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   2014| September-December  | Volume 7 | Issue 3  
    Online since April 19, 2018

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Discovery of first-in-class therapeutics – venlafaxine (Effexor®), desvenlafaxine (Pristiq®), temsirolimus (Toresil®), ILS-920 and gemtuzumab ozogamicin (Mylotarg®)
Magid Abou-Gharbia
September-December 2014, 7(3):317-331
The pharmaceutical industry today is experiencing unprecedented difficulty and faces enormous challenges, which include the industry's declining efficiencies, patent expirations for key drugs, fierce price competition from generic drugs, mergers and acquisitions, high regulatory hurdles, declining innovation and the industry's perceived tarnished image. Pharma has embarked on a range of initiatives to address these challenges, maintain its commitment to innovation and continue its mission to alleviate human suffering through the discovery of new medicines. This review covers the following themes: (1) drug discovery – highlighting process, targets, approach and current pharmaceutical platforms (small molecules, biologics and vaccines); (2) today's realities – highlighting current challenges facing the pharmaceutical industry, especially the innovation gap, and Pharma's commitment to innovation; (3) commitment to innovation and success stories focusing on selected examples of first-in-class therapeutics, such as the serotonin–noradrenaline reuptake inhibitor antidepressants venlafaxine (Effexor®, Pfizer, Surrey, UK) and desvenlafaxine (Pristiq®, Pfizer, Surrey, UK), immunophilin mammalian target of rapamycin modulator temsirolimus (Toresil®, Pfizer, Surrey, UK), the neuroprotectant ILS-920 for stroke therapy and the first conjugate anticancer drug gemtuzumab ozogamicin (Mylotarg®, Pfizer, Surrey, UK). Although many high drug discovery hurdles remain, the future holds great promise. The search continues for major breakthrough therapies that address unmet medical needs, such as disease-halting drugs for the treatment of Alzheimer's disease, drugs to eradicate hepatitis C and acquired immune deficiency syndrome, and drugs to attack resistant cancers, treat strokes and alleviate cardiovascular disease.
[ABSTRACT]   Full text not available  [PDF]
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Imatinib (Glivec®) as a paradigm of targeted cancer therapies
Brian J Druker
September-December 2014, 7(3):277-287
Imatinib (Glivec®, Novartis Pharmaceuticals UK Ltd, Basel, Switzerland) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukaemia and the steps for the development of an agent to specifically inactivate this abnormality. The results of unprecedented clinical trials are reviewed alongside a description of resistance mechanisms and the development of novel tyrosine kinase inhibitors to circumvent resistance. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases is described. Finally, the application of the paradigm of targeting molecular pathogenetic events to other malignancies is explored.
[ABSTRACT]   Full text not available  [PDF]
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Inhibitors of the ‘point of no return’ in human immunodeficiency virus infectivity – discovery of novel antihuman immunodeficiency virus integrase compounds with dual mechanism of action
Vasu Nair, Maurice O Okello
September-December 2014, 7(3):389-402
Although the global therapeutic response to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has seen tangible progress, this viral pandemic continues to ravage many worldwide communities nevertheless. At least 34 million people in the world are infected with HIV and a few million additional HIV infections occur each year. Moreover, co-infection of HIV and tuberculosis (TB), and particularly multidrug-resistant (MDR)-TB, has taken the pandemic to a substantially elevated level of seriousness with significant increases in mortality. Although progress has been made in the field of anti-HIV active integrase inhibitors and their use in combination therapeutics against HIV/AIDS, some very significant challenges still remain to be surmounted with next-generation integrase inhibitors for HIV/AIDS. These include appropriate profiles with respect to phase I and II metabolism, minimizing adverse drug–drug interactions, cross-resistance issues and, very importantly, HIV co-infections involving drug-resistant infections. In our laboratory we have discovered a novel class of HIV integrase inhibitors, exemplified by 4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide (compound 2), which exhibits potent anti-HIV activity against a large and diverse set of HIV isolates. This drug displays low cytotoxicity and its resistance and related drug susceptibility data are also positive. Its profile with respect to phase I and II metabolic isozymes/isoforms of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase are very favourable, which is of significant advantage in drug–drug interaction issues. Preclinical studies in animals revealed a positive pharmacokinetic profile and no adverse treatment-related findings. The ability to synthesize pure compounds of this family in very high yields, and therefore the potential for worldwide availability, is another positive aspect of this drug discovery. Finally, the most significant part of this drug discovery is the remarkable dual mechanism of action of these conceptually new small molecules against both HIV and MDR-TB.
[ABSTRACT]   Full text not available  [PDF]
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Haematopoietic cell transplantation – from its birth to the twenty-first century
Rainer Storb
September-December 2014, 7(3):333-341
After more than 60 years of investigations into the use of allogeneic haematopoietic cell transplantation for treatment of otherwise fatal malignant and non-malignant blood disorders, this procedure has been transformed from one that was thought to be plagued with insurmountable difficulties to a standard therapy for many haematological diseases. How have these problems been overcome and how was this procedure extended to include patients who were too old or medically unfit to tolerate conventional, high-intensity transplant approaches?
[ABSTRACT]   Full text not available  [PDF]
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Progress in vaccination
Stanley A Plotkin
September-December 2014, 7(3):343-353
During the lifetime of the author, vaccination has evolved in the complexity of its targets and the technologies used to overcome that complexity. This point is illustrated using the development of several vaccines. Rubella was, and in some countries still is, a major cause of birth defects when infection occurs during pregnancy. In order to prevent infection by a wild virus, a strain was isolated from a congenital infection and attenuated by passage in human fibroblasts at low temperature. The resultant virus was attenuated and could immunize mothers and thus prevent congenital infection and abnormalities. Although rabies vaccines had been developed in the nineteenth century, the available vaccines were poorly immunogenic and sometimes failed to protect. The virus was adapted to cell culture and inactivated with beta-propiolactone. This resulted in highly immunogenic vaccines that can protect after three or four doses only. Infantile gastroenteritis is a problem throughout the world and its major cause is the rotaviruses. In order to prevent infection, a bovine rotavirus was combined with antigens from human strains by the technique of reassortment of segmented RNA. The resulting vaccine was attenuated but could infect infants and generate protective responses at the intestinal level. Finally, cytomegalovirus is now the number one infectious cause of congenital abnormalities. To prevent this virus from infecting pregnant women, a variety of approaches are being taken to develop a vaccine, including using glycoproteins from the virus, developing vaccine replication-defective strains and DNA plasmids.
[ABSTRACT]   Full text not available  [PDF]
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Graft-versus-host disease, a major complication after stem cell transplantation – home care for prevention and stromal cells for therapy
Olle Ringden
September-December 2014, 7(3):375-387
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation (HSCT). Although severe acute GVHD is associated with a high mortality, chronic GVHD is associated with a strong anticancer effect. Patients suffering from leukaemia who undergo HSCT have a reduced risk of recurrent disease if they develop chronic GVHD. During the neutropenic phase after HSCT, patients are isolated in the hospital, sometimes in laminar airflow rooms. We challenged this by allowing patients to be treated at home. A nurse from the unit visited and checked the patient daily. Compared with hospital controls, home-care patients had a decreased risk of acute GVHD, which was associated with number of days treated at home during neutropenia. Home care did not affect chronic GVHD or relapse and, therefore, home-care patients had a trend for better survival than those treated in the hospital. Stromal cells such as mesenchymal stem cells (MSCs) or placenta-derived decidual stromal cells suppress alloantigen-induced T-cells in vitro. This effect was seen despite HLA incompatibility between MSCs and stimulatory or allo-reactive cells in vitro, enabling the use of third-party stromal cells in the clinic. Because stromal cells home to target organs of tissue toxicity, and have low immunogenicity, they may be useful in regenerative medicine such as acute and chronic GVHD, haemorrhages and tissue toxicity. I was the first to use MSCs for life-threatening acute GVHD with miraculous response in some, although not all, patients. Clinically, MSCs were found to completely reverse severe acute GVHD in approximately 50% of patients. Among patients with chronic GVHD, the complete response rate was approximately 25%. Stromal cells interfere with coagulation and reversed haemorrhagic cystitis and may stop major haemorrhages in patients who have undergone HSCT. In addition to GVHD and haemorrhages, stromal cells may be used for treatment of graft failure and allograft rejection in organ transplant patients, for tissue toxicity in cancer patients and to treat autoimmune disorders. To conclude, GVHD is a limiting severe side-effect of HSCT which may be decreased by home care. Stromal cells have potential in regenerative medicine and have healed severe GVHD, although improvements are warranted.
[ABSTRACT]   Full text not available  [PDF]
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The golden anniversary of the measles vaccine
Samuel L Katz
September-December 2014, 7(3):421-424
Developed in the Enders laboratory of Boston Children's Hospital (Boston, MA, USA) and Harvard Medical School (Boston, MA, USA) from 1954 to 1963, the live attenuated measles virus vaccine, ‘Edmonston’, was the product of multiple passages through varied cell culture systems and embryonated hens' eggs, and studies in susceptible cynomolgus monkeys prior to introduction to adult humans and then susceptible children. Successful results enabled widespread studies in American children, leading to licensure in March 1963. Extension of clinical investigations then proceeded in Nigeria among health-compromised susceptible children, demonstrating the safety and effectiveness of the Edmonston vaccine among these young people. With national and international adoption of routine vaccination, measles was reduced to an uncommon childhood infection in many countries and, with the progress to a two-dose schedule, was eliminated from the entire western hemisphere by 2002. The World Health Organization's inclusion of measles vaccine in its Expanded Program of Immunization since 1974 has reduced global mortality from measles and its complications from several million annually to approximately 150 000 by 2011. Leading the elimination efforts since 2001 has been the Measles Initiative, which was broadened in 2012 to include rubella vaccine. The vaccine induces enduring (lifelong) immunity and is effective against all 23 known measles virus genotypes.
[ABSTRACT]   Full text not available  [PDF]
  222 33 -
Cell therapy for cancer – our synthetic future
Carl H June
September-December 2014, 7(3):355-365
It is now well established that the immune system can control and eliminate cancer cells. Adoptive T-cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immunocompromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this article. Various chimeric antigen receptor designs, manufacturing processes and study populations, among other variables, have been tested and reported in recent clinical trials. Many questions remain unanswered in the field of engineered T-cells, but the encouraging response rates pave a wide road for future investigation.
[ABSTRACT]   Full text not available  [PDF]
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Drugging the cancer genome – discovery of small-molecule targeted therapeutics for personalized, precision medicine
Paul Workman
September-December 2014, 7(3):289-303
This article describes my research on the discovery of innovative small-molecule targeted therapeutics for use in personalized, precision cancer medicine. This is exemplified by two particular examples. Firstly, I describe our discovery of novel and effective small-molecule inhibitors of the molecular chaperone HSP90 – and especially the leading clinical agent, AUY922, which is showing strong activity in HER2-positive breast cancers that have become refractory to trastuzumab (Herceptin®, Roche Ltd, Basel, Switzerland) and also in non-small cell lung cancers, including those that are resistant to oncogenic driver protein kinase inhibitors – with general potential to overcome or prevent the problem of drug resistance. Secondly, I discuss our discovery of pathfinding small-molecule inhibitors of class I PI3 kinases, especially the first-in-class pan-class I-selective inhibitor GDC-0941, for which clinical responses have been observed in breast and ovarian cancer, gastrointestinal stromal tumours, multiple myeloma and melanoma. More broadly, our Cancer Research UK Cancer Therapeutics Unit has discovered 17 innovative drug candidates since 2005 and progressed seven of these into biomarker-led, hypothesis-driven clinical trials with successful pharmacodynamic biomarker modulation in all cases and clinical responses in most to date, exemplifying the use of our ‘Pharmacologic Audit Trail’ concept for drug discovery and clinical development. Furthermore, our CYP17 inhibitor abiraterone (Zytiga®, Janssen Pharmaceuticals Inc., NJ, USA), designed and synthesized in our unit and initially trialled in our partner hospital, The Royal Marsden Hospital (London, UK), was approved for late-stage castration-resistant prostate cancer in 2011. Thus, we have developed a successful model for high-quality academic drug discovery in the non-profit setting (Anonymous. Drug discovery gets an academic push. Cancer Discov 2011; 1:93–4). Importantly, this provides a creative derisking solution for the innovation gap or ‘valley of death' that often divides basic research from clinical translation. This new model is especially critical at a time when the adverse economic climate and other pressures have led to downsizing and increased risk aversion in the large pharmaceutical companies together with reduced venture investment in biotechnology companies. Having taken on the early high-risk research of new targets, we have also been very successful in partnering our drug discovery projects with industry at the appropriate stage using a range of commercial models with speed-to-patient benefit as the main driver [Houlton S. Fast, flexible and flourishing. Chemistry World, 2012. URL: www.rsc.org/chemistryworld/more/?author=35&date-range=2-5+years (last accessed 30 September 2014)]. Before focusing on our work on what I refer to as ‘drugging the cancer genome’, and particularly the examples of HSP90 and PI3 kinase inhibitors, I provide a short summary of the background to molecularly targeted cancer drug discovery and development together with brief comments on my early research on hypoxia-targeted drugs and signal transduction inhibitors, with the aim of setting the context for what follows. To finish, I offer some concluding remarks and future perspectives on the discovery, development and use of personalized, precision medicines for cancer.
[ABSTRACT]   Full text not available  [PDF]
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Antiproliferative and pro-apoptotic actions of oestrogen receptor β in prostate cancer
Jan-Ake Gustafsson, Anders Ström
September-December 2014, 7(3):403-409
Oestrogen receptor (ER) β, the second ER, appears to be a tumour suppressor in most tissues that have been investigated. Recently, studies of prostate cancer have shown that tumour-suppressive effects of ERβ occur through varying mechanisms including increased apoptosis, reduced invasiveness and epithelial mesenchymal transition as well as inhibited proliferation. It has been suggested that ERβ is a potential drug target for the treatment of prostate cancer.
[ABSTRACT]   Full text not available  [PDF] [CITATIONS]
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The evolution of targeted therapy of the erbB2/neu oncoprotein for human cancer therapy
E Aaron Runkle, Mark I Greene
September-December 2014, 7(3):367-373
The recognition that the erbB2/neu oncogene encodes a cell-surface receptor led to the development of targeted therapy. The erbB2/neu oncogene was found to encode a tyrosine kinase receptor that can form active dimers as a consequence of mutation or amplification. The receptor protein p185erbB2/neu was found to be able to dimerize with itself or with other members of the erbB family to create heteromers with active enzymatic activity and to diversify signalling and transforming patterns. When mutated or amplified, these homodimeric or heterodimeric kinases lead to human cancers, including breast and stomach malignancies. The first targeted therapeutics were monoclonal antibodies that were directed at the ectodomain of the p185erbB2/neu protein and resulted in receptor down-modulation and kinase inhibition. Unexpectedly, disabling the erbB2/neu kinase complex caused the malignant cells to convert to a more normal phenotype. The first demonstration that malignant properties could be reversed challenged all thinking at the time that malignant transformation could progressively lead to more phenotypically abnormal cells. Subsequent to phenotypical reversion, the tumour cells become sensitive to extrinsic death signals from radiation and chemotherapy. The disabling of oncoproteins that determine malignancy is an approach that is now a standard therapy for human cancer.
[ABSTRACT]   Full text not available  [PDF]
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Repurposing failed pharmaceuticals as the first targeted medicines for the treatment and prevention of breast cancer
V Craig Jordan
September-December 2014, 7(3):305-315
The selective oestrogen receptor modulators (SERMs) tamoxifen and raloxifene (Evista®, Eli Lilly, Indianapolis, IN, USA) are both pioneering medicines that have improved the health and life expectancy of millions of women around the world. These are targeted therapies to treat or prevent breast cancer by blocking the tumour oestrogen receptor (ER) to prevent oestrogen-stimulated growth but, at the same time, modulate bone to express oestrogen-like effects to prevent fractures. Raloxifene was the first medicine to be approved for the prevention of both breast cancer and osteoporosis; however, both drugs were not initially destined to be developed at all. Tamoxifen was intended to be a contraceptive, and raloxifene was to be a breast cancer drug targeted to tumour ER, but both applications failed. In both cases, drug development was terminated. Nonetheless, the abandoned drugs were repurposed through careful laboratory models of human disease to be resurrected as ‘firsts’ in their class of targeted medicines. Tamoxifen became the ‘gold standard’ as the antihormone therapy for prevention and treatment of all stages of breast cancer, in women, ductal carcinoma in situ and male breast cancer. No other medicine has that distinction. Raloxifene was the first SERM to be approved for two completely different diseases, the treatment of osteoporosis and the prevention of breast cancer. These targeted therapies changed medicine.
[ABSTRACT]   Full text not available  [PDF]
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Rotarix™ from early discovery to widespread use
Richard L Ward, David I Bernstein
September-December 2014, 7(3):411-420
Prior to the introduction of rotavirus vaccines, rotavirus was the predominant cause of childhood gastroenteritis worldwide. In this review, we discuss the rationale for developing a rotavirus vaccine and, more specifically, the development of a live attenuated single-strain vaccine. Early trials are described as well as the later trials in the developing world. The early impact of rotavirus vaccines has been even better than expected but challenges remain in making the vaccines available in areas where the burden of disease is greatest.
[ABSTRACT]   Full text not available  [PDF]
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With Head, Heart and Hands, Make a Medical Professional by Abdul Jabbar Mehdi Salih
Harald Rosen
September-December 2014, 7(3):275-275
Full text not available  [PDF]
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