Mapping Cancer’s Blueprint: Genetics, Metabolism and Targeted Therapies

Mapping Cancer’s Blueprint: Genetics, Metabolism and Targeted Therapies Cancer is a major public health problem, claiming more than 9 million lives per year since 2015. Genetic mutations and the adaptation of multiple metabolic processes are required to satisfy the high energy demands of malignant cellular growth, proliferation and survival. In this infographic, we will explore the role of metabolism and genetics in cancer progression and their clinical implications. What causes cCaAnNcCEeRr? Inherently known as a genetic disease, cancer develops when normal cells become genetically altered, creating abnormal cells that divide and multiply. These cells then create “cancer clusters”, known as tumors. Cancerous cells may break away from tumors and travel to other areas of the body through the lymphatic system or bloodstream – known as metastasis. Healthy cell Cancer cell Tumor Metastasis Genetic alterations that can contribute to cancer typically affect three specific genes: DNA Tumor Proto repair suppressor oncogenes genes genes Mutations in these genes alter the underlying DNA sequence, affecting the structure and function of corresponding proteins. Types of mutatiions Missense DNA C T A T T C T A G G G T A Original mutations: Amino LEU TRP VAL Acids When a single nucleotide is substituted C T A T G T G T A DNA resulting in a codon that encodes for a Mutation Amino LEU CYS VAL different amino acid. Acids Nonsense C T A T T C T A G G G T A DNA mutations: Original Amino LEU TRP VAL Acids Results in a premature stop codon that A C T A T G G T A DNA halts translation and typically results in Mutation Amino LEU STOP a truncated, non-functional protein. Acids Frameshift DNA mutation: C T A T T C T A G G G T A Original Amino LEU TRP VAL Acids When one or more nucleotides are added or deleted, shifting the reading G DNA C T A A T G G T Mutation frame downstream of the mutation. This Amino LEU MET GLY disrupts the normal sequence of codons Acids and alters the resulting amino acids. Chromosomal rearrangements: Structural abnormalities that can be caused by the deletion, duplication, inversion or translocation of pieces of the chromosome. They can affect multiple genes. Cance RIISK FACTORS Cancer risk factors are characteristics or exposures that increase an individual’s likelihood of developing cancer. Understanding cancer risk factors is vital as some could be modified or managed, potentially reducing the chance of cancer development. Some main risk factors are: Hormone Family therapy history Radiation Sedentary exposure behavior Smoking malnutrition Environmental factors Cance metaboliism 1 2 Cancer metabolism is the process of cancer Metabolic reprogramming is an emerging cells making the energy they need to hallmark of cancer cells, enabling grow and spread. Compared to them to meet increased nutrient healthy cells, cancer cells use more and energy demands while glucose and create less energy. withstanding the challenging tumor microenvironment. 3 4 This reprogramming can be a result of Metabolic imbalance may also either mutations in metabolic genes precede genetic change leading to themselves or oncogenic mutations in tumor initiation. Examples of this include signaling pathways. Oncogenic mutations cases of hypoxia, inflammation or metabolic can result in altered metabolic gene expression diseases (i.e., obesity and diabetes). or differential post-translational modifications of metabolic enzymes – leading to differential activity or protein localization. Early discovery of cancer metabolism In the 1920s, Nobel laureate Otto Warburg and colleagues showed that under aerobic conditions, tumor tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues – a phenomenon known as the Warburg effect Glucose has been a significan focus of Understanding the relationship between understanding cancer metabolism because it genetic and metabolic changes contributing is avidly taken up by many tumors. However, to tumor initiation, is essential for designing researchers are now also exploring how to interfere efficient therapeutic approaches targeting with other metabolic pathways, such as amino the metabolism of tumors. acid metabolism, to prevent cancer development or spread. How can we study cancer metabolism 1 2 New technologies – such as positron emission A PET scan involves an injection of a safe tomography (PET) scan – are allowing metabolism radioactive tracer that helps detect diseased to be characterized in unprecedented detail (i.e., cancer) cells. The result is incredibly detailed and could provide non-invasive options for images of dynamic metabolic processes, in a detecting metabolic biomarkers. non-destructive manner – meaning there is no need to sample tissue and break it down, we can look at it in its natural location. 3 4 Application of this research would be to identify One of the challenges of being guided by metabolically rich or replete regions of tumors metabolic phenotypes, is the unknown of how – helping to tailor treatments. This is done plastic these processes are. Tumors evolve using radiotherapy, where hypoxic regions over time, but as serial non-invasive metabolic are ‘painted’ onto scans ahead of intensity imaging can be conducted, treatments can modulated radiation therapy. be monitored and adapted accordingly. Cancer metabolism: A target for clinical intervention 1 2 Cancer cells can switch their metabolic Cancer metabolism is now a target pathways, enabling adaptation for researchers to stop or slow down to differen microenvironments cancers, with a goal of leaving and evading therapeutic healthy cells alone. interventions. 3 4 There is great interest in exploiting Choosing metabolic interventions cancer genetic analysis for patient based on genomic and metabolic stratification and/or dietary interventions data could lay the foundation for the in combination with therapies that target successful use of metabolism-based anti metabolism. tumor strategies. 5 A recent example of this is enasidenib, an isocitrate dehydrogenase 2 (IDH2) inhibitor – approved by the US Food and Drug Administration – for the treatment of relapsed or refractory acute myeloid leukemia in patients bearing IDH2 mutations. targeted Ttherapiies Targeted therapy is a type of cancer treatment that targets proteins controlling how cancer cells grow, divide and spread. It is the foundation of precision medicine. As researchers learn more about DNA changes, proteins that drive cancer and cancer metabolism, they are better able to design treatments. Targeted therapies may be used in the treatment of several types of cancer including: Bladder Breast Lung Kidney Gastric Melanoma Types of targeted Ttherapiies Most targeted therapies are either small-molecule drugs or monoclonal antibodies (mAbs). Small molecule mAbs medicines mAbs are immune system proteins that are created in the lab. Like the body’s own Small molecule medicines are drugs that can antibodies, mAbs recognize specific protein enter cancer cells due to them having a low targets on cancer cells. molecular weight. Once inside cancer cells, the drug can affect other molecules (e.g., proteins), There are many different mAbs to treat blocking signals that inform tumor cells to grow, cancer, which work in different ways to kill which may cause cancer cells to die. the cancer cell or stop it from growing. Often, the generic names of small molecule mAbs “-mab” at the end of their generic name. medicines end in “-ib”. For example, imatinib For example, trastuzumab and rituximab. treats chronic myelogenous leukemia and other cancers. How do How do targeted Ttherapiies work work Interrupt signals that Help the immune cause cancer cells system destroy to grow and divide cancer cells without order Prevent signals Deliver toxins to that stimulate kill cancer cells angiogenesis Starve cancer Cause cancer cells of hormones apoptosis needed for cell growth Targeted therapies do come with some drawbacks – drug resistance and difficulti producing the drug – and some side effects including: High blood pressure Fatigue Problems with blood clotting and wound healing Sores Nail changes Loss of hair color Skin irritations