China
Africa
Explore chapters and articles related to this topic
Cancer and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Tormod S. Nilsen, Pernille Hojman, Henning Wackerhage
So how did researchers identify driver mutations? Cancer genes were mainly discovered by studying the function of genes and through improved bioinformatical analyses of cancer genomes (16). The most frequently mutated cancer gene is the tumour suppressor also known as the “Guardian of the Genome” p53 (17) as its normal function is to prevents cells with DNA damage from expanding. If p53 is lost, cells with DNA damage will proliferate. A common cancer oncogene is KRAS, where gain-of-function mutations generate a highly active KRAS-protein that drives cancer development and growth. Gain-of-function mutations of KRAS often change the regulatory glycines at position 12 and 13 as well as the glutamine at position 61 within the protein which makes the KRAS-protein more active (18). The loss of p53 through a disabling mutation or the gain of KRAS through an activating mutation in many cell types progresses these cells towards cancer (18). More formally, tumour suppressor genes and oncogenes are defined as genes whose inactivation or activation by mutation increases the selective growth advantage of the cell in which is resides (19). However, with few exceptions, one gene's function changing mutation is not enough to drive cancer. In most cases, several mutations are required (19) to trigger the hallmarks that contribute to a full-blown cancer (10).
Validation Strategy for Biomarker-Guided Precision/Personalized Medicine
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
A typical example for this design comes from a US-based phase III trial testing cetuximab in addition to infusional fluorouracil, leucovorin and oxaliplatin as adjuvant therapy in metastatic colon cancer (Amado et al. 2008). While the trial has been amended to accrue patients only with KRAS–wild-type tumors, approximately 800 patients with KRAS mutant tumors have already been enrolled. The primary analysis in this study was performed at the prespecified 0.05 level in the patients with wild-type KRAS. A sample size of 1,035 patients with wild-type KRAS per arm would result in 515 total events, providing 90% power to detect an HR of 1.33 for this comparison using a two-sided log-rank test at a significance level of 0.05. If this subset analysis is statistically significant at significance level, then the efficacy of the regimen in the entire population will also be tested at 0.05 level, as this is a closed testing procedure. This comparison using all 2,910 patients will have 90% power to detect an HR of 1.27 comparing the two treatment arms, based on a total of 735 events.
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
KRAS is a member of the Ras family that promotes cell growth and division. This pathway is activated by the binding of guanosine triphosphate (GTP) and phosphorylates downstream signaling proteins. The process continues until the GTP is converted to guanosine diphosphate (GDP) through an intrinsic GTPase activity that is present in the Ras family enzymes. While the Ras family includes both HRAS and NRAS, in addition to KRAS, KRAS alone has been implicated in the lung carcinogenesis.
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
RAS mutations account for 13% of all human cancers, among them, about 80% of the cases are associated with KRAS mutants. KRAS mutations are prevalent in many solid tumors such as lung, colorectal, and pancreatic cancers. Most frequented point mutation of KRAS alleles specific cancers are mainly at G12D (35%), G12V (29%), G12C (21%) and G13D (10%) [11,12]. The biochemical effect of these mutations on RAS results in impaired intrinsic GTPase activity or insensitivity for GAP proteins [13]. These alterations in the cell lead to a substantial accumulation of active GTP-RAS population. Hyperactive GTP-RAS induces consistent downstream signaling, which causes uncontrolled cell growth and oncogenic transformation [14]. In KRAS, four druggable allosteric pockets have been identified as pocket P1 near β-sheet, pocket P2 in switch II region (S-IIP), pocket P3 at C-terminal, and pocket P4 (S-IP) present near the switch I region [15]. It is observed that P1 and P2 binding pockets are usually utilized for the development of KRAS inhibitors.
KRAS mutations in metastatic colorectal cancer: from a de facto ban on anti-EGFR treatment in the past to a potential biomarker for precision medicine
Published in Expert Opinion on Biological Therapy, 2021
Dahna Coupez, Pauline Hulo, Yann Touchefeu, Marc G Denis, Jaafar Bennouna
One of the prerequisites for KRAS activation is its attachment to the plasma membrane. This involves farnesyl transferases that catalyze the addition of an isoprenyl group to the cysteine of the terminal CAAX motif [35]. In the 2000s, farnesyltransferase inhibitors were evaluated for metastatic CRC. In highly pre-treated mCRC, tipifarnib was compared to placebo and showed no statistical impact on OS or PFS [36]. The existence of alternative pathways, such as the one involving geranylgeranyltransferase I for RAS prenylation, could explain the lack of efficacy of farnesyltransferase inhibitors [37]. Post-translational modifications of RAS also involve phosphodiesterase-δ (PDE-δ), which helps in the translocation of RAS from the Golgi apparatus to the plasma membrane. Inhibitors of PDE-δ, such as deltarasin or deltazinone 1, have been tested in pre-clinical models [38].
Interleukin 8 as predictive factor for response to chemotherapy in colorectal cancer patients
Published in Acta Clinica Belgica, 2021
Claudia Burz, Anca Bojan, Loredana Balacescu, Vlad-Vasile Pop, Ciprian Silaghi, Iulia Lupan, Cornel Aldea, Daniel Sur, Gabriel Samasca, Calin Cainap, Bogdan Chiorean
CRC represents a major health problem worldwide, being the third most common type of cancer in both women and men according to Globocan 2018 [1]. Prognosis of CRC patients remains difficult to predict, as it is influenced by many factors that depend on tumor characteristics and on each individual patient. Psychological disorders, like anxiety and depression, are often observed in cancer patients and are related to many factors including social conditions, associated co-morbidities, tumor progression or chemotherapy toxicity [15]. Several factors including tumor stage and size and KRAS mutation status have proved their importance as prognostic factors but until now there are not predictive factors to chemotherapy in these patients. Identification of predictive factors for chemotherapy that allows individualized treatment with maximum efficacy and few side effects are pivotal in cancer patients. Moreover, the existence of predictive factors for psychological disorders should allow palliative care intervention with psychological support at the beginning of treatment which may improve quality of life.