Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 9, Issue 3, 2011

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Full text available

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It is now almost twenty years since pharmacogenetics was heralded as the technology most likely to revolutionize medicine by providing personalized medicine to patients and health consumers. While much attention has been focused on the scientific limits and policy failures that have prevented the widespread uptake of personalized medicine to date, this feature article examines the socio-cultural and political aspects of pharmacogenomics and other related technologies such as online genetic testing that aim to deliver personalized medicine. I suggest that science and technology are ‘ co-produced’ with, and shaped by, culture, politics and economics in relation to one another. Drawing on the UK Nuffield Council of Bioethics' recently published report, Medical Profiling and Online Medicine: The Ethics of Personalized Healthcare in a Consumer Age, I explore the concept of the ‘consumer’ that has been built into these technologies and argue that despite the push from the commercial sector and the often uncritical acceptance of this by governments, the commercialization of personalized medicine will not succeed unless the benefits are considered as beneficial by those who use it. Such technologies do have the potential to improve healthcare but in order for this to be realized we need a more in-depth understanding of what patients and consumers actually want from such services and we must engage with them as well as doctors and other healthcare professionals. In particular more research is needed to document the experiences of patients and consumers who have utilized services to date, as well as how personalized medicine in its broadest sense is already being delivered by doctors and healthcare practitioners in the clinical context. Finally, a more robust ‘ contextualized’ development of personalized medicine will take considerable effort to achieve if we are to ensure that health inequalities are not further exasperated between the populations of more technologically and economically advanced countries and those living in poor less economically developed ones.

Synthetic biology and personalized medicine have yet to become intimately involved, but such involvement has many incentives. An examination of each of these fields reveals the potential interfaces between these interventionoriented approaches to biological processes. Personalized medicine would gain from synthetic biology powerful therapeutic tools while synthetic biology would gain from personalized medicine a compelling motivational framework for designing customized biological interventions. This Feature Article will bring out the complementarity of synthetic biology and personalized medicine by proposing their potential hybrid form, called here constructive personalized medicine. Its diagnostic, therapeutic, predictive and preventive aspects would build on and integrate other achievements in genomics, systems biology and traditional and translational medicine. By imagining a future in which constructive personalized medicine comes into being, its challenges, risks and shortcomings can also be anticipated. Given the rapid pace of change in post-genomic molecular biology, and the push towards translational medicine and science, such anticipations are necessary and useful even prior to approaches such as constructive personalized medicine being actualized. Indeed, analysing future developments is valuable for building a broad capacity to deal with social change emergent from new technologies and configurations of science, regardless of whether those emergent activities ultimately fail or succeed.

Acquired resistance to Herceptin is a major clinical problem in the treatment of HER2-overexpressing breast cancer. Understanding the molecular mechanisms leading to resistance will allow identification of novel therapeutic targets and predictors of therapeutic response. To this end, up-regulation of anti-apoptotic proteins has been associated with resistance to the HER2-targeted drug lapatinib, but has not yet been linked to Herceptin resistance. The aim of the current study was to determine if the Bcl-2 anti-apoptotic protein is a potential therapeutic target in cells with acquired Herceptin resistance. The BT474 HER2-overexpressing breast cancer cell line and BT474-derived acquired Herceptinresistant clones were used as models in this study. Bcl-2 and Bax expression were assessed by Western blotting. Proliferation assays were performed on cells treated with the Bcl-2 inhibitor ABT-737 in the absence or presence of Herceptin. Finally, the effect of PI3K inhibition or IKK inhibition on Bcl-2 expression and Herceptin sensitivity was examined by Western blotting and established proliferation assays. We show that cells with acquired resistance to Herceptin have an increased Bcl-2:Bax ratio. Resistant cells have increased sensitivity to ABT-737. Further, pharmacologic inhibition of Bcl-2 improved sensitivity to Herceptin in acquired resistant cells. Finally, PI3K and IKK inhibition downregulated Bcl-2 expression and increased sensitivity to Herceptin in resistant cells. Taken together, these new observations support further study of Bcl-2-targeted therapies in Herceptin-resistant breast cancers, and importantly, future investigation of Bcl-2 expression as a potential predictor of Herceptin response in patients with HER2-overexpressing breast cancer.

South Africa, like many other developing countries, stands to benefit from novel diagnostics and drugs developed by pharmacogenomics guidance due to high prevalence of disease burden in the region. This includes both communicable (e.g., HIV/AIDS and tuberculosis) and non-communicable (e.g., diabetes and cardiovascular) diseases. For example, although only 0.7% of the world's population lives in South Africa, the country carries 17% of the global HIV/AIDS burden and 5% of the global tuberculosis burden. Nobel Peace Prize Laureate Archbishop Emeritus Desmond Tutu has coined the term Rainbow Nation, referring to a land of wealth in its many diverse peoples and cultures. It is now timely and necessary to reflect on how best to approach new genomics biotechnologies in a manner that carefully considers the public health needs and extant disease burden in the region. The aim of this paper is to document and review the advances in pharmacogenomics in South Africa and importantly, to evaluate the direction that future research should take. Previous research has shown that the populations in South Africa exhibit unique allele frequencies and novel genetic variation in pharmacogenetically relevant genes, often differing from other African and global populations. The high level of genetic diversity, low linkage disequilibrium and the presence of rare variants in these populations question the feasibility of the use of current commercially available genotyping platforms, and may partially account for genotypephenotype discordance observed in past studies. However, the employment of high throughput technologies for genomic research, within the context of large clinical trials, combined with interdisciplinary studies and appropriate regulatory guidelines, should aid in acceleration of pharmacogenomic discoveries in high priority therapeutic areas in South Africa. Finally, we suggest that projects such as the H3Africa Initiative, the SAHGP and PGENI should play an integral role in the coordination of genomic research in South Africa, but also other African countries, by providing infrastructure and capital to local researchers, as well as providing aid in addressing the computational and statistical bottlenecks encountered at present.

Cancer is reported to become one of the leading causes of death worldwide. A number of reasons such as lack of drug efficacy, development of drug resistance and toxicity are contributing towards the development of novel therapeutic alternatives such as cancer vaccines. Tremendous improvements in our understanding of tumor immunology and availability of the state of the art proteomic technologies have made the development of therapeutic cancer vaccines, also known as personalized cancer vaccines, a reality. This new era is labeled as “vaccinomics” because it involves integration of information from newly established fields of “omics” that includes genomics, proteomics, metabolomics and high-throughput bioinformatics. Several different approaches can be explored to develop personalized therapeutic vaccines and cancer therapy, which include the use of tumor specific or associated antigens and peptides, granulocyte macrophage colony-stimulating factor, patients' own tumor cells or immune activating cells such as antigen presenting cells like dendritic cells, tumor banking, personalized tumor graft, and personalized oncology panel. These approaches have shown significant promise in various stages of clinical trials, with its share of failures. Recently, the US FDA has approved the first personalized cancer vaccine against prostate cancer; Sipuleucel-T. This has indeed opened the door for a new and exciting era of personalized cancer interventions. This review focuses on some of the most promising personalized cancer vaccine technologies and products under development and, at the same time, highlights some of the failures from which we can learn to improve the field of personalized cancer vaccine. Finally, we underscore that personalized medicine as a field will be well served by expanding its boundaries so that personalized vaccine based therapeutics can be included as a new subfield that can meaningfully benefit global public health.

Bone marrow transplantation is a form of cell therapy that has been in practice for decades for the treatment of hematological disorders and solid tumors. Immunosuppressive therapy has been a mainstay for treatment, but the severity of the adverse effects has made it an undesirable choice. Mesenchymal stem cells (MSCs), which reside in the vascular regions of the bone marrow, have been shown to serve as cellular support for the hematopoietic stem cell (HSC) niche. Furthermore, the immune suppressive properties of MSCs have been explored in the treatment of inflammatory and autoimmune disorders. Thus, co-therapy with MSCs has been shown to facilitate engraftment of hematopoietic cells by suppressive graft versus host disease (GvHD). Although the mechanism by which MSCs suppress GvHD is unclear, the experimental evidence suggests that this partly occurs by modulation of immune response such as the induction of regulatory T cells. This paper discusses the role of MSCs as co-therapy for the future of stem cell transplantation, with the overarching theme of personalized medicine for cell-based health interventions.