosed with cancer suffer from mental health disorders such as depression and anxiety. As pharmaceutical companies continue their pursuance to develop novel anti-cancer drugs, there is a steady growth in the industry pipeline of drug candidates, clinical-trials and available clinical and real-world data. In our blog below, we discuss in brief the scope for drug discovery in oncology.

 

Introduction:

Cancer is a broad term used to describe diseases that result from cellular changes causing uncontrolled growth and division of cells. The UK alone witnesses more than 360,000 new cancer cases every year; with lung, bowel, prostate and breast cancers accounting for 53% of these cases. Early diagnosis generally leads to better prognosis and treatment of the disease. From sole reliance on post-mortem description of macroscopic tumour in the early 19th century, to incorporation of genetic information into diagnostic algorithms, cancer research has witnessed many scientific innovations. Rapid growth of high-throughput technologies such as genomics, proteomics, transcriptomics, metabolomics and epigenomics, backed by advancements in bioinformatics, analytical tools and infrastructure has significantly improved the ability to obtain molecular information for cancer diagnostics. The understanding of different technologies used in pathology is absolutely vital for effective clinical management. However, the challenge still remains on how to translate these technical developments into clinical benefits for patients.

 

Cancer and drug discovery:

Whilst surgery, radiotherapy, laser therapy and combination therapy have several benefits, chemotherapy is still the most widely used method of treatment around the world. However, chemotherapy has its own challenges such as drug toxicity and resistance developed by the tumour.

Anti-cancer drugs are commonly grouped into four classes: cytotoxic, endocrine, targeted therapies and vaccines. Depending on the state of tumour and patient, these drugs can be prescribed in different ways. They can be given before surgery to shrink the size of the tumour, or can be the main form of treatment. They can also be given following surgery and radiotherapy to reduce the chances of reoccurrence. In cases of advanced cancers where surgery is not possible, drugs can be given to reduce the tumour size and alleviate symptoms.

Fun fact- cancer drugs

The first step towards finding a novel anti-cancer drug is identifying a ‘druggable’ biological target that is involved in the pathology of the disease. Once the target is identified and validated, cell lines are chosen or developed such that they show properties similar to the cancer in question. This is followed by screening of thousands of compounds to identify ‘hits’ that show some form of desirable activity on these cell lines. It is only after a ‘lead’ molecule is developed from these ‘hits’, with the required safety and efficacy profile, that the clinical phase begins.

 

Working with a specialised CRO on oncology projects:

In today’s economic environment, more and more drug discovery companies outsource their research to CROs (Contract Research Organisations). CROs not only provide services in a timely, efficient and cost-effective manner, but also fill in skill gaps that sponsor organisations may have.

Aurelia Bioscience, a UK based CRO, has decades of experience in pre-clinical discovery, designing and developing low, medium and high throughput assays for pharmacological profiling, hits-to-lead, lead identification and lead optimisation for oncology and other drug discovery projects. They work on a wide range of targets, including kinases that are known to play an important role in carcinogenesis and metastases of different types of cancers through uncontrolled phosphorylation events leading to abnormal activation of certain cell cycle regulation pathways. Modulation of these pathways by compounds can reduce this abnormal activation leading to a decrease in cancer progression. An example of a new technology to examine kinase activity and the binding of compounds in a cellular environment is shown below using DDR-1 as an exemplar kinase in a Promega NanoBRET target engagement assay.

 

Competitive inhibition (A) of compound binding to DDR1 kinase in living cells. By studying both the association (B) and dissociation (C) rate of compounds from each of the target kinase it is possible to consider introducing kinetic binding parameter evaluation during compound SAR development.

Competitive inhibition (A) of compound binding to DDR1 kinase in living cells. By studying both the association (B) and dissociation (C) rate of compounds from each of the target kinase it is possible to consider introducing kinetic binding parameter evaluation during compound SAR development.

The team also has scientific expertise in areas that are closely associated with cancer, such as autophagy and hypoxia. Although autophagy is an evolutionarily conserved process essential for survival, differentiation, development, and homeostasis, its dysregulation is linked to pathogenesis of several disease states. Whilst in the early stage of tumorigenesis, autophagy is known to suppress the tumour by clearing damaged cellular content, it promotes tumour progression in advanced stages. Aurelia Bioscience has studied autophagy using a number of technologies including high throughput Western Blotting to measure LC-3, a protein important in autophagy. Follow the link to a webinar on ‘A Multimodal Assay for Quantitating and Interpreting Changes in Autophagic Flux’. 

Densitometry plot taken from an advanced Western Blotting technology called WES (Protein Simple) looking at the autophagy marker LC3 in U2OS cells following treatment with compounds designed to up- and down-regulate LC-3 protein expression

Densitometry plot taken from an advanced Western Blotting technology called WES (Protein Simple) looking at the autophagy marker LC3 in U2OS cells following treatment with compounds designed to up- and down-regulate LC-3 protein expression

 

Similarly, mostly harmless under normal conditions, hypoxia enhances malignant progression and increases resistance to radiotherapy in patients suffering from cancer.

Influence of normoxia and hypoxia on proliferation, VEGF secretion and glucose metabolism in cells and the effect of Temsirolimus on the cells. Inhibition of VEGF secretion and glucose uptake with a single concentration of Temsirolimus (10µM)

Influence of normoxia and hypoxia on proliferation, VEGF secretion and glucose metabolism in cells and the effect of Temsirolimus on the cells. Inhibition of VEGF secretion and glucose uptake with a single concentration of Temsirolimus (10µM)

Traditionally, drug discovery processes rely on cell-based assays using two dimensional (2D) monolayered cells cultured on flat and rigid surfaces. Although 2D cell cultures are still very useful in providing information on biological targets and pathways, they have several limitations. Since almost all cells in the in vivo environment are surrounded by other cells within a three- dimensional environment, there is an increasing demand for three-dimensional (3D) cell culture systems that are more reflective of in vivo cellular responses. Scientists at Aurelia Bioscience work with 3D techniques such as spheroid models that can be easily adapted for medium to high-throughput screening and give highly reproducible results. These models are particularly useful in cancer biology, as they are able to express chemical gradients of various nutrients, oxygen and catabolites found in tumour, and thus provide an accurate representation of tumour physiology.

U-87 MG cell spheroid stained with Live and Dead stains and imaged with CellInsight™ CX5 High Content Screening (HCS) Platform. Spheroid was seeded at 1000 cells and cultured in 384 well Costar ULA spheroid plates for 7 days. Focus is across centre of spheroid. Hoechst (blue)- Nuclei Calcein AM (green)- Viability Propidium Iodide (red)- Dead cells

U-87 MG cell spheroid stained with Live and Dead stains and imaged with CellInsight™ CX5 High Content Screening (HCS) Platform. Spheroid was seeded at 1000 cells and cultured in 384 well Costar ULA spheroid plates for 7 days. Focus is across centre of spheroid.
Hoechst (blue)- Nuclei
Calcein AM (green)- Viability
Propidium Iodide (red)- Dead cells

 

Are you a drug discovery company looking to develop anti-cancer agents? Why not get in touch with the team at Aurelia Bioscience and take your project to the next level!

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