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Precision Medicine The sequencing of the human genome in 2003 opened up many new doors for discoveries in genetics and wider life sciences and medicine. Understanding the genetic basis of disease was naturally expected to lead to better targeted therapies. The steep decline in the cost of sequencing...

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Precision Medicine The sequencing of the human genome in 2003 opened up many new doors for discoveries in genetics and wider life sciences and medicine. Understanding the genetic basis of disease was naturally expected to lead to better targeted therapies. The steep decline in the cost of sequencing, pursuant to the invention of ‘next-generation’ technologies, facilitated the discovery of many more causative genes, and more recently, application to individual patients. The term ‘precision medicine’ was first given prominence by a publication from the US National Research Council. In the appendix of said publication, the authors clarify that, opposed to the term ‘personalised medicine’, it was intended to convey that, although therapeutics are rarely developed for single individuals, increasingly, subgroups of patients could be defined, often by genomics, and targeted in more specific ways. The timing does seem right for a new approach: genomic data are more readily available, we have a greater understanding of population-scale genetic variation and approaches to data integration with electronic medical records will lead to much improved characterisation of phenotypes. However, for precision medicine to succeed, it also needs to be more accurate. Current algorithms for genome analysis were developed for population or cohort variant discovery where the consequence of reduced accuracy was a lost opportunity for discovery, whereas an inaccurate clinical genetic test could lead to very serious consequences for individuals and families with genetic disease. Familial Health History: FHH is a simple yet invaluable tool for the delivery of personal health risk information. It’s a kind of personalised treatment easily and already put into practice. FHH assessments help identify people at higher risk for disease, enabling pre-emptive and preventative steps, including lifestyle changes, health screenings, testing and early treatment as appropriate. Assessment and integration of FHH information have not been embraced by the healthcare community. There are 3 challenges to incorporating FHH into the public’s health: - Accessible, standard collection methods - Healthcare provider access - Clinical guidance for interpretation and use

Cystic Fibrosis: Subclasses of CF are defined according to the functional effects of specific genetic variants of CFTR. 6 subclasses are defined: - I = No functional protein (G542x) - II = Trafficking defect (DeltaF508) - III = Defective regulation (G551D) - IV = Decreased conductance (R117H) - V = Reduced synthesis (3120+1G>A) - VI = Reduced stability (Q1412x)

The first drug approved for a subclass of CF was Ivacaftor, which increases the opening probability of channels on the cell surface (a CFTR potentiator). It was initially approved for class III CF, for which the trafficking of CFTR is fine, but the regulation is defective. The most comment variant, DeltaF508, results in the destruction of a misfolded CFTR protein (Class II). For this a combination of Lumacaftor (to enhance intracellular processing and trafficking) and Ivacaftor may be optimal. In this, Lumacaftor aids in the correct trafficking of mutant CFTR by providing a proteasomal escape. However, when the defective CFTR reaches the cell surface, it has a gating abnormality similar to G551D and hence Ivacaftor, as it does in G551D patients, aids by increasing channel opening times.

Diabetes: Diabetes is a heterogeneous disease. Although classifications into type 1 and type 2 with their distinct pathophysiological mechanism have had clear implications for therapy, it is still insufficient in explaining the wide variety of clinical manifestations of this disease. Currently, despite extensive epidemiological and physiological characterisation, we’ve fallen short in cataloguing risk factors, identifying triggering events, elucidating pathophysiological pathways, outlining prognostic course, selecting effective therapies and predicting complications. Recent attempts to tailor type 2 diabetes therapy have focused on personal, social and economic considerations rather than on a lucid molecular understanding of the underlying disease process. As much as oncology has really pioneered precision medicine through molecular diagnosis and tailored treatment based on genetics, diabetes care has also seen tremendous progress. Metaanalyses of Genome Wide Association Studies and ongoing comprehensive sequencing experiments have yielded a plethora of genetic associations which can open doors on to the pathophysiology of type 1 and type 2 diabetes. While these genomic explorations have explained only a small fraction in the genetic contribution to the phenotype, in conjunction with physiological measures, they can be used to improve our nosology of the disease and we can begin to characterise clusters that may define sub types. Genes: Many other diseases have a genetic basis behind the choice of therapy and there are several strong cases of genotype-directed precision medicine for diabetes also. Activating mutations in the ATP-dependent K channel gene KCJN11 cause a severe form of neonatal diabetes which is not easily controlled by insulin therapy. Because KCJN11 is also expressed in the brain, many of the children have developmental defects. Switching the children to high doses of sulfonylureas, which target the sulfonylurea receptor, not only control the diabetes but normalises the developmental defects. Metformin: Metformin is the first choice of therapy in T2D, however, response to metformin therapy is not uniform and a proportion of patients develop unpleasant gastrointestinal side effects. Metformin is not metabolised and excreted almost unchanged in the urine, ergo, response to metformin is not influenced by genetic variation in metabolic enzymes. Still, the absorption and bioavailability of metformin varies considerably. Metformin is an organic cation and as such is transported by cation transporters. Patients homozygous for a loss of function variant in the organic cation transporter 1 gene show reduced

effectiveness of metformin. Similarly patients with genetic variation resulting in reduced function of the multidrug and toxin extrusion protein 1 (MATE1) gene show reduced response to metformin. Sulfonylureas: Sulfonylureas have been the main insulin secretagogues in the treatment of T2D for decades and often considered first line treatment in non-obese patients. Most patients respond well to sulfonylureas. Sulfonylureas are metabolised in the liver by CYP2C9. There are 2 variants of this gene that have reduced function, which result in decreased clearance of sulfonylureas in the liver and thus a better effect of said drugs.

Precision Oncology: Not all patients respond equally to cancer therapeutic compounds. Recent advances in genomic, proteomic and transcriptomic technologies with the ever increasing understanding of the molecular mechanisms of cancers allow specific genes to be identified that contribute to cancer and can help to target treatment more efficiently, accurately and precisely. The traditional one-drug-fits-all approach to drug development and clinical therapy has been ineffective. 38-75% of patients fail to respond to treatment across various diseases, with cancer having the lowest response rate at 25%. Adverse drug reactions are also a major problem. 16% of drugs approved in the US have been shown to have adverse reactions.

Breast Cancer – HER2 – Trastazumab, Pertuzumab Breast cancer is the most common cancer to affect women worldwide with 1,000,000 cases reported annually worldwide. It is well known that cancers are diverse in their natural history and the molecular mechanisms behind the development of breast cancer tumours are heterogenic. Hence it’s a disease categorised into 5 distinct subtypes: - Luminal-like subtypes A and B (expression of hormone receptors and luminal CK-8 and CK-18) - Basal-like (also called Triple Negative Breast Cancer) where there is no expression of oestrogen receptors, progestin receptors and HER2 - Her2-positive - Normal-like This classification underlies important clinical information. For example, a survival analyses showed that patients in different groups had varying outcomes and prognoses. The basal-like had a poor prognosis, which is different from the two oestrogen receptor positive groups. HER2+: One of the most significant and successful developments in personalised medicine is the development of therapies against HER2+ breast cancer. Specific drugs targeted to HER2+ include monoclonal antibodies such as Trastazumab and Pertuzumab, and tyrosine kinase inhibitors such as Lapatinib, have proven effective therapeutic agents for HER2+. Despite the improved outcomes achieved so far, innate and acquired resistance significantly hinders the efficacy of these drugs and is a significant challenge that must be overcome if this kind of

targeted therapy is to become a gold-standard option. Trastuzumab: HER2 is an attractive therapeutic target for breast cancer. Trastuzumab is a humanised recombinant monoclonal antibody that binds to the juxtamembrane region of HER2. It was the first HER2-targeted therapy approved by the US FDA for metastatic breast cancer. It’s not abundantly clear how trastuzumab exerts its anti-tumour activity. Several possibilities have been proposed, including both intra and extra cellular action. The EC action is through an immune-mediated response. Traztuzumab has an IgG1-Fc structure that can be detected by FCRs on immune effector cells, principally the natural killer cells. Once trastuzumab binds to target cells it recruits immune effector cells to attack the target cells, known as antibody-dependent cellular cytotoxicity. IC action could be through these mechanisms: - Inhibition of IC signal transduction - Stimulation of HER2 internalisation and degradation - Inhibition of DNA repair - Inhibition of proteolytic cleavage of HER2 EC domain - Inhibition of angiogenesis The Ec mechanisms have been supported in in vitro and in vivo studies; the IC mechanisms are either controversial or challenged by recent data. Pertuzumab: Pertuzumab was recently approved by the US FDA to be used in conjunction with trastuzumab and docetaxel to treat HER2+ breast cancer due to the improved outcome compared to combinatorial treatment of trastuzumab and docetaxel alone (docetaxel is a spindle toxin chemotherapy agent that binds with high affinity to tubulin monomers in microtubulin, stabilising said filaments, making it difficult for metastasis to proceed). Pertuzumab is a fully recombinant human monoclonal antibody and represents a new class of agents that prevent HER2 dimerisation. It binds to HER2 near the centre of its dimerisation domain, blocking the binding pocket for receptor dimerisation. Ergo, pertuzumab blocks both the homodimerisation of HER2 and the heterodimerisation with other HER receptors. This reduction in dimerisation will hopefully lead to an inhibition of downstream HER2 signalling.

Lapatinib and TKIs: Lapatinib is a dual TKI that targets both HER2 and EGFR. It’s been shown to stabilise HER2 and enhance trastuzumab-induced cell toxicity in HER2 over-expressing breast cancer cells. Lapatinib also blocks growth of HER2+ cells in culture and in tumour xenografts. It has been observed in one particular study that combinatorial therapy between lapatinib and trastuzumab dramatically reduced the size of HER2+ tumours. In less than 2 weeks, 11% of patients’ tumours had disappeared and a further 17% had their tumour size reduced to less than 5mm. Further division of HER2+ breast cancer:

Although trastuzumab treatment has shifted the paradigm in the treatment of HER2+ breast cancer, patients’ individual sensitivity to trastuzumab varies, with only around 30% of HER2+ patients responding to it. One of the major issues is resistance. Multiple resistance mechanisms exist; hence elucidation and identification of these mechanisms are essential for designing efficient personalised therapy. Preclinical evidence has suggested that inhibition of HER2 and other Her family receptors and/or the downstream signalling partners by combination of trastuzumab with lapatinib and other targeted therapies reduces resistance and improves efficacy of the treatment. Targeting both HER2 and ER in HER2+ breast cancer would be superior to either therapy alone as HER2 and ER signalling might compensate each other.

Gastrointestinal Stromal Tumour – KIT – Imatinib (Gleevec) Gastrointestinal Stromal Tumour (GIST) is a rare primary neoplasm of the GI tract. In the past, surgery has been the only effective treatment. However, the diagnosis and treatment of GIST has been revolutionised over the last decade, since the expression of RTK KIT was shown to occur on these tumours. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT RTK, an important factor in the pathogenesis of the disease. The development of specific RTK inhibitors such as Imatinib has led to a breakthrough in treatment of advanced GIST. Treatment with this drug has lead to overall response rates in excess of 80%; side effects are common but usually manageable. Imatinib Imatinib was developed as an RTK inhibitor. It’s been shown to also inhibit the intracellular kinases ABL and BCR ABL fusion protein in chronic myeloid leukaemia, but was subsequently found to have comparable activity against the Kit receptor and PDGFR. Imatinib is a competitive inhibitor of the ATP binding site. Hence it blocks the transfer of phosphate groups from ATP to tyrosine residues of the substrates. This interrupts the downstream signalling process that leads to cell proliferation, including MAPK and Akt. If a GIST has been surgically removed, many doctors recommend taking imatinib for at least a year post surgery to lower the risk of the cancer coming back (adjuvant therapy). Many doctors recommend up to 3 years post surgery for patients with a higher risk of tumour recurrence. For specifically large GISTs, imatinib may be used first to try and shrink the tumour and increase surgery success rate (neoadjuvant therapy). Often used in combination with adjuvant therapy. Sunitinib: This is a useful drug in treating GIST when imatinib proves ineffective or when the side effects of imatinib become too much for a patient. Sunitinib targets KIT and PDGFRA as well as several other proteins that imatinib doesn’t target. Sunitinib helps some patients by slowing the growth of the tumour. It can also shrink tumours in a small number of patients, increasing the life expectancy of someone with a GIST. Regorafenib: This is the tertiary drug option after imatinib and sunitinib. It has the same effects as the previous two but to a lesser extent.

Melanoma – BRAF – Vemurafenib, Dabrafenib Melanoma is a cancer of the skin. One of the major driving factors behind melanomas is the deregulation of Braf in ~50% of melanomas. This is caused by the V600E mutant. Braf is part of the RAS-RAF-MAPK pathway. Initially Soraferinib was used to target oncogenic Braf. It had an unfortunately disappointing efficacy in melanoma but also inhibits VEGF and is currently a highly potent anti –angiogenic drug used in renal cancer. Vemurafenib: The first BRAF inhibitor to be approved in 2011. This is a highly specific inhibitor for V600E Braf. It competitively binds the ATP pocket, interacting with W351 and D594. In some patients, drastic results were seen in as little as 2 weeks, it was thought to be a new wonder drug. However within a year, patients were returning to the clinic with a relapse due to resistance that we will discuss later. Dabrafenib: Another Braf inhibitor that has shown similar efficacy was approved in 2013. Resistance: Other than being a slamming Muse album, resistance of mutant BRAF melanoma cells to vemurafenib and dabrafenib can prove to be an issue. What can happen is that the melanoma cell’s biochemical mechanisms and signalling pathways can compensate for Braf inhibition. It can do this by activating expression of Craf that circumvents Braf and carries on the signal. Other RTKs are also found to be upregulated such as EGFR, VEGFR, and PDGFR. Another kinase, COT, is also found to be upregulated and this directly activates the downstream MEK. Trametinib: As much as the two BRAF inhibitor above are effective in their jobs, resistance develops to them anywhere between 6-12 months. However, preclinical studies suggested that another novel group of agents, the MEK inhibitors showed stronger inhibition of both BRAF and NRAS mutated cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. There are other MEK inhibitors also in development. Combinant inhibition of MEK and BRAF has shown more durable and greater tumour response than Braf monotherapy, by overcoming the multiple genetic mechanisms of escape.

Chronic Myeloid Leukaemia - BCR-ABL – Gleevec CML is a cancer of the blood, there are ~5000 incidences/year in the US and ~600/year in the UK. It represents 10-20% of all leukaemias. It’s caused by a chromosomal translocation that results in something called the Philadelphia chromosome. This is the fusing of chromosome 9 and 22 at the BCR gene locus and the ABL Kinase gene locus. The fusion protein created called BCR-Abl is massively upregulated and causes uncontrolled proliferation of myeloid cells.

Imatinib was the first drug to specifically target BCR-Abl and quickly became the standard treatment for CML patients. Almost all CML patients respond to imatinib treatment with over 90% seeing a haemolytic response whereby there is a normalisation of the white blood cell count. Resistance: Resistance to Imatinib can however develop. Generally speaking, the later the CML progression the higher the percentage of patients that have innate resistance. Resistance to imatinib is caused by a single nucleotide polymorphism at the 315 position on Abl. Threonine 315 is mutated to Isoleucine 315 in the active site. Ile is a larger, bulkier, hydrophobic amino acid and prevents imatinib from binding the ATP active site. Imatinib resistance is becoming a serious problem, with resistance increasing by 4% each year. Despite this resistance, there are other drugs that have better sensitivity, depending on the mutation present in BCR-Abl. For example Dasatinib or Nilotinib are also prescribed. Both Dasatinib and Nilotinib can be used as a first treatment for CML as well as when people can’t take imatinib or they don’t initially respond to it. Dasatinib has a higher affinity for the ATP binding pocket than imatinib.

Conclusion: The past decade has seen a rapid acceleration of our understanding of the genetic basis of many diseases. With this greater understanding comes the possibility of redefining disease at a higher resolution and targeting with more precise therapy. However, for precision medicine to succeed, genomics must also be more accurate. Whereas in cohort discovery, if a base is missed or an algorithm is insensitive, all that is missed is an opportunity for discovery. In clinical medicine, failing to make a diagnosis, or making diagnosis in error, could have devastating consequences for individuals or families....