Specific Molecular Alteration in Cancer Development - Essay Example

Sur Lecturer Using either the BCR-ABL oncogene or the ERBB2 (HER2/NEU) oncogene as your example, describe one specific molecular alteration which plays a role in cancer development, and discuss how it has been exploited to improve cancer treatment. 1. Target identification: Identification of the molecular defect in cancer. Previous research into lung carcinoma led to the discovery of ERBB2 analogous mutations. Further research indicated that two to four percent of patients exhibited ERBB2 kinase domain mutations. These mutations contributed to increased invasiveness and survival as well as tumorigenicity especially in the cell based transformational assays. The pathological and clinical characteristics of the patients presenting with ERBB2 mutations tend to be more associated with the female gender patients, nonsmokers, patients of Asian origin as well as the adenocarcinoma subtype. This tends to mimic findings on the NSCLC prompted by EGFR mutations (Yarbro, Debra and Barbara, 15). The discovery on activation of mutations amidst the kinase domain in the ERBB2 offers additional therapeutic opportunities and possibilities. Upon conducting an experiment. Researchers noted that mutations of the ERBB2 would be insignificantly influenced by EGFR-TKIs. Conversely, ERBB2-directed TKIs depicted properties of anti-proliferation. Neratinib(HKI-272) had restored hope in the ERBB2-mutant NCI-H1781 cell lineup with preclinical data however, the resultant evaluation of registered a different finding. Patients presenting with EGFR that drives lung cancers were used in the noted evaluation whereby the findings indicates lack of support for the single agent inhibitor(McKinnell, Parchment, Perantoni, Pierce and Ivan, 23). Competitive inhibitors such as the TKIs prevent the ATP form attaching onto its natural site. This occurs because the small molecules TKIs portray higher affinity to ATP binding site within the kinase region. TKIs within the ERBB molecules can be categorized broadly into reversible and irreversible inhibitors. The reversible inhibitors include lapatinib, erlotinib and gefitinib. They can be produced from the receptors. On the other hand, the irreversible inhibitors include afatinib, dacomitib, pelitinib and neratinib. These inhibitors modify the receptors covalently (McKinnell, Parchment, Perantoni, Pierce and Ivan, 24) 2. Target validation: Characterization of the biological role of the molecular defect in cancer development. In part as a result of the constitutive active formation of the ERBB2 could be preferred as the dimerization associate for the rest of the family members of the ERBB. The ERBB2 heterodimers exhibit higher potency for transmitting signals from the extracellular sources. These potency occur despite the availability of four receptors. The functions of these receptors mainly involve allowing numerous pairings which contributes towards unit patterns in the pathways of downstream engagement. The most significant signaling heterodimer, composed of both the ERBB3 and ERBB2, operates as the oncogenic unit. Absence of the catalytic activity of the kinase allows the ERBB3 to heterodimerize with the other ERB molecules. Primarily, the fundamental signaling tool for the ERBB2-ERBB3may be inevitable for the vital activation of the PI3K/Akt pathway. Essentially ERBB2 lacks a direct docking position for PI3K. On the other hand, ERBB3 operates the function of docking on six binding positions of tyrosine the supervisory subunit of P13K. Research conducted previously on this topic indicates a positive correlation between higher activation of Akt and ERBB2 in breast cancers (Aggarwal, Young and Shishir, 100) Through research, oncogenic activation of ERBB2 present with three principal mechanisms which have been identified in the contemporary world. These mechanisms include amplification and overexpression, molecular alterations in the receptors and inhibition of phosphatase activity. The rising number of receptor molecules for cell surface which populate tend to increase the opportunities for phosphorylation of receptor tyrosine and dimerization. This functions could take place in the presence or absence of ligand binding. Amplification and overexpression of the ERBB2 tend to be associated with highly aggressive tumors and poor outcome (Adjei and John, 67) 3. Drug discovery: Development of therapeutic agents targeted against the molecular defect Evolution of sequencing technology in the current world contributes to successful defeat over the challenges of scale and cost in research. In addition, these advances have enabled researchers to identify thousands of operative mutation activities in the somatic cells in one cancer sample. In bioinformatics algorithms, can progressively help towards exploring on the mutational signature landscapes when combined with intense parallel sequencing. Additionally, this combination could aid in distinguishing further on the passenger mutations from the driver mutations. This functions can be determined through molecular sequencing in an individual’s DNA. The DNA can be obtained from tumor biopsy specimens in order to ascertain the alterations in the genetic and epigenetic makeup of the specimen. Any alterations observed needs to be analyzed further so as to determine the time of clinical appearance as well as the time of resistance to therapy or medication. Furthermore, newer therapeutic targets may have been achieved following intensive multiple fusion in the genes in numerous cancers. These targets arise as a consequence for the major advances in addition to the high output technics and mechanisms such as the wholesome genome sequencing. Nevertheless, analysis and implementation of findings and recommendation obtained from the consortia of gene sequencing may require more intensive or comprehensive efforts in multi-disciplinary efforts in translation into the clinic (Cavalli,80) 4. Clinical application: Use of the novel therapy in the treatment of cancer. For solid cancers cases, the initial targeted molecular antibodies may be directed towards the epitopes of the actual cancer cells involved the anti-EGFR (ErbB1) as well as the Trans membrane RTKs and the anti HER2 (ErbB2). The contrastingly partially potential of the unmet therapies target at EGFR, therapies targeted as HER-2 have led to the revolutionized treatment among fifteen to thirty percent of patients of breast cancers. These therapies contribute to the harboring and amplification of the ERBB2 gene as well as an overexpression of the HER-2 protein. In the previous eras where therapies focused on the HER-2 therapies, breast cancers associated with the amplified ERBB2continuously contributed to a specific poor prognosis. . Trastuzumab (Herceptin®; Genentech: San Fransisco, CA, USA) became the first humanized mAb to be approved in 1998 by FDA despite the interference with with the HER2/ Neu receptor (Walker and Ralph 64)  Since then, major progresses and impacts have been made in the management of HER2-positive breast cancers through adjuvant therapy. In its early stages, stage 0-3, the HER-2-positive breast cancers tend to present a quite positive reaction to Trastuzumab. Furthermore, research indicates that nearly fifty percent of all the HER-2-positive breast cancers being treated with Tarstuzumab do not get the tumors or recurrent tumors. However, in metatstaci breast cancer, acquired resistance or innate resistance which often occur in nearly all the cases reported pose a big challenges. These challenges often tend to be common among the various types of oncology therapies and management. Recently, a more advanced version of the Trastuzumab, trastuzumabemtansine (T-DM1, Kadkyla®; Genentech), can now be accesed for metastatic HER2-positive breast cancers (Vegf and Cancer, 50) Work cited Adjei, Alex A, and John K. Buolamwini. Novel Anticancer Agents: Strategies for Discovery and Clinical Testing. Amsterdam: Academic, 2006. Internet resource. Aggarwal, Bharat B, Young-JoonSurh, and ShishirShishodia. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. New York, NY: Springer, 2007. Internet resource. Cavalli, Franco. Textbook of Medical Oncology. London: informa healthcare, 2009. Print. McKinnell, Robert G, Ralph E. Parchment, Alan O. Perantoni, G B. Pierce, and Ivan Damjanov. The Biological Basis of Cancer. Cambridge: Cambridge University Press, 2006. Internet resource. Vegf and Cancer. Springer Verlag, 2013. Print. Walker, John M, and Ralph Rapley. Molecular Biomethods Handbook. Totowa, NJ: Humana Press, 2008. Internet resource. Yarbro, Connie H, Debra Wujcik, and Barbara H. Gobel. Cancer Nursing: Principles and Practice. Sudbury, Mass: Jones and Bartlett Publishers, 2011. Print. Read More