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Publications total: 16
  Jun 6th,2016

Shift in cancer therapy: The promise of cancer molecular signatures

Introduction:

Cancer is probably the biggest burden on the healthcare sector today and according to the World Health Organization, it is the main cause of mortality and morbidity across the globe. It is estimated that by 2020, the number of cancer case will cross the 20 million mark affecting more than 15 million people across the world (WHO, 2015). Thanks to the phenomenal progress in cancer research and high throughput sequencing technologies researchers today are getting a deep insight into the molecular mechanism of cancer progression and heralding a paradigm shift in the way cancer diagnosis and intervention is carried out. Molecular alterations at the level of DNA, RNA and microRNA are being identified in patients suffering from cancer and prospects are being created to use them as molecular signatures as an aid in the diagnosis and treatment of the conditions (Sethi, Ali, Philip & Sarkar, 2013). Current cancer treatment paradigms such as chemotherapy and radiation severely affect the healthy tissues and cells and cause manifestation of harmful side-effects. With targeted cancer therapy guided by molecular signature, only the cancer-affected cells in an organ can be targeted ensuring a much better treatment outcome and significantly less deleterious side effects ("news-medical", 2008). According to the current medical convention, the different types of cancer are defined or categorized by the organ or the location of the body where the condition is manifested such as breast cancer, kidney cancer or lung cancer. However it needs to be noted that an organ or a tissue is made of a wide range of cell types and it is possible that cancer affects only specific cells within an organ. So it will be more beneficial if cancer diagnosis and treatment is carried out according to the cells that are showing molecular alterations and not the organ in general. In a recent study, researchers at the University of California, San Francisco analyzed more than 3000 tumor samples from 12 different cancer types using state of the art high throughput sequencing techniques and observed that many of them do not fit into the standard organ specific definition. The study also led to the identification of new molecular signatures that can be used to define new classes of cancer (Hoadley et al., 2014).


Molecular signatures for cancer diagnosis, characterization and treatment:

A host of studies have already been successful in highlighting the efficacy of molecular signatures or alterations in facilitating diagnosis and treatment of malignancies at a very primitive stage (Ali et al., 2011);(Sethi et al., 2012). The characterization of cancer molecular signatures can also provide a very accurate assumption of the disease prognosis and treatment outcome and can even help in early differentiation of different types of tumours. The identification of molecular signatures specific to a tumour can also go a long way in the conceptualization and development of highly personalized onco-therapeutic strategies. In true sense, the possibility of the use of cancer molecular signatures in making an early diagnosis of malignancies at the molecular level has created a new field of medical diagnosis called molecular oncodiagnostics (Liu, 2003); (Manzeniuk, Malakho, Pekhov, Kosorukova & Poltaraus, 2006). While histopathological examination can aid in the diagnosis of cancer at the organ level, identification of molecular signatures can aid in the characterization of cancer at the cellular level allowing highly cell-specific interventions without any effect on the neighbouring healthy cells. This can not only ensure better treatment outcome but can bring other benefits to the patients such as substantial reduction of treatment side-effects. Molecular signatures or alterations that can be used for early cancer diagnosis are detected at the DNA, RNA as well as at the protein level. For DNA sequences, alterations could occur in the form of replications, deletions, insertions and mutations while for RNA molecular signatures could take the form of post transcriptional modifications (Sethi et al., 2012). With regards to protein sequences, alterations could appear during the translation and post translational phases (Demidyuk et al., 2013); (Goldstein, Paull, Ellis & Stuart, 2013). Another molecule that is rapidly become significant for early diagnosis of malignancies is microRNA. These molecules are made up of short nucleotide sequences and are closely involved in cancer initiation, development and metastasis (Sethi, Ali, Philip & Sarkar, 2013). Furthermore, research has shown that microRNAs are highly specific to different kinds of tumours and this aspects is widely being used now for early identification and characterization of malignancies (Liang, Ridzon, Wong & Chen, 2007); (Lu et al., 2005). During malignancy microRNA molecules show alteration either in the form of up-regulation or downregulation. Studies have established that upregulated microRNa molecules can facilitate carcinogenesis while downregulated molecules cause suppression of tumour proliferation (Fazlul H. Sarkar, 2012). Thus it can be clearly seen why identification and characterization of molecular signatures or alterations such as these can be extremely helpful in early diagnosis of cancer.

These interesting developments clearly point towards a change in the paradigm of cancer diagnosis and treatment in the present time. The focus today is rapidly shifting from generalized diagnosis and treatment protocols to more specific and personalized paradigms that are based on molecular changes. However for any molecule to qualify as a early cancer signature it has be detectable in a wide variety of biological samples such as blood, aspirated tissue fluids and even tissues of different kinds (Gall et al., 2013); (Ali, Saleh, Sethi, Sarkar & Philip, 2012). Thanks to the rapid development of gene sequencing technologies and molecular biology techniques, researchers today have identified a wide range of molecules that may not be detectable in all forms of specimens mentioned above and this may greatly affect their applicability in cancer diagnosis. In this context the microRNA molecules appear as ideal molecular targets for early cancer characterization because they are detectable in all forms of biological specimens obtained from patients. Additionally, microRNA molecules are ideal molecular signatures for early cancer diagnosis and treatment because of their close involvement in different malignancy-related cellular alterations such as uncontrolled cell proliferation and differentiation. Current scientific evidences also suggest that when initial cancer interventions fail in patients they are very less likely to respond to any further conventional cancer treatments (CARIS, 2016). So once again the promise of alternative and more specific cancer interventions based on molecular markers, alterations and signatures becomes clearly visible. Molecular signatures are able to bring into focus, highly unique and novel clues about the specific tumour type affecting a patient. Intervention decisions that are based on such clues are much more likely to show positive results and conversely the clues can also help identify the kind of interventions that are most likely to fail. In essence, the molecular signatures truly facilitate highly personalized treatment for patients suffering from a wide variety of cancers.


Conclusion:

Cancer is still one of the largest causes of death across the world and there is scope for considerable development in cancer diagnosis and therapeutics. While radiation and chemotherapy are effective in arresting cancer proliferation in different scenarios, early diagnosis remains a major determining factor in ensuring good prognosis. Furthermore, side effects of chemotherapy is a costly trade-off that patients are forced to bear. The use of molecular signatures or alterations for early diagnosis of cancer is heralding a major paradigm shift in cancer management and creating unique avenues for highly personalized oncotherapeutics. Oncologists and pathologists no longer have to depend on morphological and pathological alterations to diagnose and treat malignancies. Molecular alterations or aberrations at the genomic and proteomic levels can now serve as signatures that can be used to formulate highly cell-specific and personalized treatment strategies. Advanced sequencing and molecular biology techniques are available today that can be used for rapid identification and characterization of these molecular alterations aiding in cancer management. The most desirable goal of cancer research today is to formulate diagnosis and treatment strategies that will not just be highly tumor specific at the cellular level but will also be highly customizable according to the genetic makeup of the patients. This, in true sense, will be pinnacle of personalized oncodiagnostics and oncotherapeutics.


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