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One Size Does Not Fit All—The Future of Cancer Therapy

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One Size Does Not Fit All—The Future of Cancer Therapy Journal of the Indian Institute of Science A Multidisciplinary Reviews Journal ISSN: 0970-4140 Coden-JIISAD © Indian Institute of Science One Size does not Fit All—The Future of Cancer Therapy Sujaya Srinivasan and Kumaravel Somasundaram* Abstract | Cancer is a complex disease where normal cells of the body are REVIEWS transformed such that they begin to divide in an uncontrolled manner and can even invade other tissues in the body. Cancer can occur in many differ- ent tissues in the body, each requiring different forms of treatment. It is a dis- ease that is caused by changes or mutations in genes, leading to a cascade of other genetic changes in the body. There is a high degree of genetic het- erogeneity in tumors of a single type of cancer, which might explain why each patient responds to standard treatments differently. This makes it necessary to tailor treatments for cancer patients based on the molecular profiles of their tumors. This is the idea behind personalized medicine, where patients are treated based on their individual genetic changes or molecular profiles. In this paper, we look at some of the molecular profiles that are commonly used Mutation: It is a permanent in different types of cancers, and some personalized therapies that already change in the DNA sequence of a gene resulting in a defec- exist. In addition, we also attempt to predict how cancer treatment will be tive gene and can alter the revolutionized by some of the new technologies that are emerging today. amino acid sequence of the protein encoded by the gene Keywords: Cancer, oncology, personalized medicine, targeted therapy, gene signatures, molecular resulting in the production of signatures, genomics, next generation sequencing a non functional protein. Prognosis: It is a prediction of the probable course and 1 Heterogeneity of Cancer Due to this heterogeneity, even within a single outcome of a disease or the Cancer is a disease of the cells in the body, where type of cancer, for example breast cancer, mortal- likelihood of recovery from a disease. the normal processes of cell division and cell death ity and prognosis of patients differ widely. Some go awry. Cells divide uncontrollably and live for- patients respond very well to standard surgery, Genetics: It is a branch of ever. It is estimated that 1 in 3 individuals develop chemotherapy and radiotherapy treatments, while biology that deals with the molecular structure and cancer at some time in their life. According to the the same treatments are ineffective in others. On function of genes, heredity, medical journal Lancet, it is estimated that in India the other hand, patients who do not have very and variation in living alone, 555,000 people died of cancer in 2010.1 aggressive forms of cancer are overtreated with organisms. Cancers can develop in various tissues in the standard chemotherapy regimens, which may lead Epigenetics: It is the study of body, and can manifest themselves in different to other undesired side-effects. Cancer research heritable alterations in gene expression or cellular pheno- ways. Cancer is caused by mutations in genes that over the last decade has uncovered that not one, type caused by mechanisms can further lead to other genetic and epigenetic but many genes can play a role in cancer devel- other than changes in DNA changes. In spite of a few genetic and epigenetic opment and progression. This explains why some sequence. changes that dominate a particular cancer, each patients require different forms of treatment, Gene: It is a molecular unit of tumor differs from the rest. Study of tumors shows which are not based on the phenotype or mani- heredity of a living organism that there is a lot of genetic heterogeneity among festation of the disease, but on their underlying and is a segment of DNA on a specific site on a chromosome them, leading to subtype classifications on the genetic or epigenetic changes. that is responsible for an basis of molecular profiles. We therefore need to inheritable trait. understand cancer as an accumulation of acquired 2 The Impact of Genomics Research Department of and inherited gene mutations, in addition to epi- on Cancer Microbiology and Cell genetic changes that could be caused both by both The main goals of cancer therapy are focused on Biology, Indian Institute interactions in the tissue microenvironment as prevention, detection and treatment. In order to of Science, Bangalore 560012, India. well as the external environment. treat cancer effectively, it is necessary to look at the *[email protected] Journal of the Indian Institute of Science VOL 92:3 Jul.–Sept. 2012 journal.library.iisc.ernet.in Sujaya Srinivasan and Kumaravel Somasundaram Genomics: entire genome as a whole, rather than individual for pathologists to distinguish between Grades It is a discipline in genetics concerned with the study of genetic changes. In a disease like cancer, due to 3 and 4, which are malignant forms of glioma. the genomes of organisms. the heterogeneity of genetic changes, the taxon- Grade 3 glioma, also known as anaplastic astro- The field includes efforts to omy and classification of tumors is increasingly cytoma (AA), is less malignant and aggres- determine the entire DNA sequence of organisms and depending on molecular profiles, rather than mor- sive, whereas Grade 4 glioma, also known as fine-scale genetic mapping. phologic characteristics. This means that genomic glioblastoma (GBM), is extremely aggressive and Proteomic: and proteomic profiles of patient tumors can help has very poor prognosis. We have developed a It is the study of all the pro- decide what type of treatment they should receive, molecular signature based on microRNA expres- teins expressed by a given cell, tissue, or organism at a given and predict the prognosis of patients. sion that can accurately classify Grade 3 and 4 2 time. Given time and under Personalized medicine is a form of therapy tumors. The expression profiles of 23 microR- specific conditions. that uses the information about a person’s genetic NAs is used to accurately classify anaplastic astro- MicroRNA: and protein profile to diagnose and treat a disease. cytoma (Grade 3) and glioblastoma (Grade 4) It is a small RNA molecule This form of medicine is especially promising for samples (see Figure 1). We have also developed encoded by the DNA, highly conserved and can regulate a disease like cancer, which exhibits a large degree a signature based on microRNA expression that the expression of genes. of heterogeneity. Personalized medicine aims to can sub-divide GBM patients into high-risk Protein: end the idea that one treatment can work for all and low-risk groups, and predict survival.3 Sev- It is a large molecule composed patients, and attempts to find therapies that fit the eral mRNA signatures have also been developed of one or more chains of amino 4,5 acids in a specific order, which individual needs of a patient. for GBM that can help in prognostication and is determined by the RNA The idea behind personalized medicine is that classification. derived from a gene. Each pro- a patient’s genomic (genetic changes in DNA), Over the last decade, several research groups tein like a hormone, enzyme, or antibody has unique functions. transcriptomic (RNA levels) and epigenetic (her- have developed molecular signatures for various itable changes in gene expression without changes cancers, but very few of these have been used in the Deoxyribonucleic acid (DNA): It is a nucleic acid containing in the underlying DNA) profiles are characterized clinic. A signature that is developed in one patient the genetic instructions used in from which target biomarkers that are known to cohort, very frequently needs to be validated in the development and function- be involved in cancer development and progres- another patient cohort, due to the underlying het- ing of all known living organ- isms and it consists of two long sion are identified. Identification of these criti- erogeneity of tumors and use of different platforms polymers of simple units called cal genes that play a key role in carcinogenesis for the validation process. Unless these signatures nucleotides, with backbones involves many scientific challenges. Once these are applicable in widely varying cohorts of patients made of sugars and phosphate groups joined by ester bonds. gene targets are identified, drugs that target these and tested in multiple cancer centers, clinicians are Ribonucleic acid (RNA): genes can then be developed. unable and reluctant to use them on patients. It is very similar to DNA, but Several examples of personalized medicine Despite the difficulties in translating molecular differs in a few important exist in clinics today. Most of them involve some signatures from research labs to the clinic, there are structural details and is usually single-stranded, while DNA is form of molecular profiling to decide the type a few success stories. The Oncotype DX™ Breast usually double-stranded in the of treatment that should be given. In some cases, Cancer Assay and the Oncotype DX™ Colon Can- cell. RNA is transcribed from a group of genes that is known to be deregulated in cer Assay (Genomic Health, Redwood CA), Mam- DNA by enzymes called RNA polymerases and it carries the the specific cancer, or is a “signature” of a certain maPrint® for breast cancer (Agendia, Amsterdam, information from a gene to subtype of the cancer is profiled to better classify The Netherlands) and the Breast Cancer Gene form a protein. the tumor. This subtyping not only helps in decid- Expression ratio (HOXB13:IL17BR) test (Quest Molecular signature: ing treatment, but in some cases is also able to Diagnostics, Lyndhurst, NJ) are used by oncolo- It is a set of genes, RNA tran- scripts, proteins, genetic vari- predict the prognosis of the patient.
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