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251. ErbB3 plays a key role in the early phase of establishment of resistance to BRAF and/or MEK inhibitors

Author

Gennaro Ciliberto, Antoni Ribas, Giuseppe Roscilli, Paolo A. Ascierto, Luigi Aurisicchio, Francesca Belleudi, Luigi Fattore, Debora Malpicci, Emanuele Marra, Rita Mancini, Maria Rosaria Torrisi, and Rosalba Camerlingo

Subjects
Medicine(all), Oncogene, Combination therapy, business.industry, Biochemistry, Genetics and Molecular Biology(all), Melanoma, Cell, Cancer, Keynote Speaker Presentation, General Medicine, Bioinformatics, medicine.disease, General Biochemistry, Genetics and Molecular Biology, medicine.anatomical_structure, Downregulation and upregulation, Cancer research, Medicine, ERBB3, business, Protein kinase B, neoplasms
Abstract

Background A major issue in the management of cancer is the development of drug resistance. In metastatic melanoma bearing V600 mutations in the BRAF oncogene, all patients undergo disease relapse after combination therapy with BRAF and MEK inhibitors. Hence, understanding the mechanisms at the basis of development of resistance is fundamental to the discovery of new therapeutic approaches. In our group we have spent the last years to identify mechanisms of early adaptation of BRAF mutated melanoma to BRAF and or MEK inhibitors. We have recently shown that the ErbB3 receptor is involved in the activation of an early feedback survival loop upon cell exposure to BRAF and/or MEK inhibitors. Upregulation of pErbB3, due to enhanced production of its ligand neuregulin-1 (HRG), causes increased AKT phosphorylation and cell survival. Furthermore, we demonstrated that activation of the ErbB3/AKT axis is abrogated by cotreatment with anti-ErbB3 mAbs previously generated in our laboratory.

Published
2015

252. Abstract 4790: Overexpression of miR-3151 leads to direct deregulation of the TP53 pathway and is associated with BRAF mutations in malignant melanoma

Author

Ann-Kathrin Eisfeld, Joseph Markowitz, William E. Carson, Ravi Patel, Albert de la Chapelle, and Malori A. Lankenau

Subjects
Cancer Research, endocrine system diseases, Cell growth, Melanoma, Cancer, Biology, medicine.disease, medicine.disease_cause, Oncology, Downregulation and upregulation, microRNA, medicine, Cancer research, Gene silencing, Carcinogenesis, neoplasms, BAALC
Abstract

Background: The BRAF gene is the most frequently mutated gene in malignant melanoma (MM). When mutated, it is associated with a more aggressive disease phenotype. Recently, intronic microRNA miR-3151 was identified in intron 1 of BAALC via deep-sequencing of MM samples. BAALC is reported to be the most upregulated gene in BRAF mutated melanoma. In acute myeloid leukemia, both high miR-3151 and BAALC are associated with poor survival. In addition, miR-3151 has direct leukemogenic activity via direct deregulation of TP53. Aims: To decipher miR-3151's role in MM carcinogenesis and to elucidate its relation with BRAF mutations. Methods/Results: miR-3151 and TP53 expression levels were determined in MM patients (n=20). Indeed, patients with high miR-3151 had lower TP53 expression. To prove direct downregulation of TP53 by miR-3151, we stably expressed miR-3151 and antagomiR-3151 in MM cell lines (Mel-39, A375, MeWo). RT-PCR and Western blots confirmed downregulation of TP53 by forced miR-3151 expression and upregulation of TP53 by antagomiR-3151. Increased levels of miR-3151 led to increased cell proliferation and decreased apoptosis by miR-3151, whereas antagomiR-3151 reduced cell growth and increased apoptosis. Concurrent Annexin/PI-staining revealed a reduction of cells in S and G2 phase in response to antagomiR-3151. Next, we determined the BRAF mutation status in the set of 20 MM patients and tested for a possible association with miR-3151 expression. BRAF mutated (BRAFmut) patients had a 5-fold higher miR-3151 expression compared to BRAF wild-type (BRAFwt) patients. To test whether BRAF mutations directly influence miR-3151, we performed si-mediated knock-down in BRAFmut cell lines (A375, Mel-39) and introduced the BRAF mutation into the BRAFwt cell line (MeWo) and then determined miR-3151 and TP53 expression. Silencing BRAF decreased miR-3151 expression and consequently increased TP53 expression, while introducing the BRAF mutation increased miR-3151 expression and decreased TP53 when compared to scramble control. Finally, as pharmacologic inhibition of aberrantly activated BRAF is a promising treatment approach for BRAFmut MM and as we had just identified miR-3151 as a downstream target of BRAF, we tested whether simultaneous knock-down of miR-3151 would add to the known effects of the BRAF inhibitor Zelboraf. The presence of antagomiR-3151 reduced the dose of Zelboraf required to achieve cell death by 60%. Summary / Conclusions: miR-3151 deregulates TP53 in MM patients, thereby increasing the proliferation of MM cell lines. AntagomiR-3151 reduced MM cell growth and increased apoptosis in vitro. High miR-3151 expression is associated with the presence of BRAF mutations in MM patients, which directly increases miR-3151 expression. Simultaneous treatment of BRAFmut cell lines with the BRAF inhibitor Zelboraf and antagomiR-3151 significantly reduced the IC50 of Zelboraf. Citation Format: Malori Lankenau, Ravi Patel, Joseph Markowitz, William E. Carson, Albert de la Chapelle, Ann-Kathrin Eisfeld. Overexpression of miR-3151 leads to direct deregulation of the TP53 pathway and is associated with BRAF mutations in malignant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4790. doi:10.1158/1538-7445.AM2014-4790

Published
2014
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253. Abstract SY17-03: Targeting BRAF and PI3′-kinase signaling for therapy of melanoma

Author

Darrin Stuart, Fernando Salangsang, Marcus Bosenberg, Victoria Marsh, Jillian M. Silva, Wayne A. Phillips, Marian M. Deuker, Nancy Pryer, Allison Landman, Reinhard Dummer, Martin McMahon, William R. Sellers, Meghna Das Thakur, and Mitchell P. Levesque

Subjects
Cancer Research, biology, Melanoma, Cancer, Drug resistance, medicine.disease, Oncology, medicine, Cancer research, biology.protein, Gene silencing, PTEN, Vemurafenib, neoplasms, Protein kinase B, V600E, medicine.drug
Abstract

Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with greater than 50% of tumors expressing the BRAF(V600E) oncoprotein. BRAF(V600E) is a constitutively active protein kinase that promotes sustained activation of BRAF→MEK→ERK signaling in the melanoma cell. Importantly, the marked tumor regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF(V600E) in melanoma maintenance. However, since most patients relapse with lethal vemurafenib resistant disease, understanding and preventing mechanism(s) of drug resistance will be critical to extending the durability of patients' responses. Although mutational activation of BRAF is often the initiating event, progression of BRAF mutated melanomas is frequently associated with silencing of the PTEN tumor suppressor, a negative regulator of PI3′-kinase signaling. Whilst PTEN silencing is common in human melanoma, mutational activation of PIK3CA (encoding the alpha catalytic subunit of PI3′-kinase) is extremely rare, even though PIK3CA mutations are common in other human cancers. Since PTEN is reported to have tumor suppressor functions independent of its PI3′-lipid phosphatase activity, PTEN silencing may have more profound tumor promoting activity than mutational activation of PIK3CA. To test this, we generated mice carrying a conditional knock-in allele of Pik3ca that permits Cre-induced expression of PIK3CA(H1047R), a mutationally activated form of PIK3CA detected in many cancer types. Expression of PIK3CA(H0147R) in melanocytes elicited no obvious phenotype, consistent with the absence of phenotype in PTEN(Null) melanocytes. As observed previously, melanocyte-specific expression of BRAF(V600E) combined with PTEN silencing led to metastatic melanoma. Interestingly, metastatic melanoma also arose from melanocytes expressing both BRAF(V600E) and PIK3CA(H1047R), although these tumors grew more slowly than their BRAF(V600E)/PTEN(Null) counterparts. Both BRAF(V600E)/PTEN(Null) and BRAF(V600E)/PIK3CA(H1047R) melanomas were sensitive to the tumor prevention effects of pharmacological blockade of class 1 PI3′-kinases. However, the clinically relevant subset of BRAF(V600E)/PTEN(Null) melanoma was resistant to pharmacological blockade of AKT. Using genetically engineered mouse models and melanoma-derived cell lines, we demonstrate cooperative anti-tumor effects of combining RAF and PI3′-kinase inhibitors, suggesting that combined pathway-targeted chemotherapy may maximize melanoma patients' therapeutic response while delaying the onset of lethal drug resistant disease. Using patient derived xenografts propagated in immunocompromised mice we explored the cause and consequences of drug resistance, which was selected by continuous vemurafenib administration. As observed previously, resistant tumors displayed continued dependence on BRAF(V600E)→MEK→ERK signaling due to elevated BRAF(V600E) expression. However, remarkably, we observed that vemurafenib-resistant melanomas displayed a striking drug dependency for their continued proliferation, such that cessation of drug administration led to regression of established drug-resistant tumors. We further demonstrated that a discontinuous dosing strategy, which exploits the fitness deficit displayed by drug-resistant cells in the absence of the vemurafenib, forestalls the onset of lethal drug resistant disease. These data highlight the concept that drug-resistant cells may also show dependency, such that altered drug dosing may prevent the emergence of lethal drug resistance. Citation Format: Martin McMahon, Meghna Das Thakur, Victoria Marsh, Jillian Silva, Allison Landman, Marian Deuker, Fernando Salangsang, Nancy Pryer, Wayne Phillips, Mitchell Levesque, Reinhard Dummer, Marcus Bosenberg, William R. Sellers, Darrin Stuart. Targeting BRAF and PI3′-kinase signaling for therapy of melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY17-03. doi:10.1158/1538-7445.AM2013-SY17-03

Published
2013
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254. Abstract 1116: Sleeping Beauty mutagenesis identifies genes and pathways that cooperate with BrafV600E in melanoma initiation and progression

Author

Marcus Bosenberg, Michael B. Mann, Neal G. Copeland, David J. Adams, Martin McMahon, Nancy A. Jenkins, Cristin G. Print, Michael A. Black, and Jerrold M. Ward

Subjects
Genetics, Cancer Research, biology, Melanoma, Wnt signaling pathway, Cancer, Microphthalmia-associated transcription factor, medicine.disease, Oncology, CDKN2A, medicine, biology.protein, PTEN, neoplasms, GNAQ, Genetic screen
Abstract

Malignant melanoma is a devastating disease the prevalence of which is on the rise. In humans, somatic mutation of BRAF, to encode the BRAFV600E oncoprotein, is an early predisposing event in melanoma initiation, but is insufficient to drive malignant melanomagenesis in the absence of additional cooperating events. We describe a genome-wide, forward genetic screen in mice restricted to pigment producing melanocytes as an unbiased approach to identify new candidate melanoma progression genes. By combining Sleeping Beauty (SB) with a Cre-activated BRafCA allele we observed frank melanomas with average latency of 36 weeks. By contrast, melanocyte specific expression of BRAFV600E elicited benign melanocytic nevi that failed to progress to malignant melanoma by one year of age. These findings confirm that SB mobilization altered genes that cooperate with BRAFV600E to promote melanoma progression. A discovery set of 1,200 statistically-defined candidate melanoma genes was identified from 70 SB|BRAFV600E tumors. Importantly, our screen identified seven SB mutated genes with human orthologs that are well established human melanoma drivers including: Cdkn2a, Pten, Gnaq, Mitf, Nf1, Rac1 and Ppp6c. Many biological signaling pathways and cellular processes were enriched for candidate melanoma genes altered in SB|BRAFV600E melanomas, including Wnt/Beta-catenin, TGFβ, PI3’-kinase and MAPK signaling pathways and biological processes regulating ubiquitin mediated proteolysis, tight junctions, cell cycle and axonal guidance. Integrated comparative oncogenomic analysis with human melanoma data sets provided a data-driven method to filter and prioritize candidate melanoma genes. The genes identified using the SB|BRAFV600E model may represent new human melanoma candidate cancer genes with potential clinical relevance to the progression and maintenance of human BRAF mutated melanoma. Citation Format: Michael B. Mann, Michael A. Black, Jerrold M. Ward, Marcus W. Bosenberg, Martin McMahon, Cristin G. Print, David J. Adams, Neal G. Copeland, Nancy A. Jenkins. Sleeping Beauty mutagenesis identifies genes and pathways that cooperate with BrafV600E in melanoma initiation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2013-1116

Published
2013
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255. Abstract 5598: Interaction between BRAF inhibitor PLX-4720 and CDK inhibitors can sensitize melanoma cells with BRAF V600E mutation

Author

Srikumar Chellappan, Tharcísio Citrângulo Tortelli, and Roger Chammas

Subjects
MAPK/ERK pathway, Cancer Research, endocrine system diseases, biology, Melanoma, Retinoblastoma protein, Cancer, medicine.disease, Molecular biology, digestive system diseases, enzymes and coenzymes (carbohydrates), Oncology, Cyclin-dependent kinase, biology.protein, medicine, Cancer research, MTT assay, Viability assay, skin and connective tissue diseases, neoplasms, V600E
Abstract

BRAF V600E mutation happens in 60% of all melanomas cases and this mutation is responsible to poor prognosis of the disease. BRAF is part of the MAPK signaling pathway and the V600E mutation of BRAF confers full activation of this survival pathway. Several clinical trials are being conducted using mutated BRAF as a target but so far, all this trials works during a certain moment but soon, melanoma cells becomes resistant to treatment by activating some survival pathways that can continues the signal initialized in the MAPK pathway. Our objective is to evaluate if the combination of BRAF inhibitors and CDKs inhibitors can suppress the acquired resistance of V600E melanoma cells to BRAF inhibitors. Two melanoma cell lines were used in this study. The SKMel 28 cell line, which has BRAF V600E mutation, and the SKMel 02, which is wild type to BRAF. Olomoucine and Roscovitine were the CDKs inhibitors used in this study, while PLX-4720 was BRAF inhibitor. Western blot and Real time PCR were used to verify some survival pathways, like the MAP3K8 and the PRKD3 pathway, that are overexpressed after BRAF inhibition and MTT assay was used to verify cell viability with both treatments combined. The combination of Olomoucine and PLX-4720 or Roscovitine and PLX-4720 could sensitize the BRAF V600E mutated melanoma cell line SKMel 28, but not the BRAF wild type melanoma cell line SKMel 02. Two survival pathways (MAP3K8 and PRKD3) which are activated after BRAF inhibition by PLX-4720 were downregulated in the presence of the CDKs inhibitors in the SKMel 28 melanoma cell line. Also, the retinoblastoma protein was not phosphorylated when the SKMel28 melanoma cell line was treated with the BRAF inhibitor together with the CDKs. The treatment with the BRAF inhibitor and the CDKs inhibitors can sensitize BRAF V600E melanoma cells by decreasing cell viability, downregulation of survival pathways induced by the BRAF inhibitor and preventing Rb phosphorylation. This strategy may overcome the acquired resistance of BRAF-mutated melanoma after treatment with its inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5598. doi:1538-7445.AM2012-5598

Published
2012
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256. Abstract C182: Antitumor efficacy of the investigational MEK inhibitor TAK-733 against melanoma cell lines and human-derived tumor explant models

Author

John J. Tentler, Heather M. Selby, Kelsey L. Brunkow, Todd M. Pitts, Aik Choon Tan, S. Gail Eckhardt, and Lindsey N. Micel

Subjects
MAPK/ERK pathway, Neuroblastoma RAS viral oncogene homolog, Cancer Research, MEK Inhibitor TAK-733, Kinase, Melanoma, Cancer, Biology, medicine.disease, Oncology, Immunology, medicine, Cancer research, Protein kinase A, V600E
Abstract

Background: Sixty-percent of melanomas express mutant BRAF oncoproteins, which result in constitutive activation of the Rasmitogen activated protein kinase (MAPK) pathway and thus abnormal growth and ultimately a malignant phenotype. It has also been demonstrated that many melanomas are dependent on the MAPK pathway for survival and proliferation. MEK is a seronine/threonine kinase that is part of the BRAF downstream signaling cascade and is responsible for the phosphorylation of ERK1/2. Interestingly, ERK1/2 appear to be the sole target of the MEK protein kinase. Without ERK1/2 nuclear translocation, the inappropriate nuclear signaling responsible for the malignant phenotype is inhibited. The development of BRAF inhibitors has provided an exciting new treatment option for BRAF mutated melanoma, but unfortunately many patients have relapsed due to downstream alternative pathway activation. Investigational drug TAK-733 (Millennium Pharmaceuticals, Inc) is a potent, novel, selective, non-ATP competitive, allosteric inhibitor of MEK 1/2. With molecular inhibition downstream of BRAF, CRAF, COT, or NRAS mutations, tumor growth would theoretically be slowed or suppressed altogether. We explored the preclinical efficacy of TAK-733 in both in vitro and in vivo models of melanoma. Based on these translational results, TAK-733 demonstrates promising pre-clinical data supportive of further clinical development. Methods & Results: 36 melanoma cell lines were exposed to TAK-733 and the IC50 was determined using the SRB method. The cell lines were then classified as sensitive (S) or resistant (R) based on an IC500.1uM, respectively. BRAF status was obtained on all cell lines and did not correlate with responsiveness to TAK-733. Immunoblotting for effector proteins was performed on both S and R cell lines after 72 hrs of treatment with TAK-733. Phospho-ERK was suppressed in both S and R cell lines, confirming TAK-733-mediated inhibition of MEK 1/2. The evidence of MEK inhibition in the relatively resistant cell lines suggests other escape pathways are also contributing to melanoma survival and proliferation. There was no evidence of up-regulation of known MAPK-associated alternative pathways involving PI3 kinase or phospho-S6. Ten patient-derived melanoma tumors (5 V600E BRAF mutant, 2 wild-type BRAF, 3 unknown) were implanted into nude mice and treated daily via oral gavage with TAK-733 10mg/kg or 25mg/kg daily. The tumors were measured three times weekly and tumor growth inhibition (TGI) was analyzed. Nine explants, regardless of BRAF status, showed statistically significant TGI, ranging 87–97%, when compared to controls. One of the ten explants (BRAF V600E mutant) was resistant to TAK-733 with a TGI of 23%. Additionally, in one sensitive explant (BRAF wild type), treatment with TAK-733 was stopped, re-growth to 1533 mm3 was allowed, and subsequent re-treatment with TAK-733 induced tumor shrinkage to Conclusion: These data demonstrate that TAK-733 exhibited robust tumor growth inhibition and regression in human melanoma cell lines and human melanoma explant models in mice. Based on these results, TAK-733 demonstrates promising preclinical data supportive of further clinical development in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C182.

Published
2011
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258. Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma

Author

Michael Cerniglia, Lidia Robert, Antoni Ribas, Amanda Lassen, Deborah Jl Wong, Mohammad Atefi, and Begonya Comin-Anduix

Subjects
MAPK/ERK pathway, Proto-Oncogene Proteins B-raf, Cancer Research, Pyridones, Oncology and Carcinogenesis, Drug Resistance, Apoptosis, Pyrimidinones, Biology, AKT inhibitor, Cell Line, chemistry.chemical_compound, Cell Line, Tumor, Oximes, medicine, Humans, Oncology & Carcinogenesis, Combination therapy, Protein kinase B, Melanoma, Protein Kinase Inhibitors, Cancer, Trametinib, Tumor, MEK inhibitor, Research, Dabrafenib, Imidazoles, Cell cycle, medicine.disease, MAP Kinase Kinase Kinases, Xenograft Model Antitumor Assays, 3. Good health, chemistry, Oncology, 5.1 Pharmaceuticals, Drug Resistance, Neoplasm, Drug resistance, Mutation, Cancer research, Neoplasm, Molecular Medicine, Growth inhibition, Development of treatments and therapeutic interventions, Proto-Oncogene Proteins c-akt, medicine.drug, Signal Transduction
Abstract

BackgroundThe clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro.MethodsAnti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures.ResultsMore than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line.ConclusionsAKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations.

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259. Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2

Author

Kikuchi, Yoshinori, Shimada, Hideaki, Yamasaki, Fumiyuki, Yamashita, Taku, Araki, Koji, Horimoto, Kohei, Yajima, Satoshi, Yashiro, Masakazu, Yokoi, Keigo, Cho, Haruhiko, Ehira, Takuya, Nakahara, Kazunari, Yasuda, Hiroshi, Isobe, Kazutoshi, Hayashida, Tetsu, Hatakeyama, Shingo, Akakura, Koichiro, Aoki, Daisuke, Nomura, Hiroyuki, Tada, Yuji, Yoshimatsu, Yuki, Miyachi, Hayato, Takebayashi, Chiaki, Hanamura, Ichiro, and Takahashi, Hiroyuki

Published
2024
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260. Tumor Ecosystem : An Ecological View of Cancer Growth and Survival

Author

Erwei Song and Erwei Song

Subjects
Medicine—Research, Biology—Research, Cancer, Tumors—Immunological aspects
Abstract

This book intends to report new concept of onco-spheres in cancer ecosystem. Onco-spheres are defined as where cancer cells (living organisms) dynamically interact with nontumor cellular (other living organisms) and noncellular components (non-living environmental factors) in the ‘host'internal environment (habitat) to construct a self-sustainable cancer ecosystem, which can be scoped at three different levels: primary/regional, distal and systemic onco-spheres. Cancer cells should be conceived as ‘living organisms', interacting with cellular or noncellular components in the host internal environment, not only with the local tumor microenvironment (TME) but also constantly communicating with a distant organ niche as well interacting with the host's nervous, endocrine and immune systems, to construct a self-sustainable ‘biosphere', as we termed the tumor ecosystem. By looking at theinteraction of cancer and host as a unique ecosystem, we will use ecology principles to further delineate the features of the dynamics of the tumor ecosystem. As the pioneer in proposing this concept, we feel that this full-scale overview of the tumor ecosystem is able to inform the readers about this concept, and to pave the way for designing novel therapeutic strategies on actionable targets within tumor ecosystem. The book is likely to be of interest to immunologist, biologist, medical students, researchers and general public who wish to learn more on this new concept of tumor ecosystem, and how this could be applied in many fields of research.

Published
2023

261. Cancer Metastasis Through the Lymphovascular System

Author

Stanley P. Leong, S. David Nathanson, Jonathan S. Zager, Stanley P. Leong, S. David Nathanson, and Jonathan S. Zager

Subjects
Cancer, Metastasis, Lymphatics
Abstract

This textbook describes in detail the process of cancer metastasis from a single cell in the primary site through its arduous journey to the sentinel lymph node as the main gateway and beyond to distant sites. The most up-to-date knowledge on key topics in the molecular biology, diagnosis, and treatment of metastatic cancer is highlighted by a large panel of experts. The book begins with a comprehensive overview of the genetic and molecular mechanisms that promote or inhibit cancer metastasis through lymphatic pathways to lymph nodes or through vascular pathways to distant sites, providing the reader with an essential basic knowledge. This is followed by further details on the role of the immune system within the primary tumor and the lymph node and the importance of the microenvironment at the metastatic site. The role of the sentinel lymph node in cancer metastasis is emphasized. Special attention is also given to state-of-the-art imaging techniques for the detection of early-stage cancer and cancer metastases, as well as the use of liquid biopsies in sarcoma, prostate, gastrointestinal, and lung cancer. Clinical patterns of malignant tumors arising in different organ systems are compared, described, and discussed with the goal of determining what similarities and/or differences exist. The book concludes with a detailed discussion of surgical intervention, radiation, and systemic therapy of primary and metastatic cancer, and briefly previews several emerging topics, such as the latest findings on personalized cancer therapy, cancer stem cells, unique molecular mechanisms of virus-induced cancer, the impact of the microbiome on cancer metastasis and the application of artificial intelligence in cancer metastasis research. By providing fundamental knowledge of the biological and clinical aspects of cancer metastasis, this book will be an important reference for cancer researchers, clinical oncologists, teachers, and students. Written by experts in the field, each chapter includes a summary of the chapter's key points and open-ended questions that address pressing issues in the field and encourage the reader to consider future directions.

Published
2022

262. DeVita, Hellman, and Rosenberg's Cancer : Short Title:

Author

Vincent T DeVita Jr, Steven A Rosenberg, Theodore S Lawrence, Vincent T DeVita Jr, Steven A Rosenberg, and Theodore S Lawrence

Subjects
Oncology, Cancer
Abstract

The standard-setting text in oncology for 40 years, DeVita, Hellman and Rosenberg's Cancer: Principles and Practice of Oncology, 12th Edition, provides authoritative guidance and strategies for managing every type of cancer by stage and presentation. Drs. Vincent T. DeVita, Jr., Theodore S. Lawrence, and Steven A. Rosenberg oversee an outstanding team of expert contributing authors who keep you up to date and fully informed in this fast-changing field. This award-winning reference is also continually updated on Health Library and VitalSource platforms for the life of the edition.

Published
2022

263. Cancer: Principles and Practice of Oncology Primer of Molecular Biology in Cancer

Author

Vincent T. DeVita, Theodore S. Lawrence, Steven A. Rosenberg, Vincent T. DeVita, Theodore S. Lawrence, and Steven A. Rosenberg

Subjects
Cancer
Abstract

Recent scientific advances have revolutionized cancer research and practice, creating a body of molecular biology information that is important to research scientists and clinical oncologists alike. Cancer: Principles and Practice of Oncology: Primer of the Molecular Biology of Cancer, 3rd Edition, keeps you up to date with all that's new in this rapidly changing field. Derived from DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology – widely regarded as the definitive clinical reference in oncology – the third edition of this popular Primer provides a single-volume, highly focused reference on every important frontier in the molecular biology of cancer.

Published
2021

264. Next Generation Kinase Inhibitors : Moving Beyond the ATP Binding/Catalytic Sites

Author

Paul Shapiro and Paul Shapiro

Subjects
Cancer
Abstract

Protein kinases are fascinating enzymes that maintain the proper function of nearly every task performed by the cells of the human body. By extracting a phosphate from the energy molecule ATP and linking it to another protein, protein kinases alter the structure and ultimate function of other proteins. In this way, protein kinases help monitor the extracellular environment and integrate signaling cues that, for the most part, are beneficial for human health and survival. However, protein kinases are often dysregulated and responsible for the initiation and progression of many types of cancers, inflammatory disorders, and other diseases. Thus, decades of research have revealed much about how protein kinases are regulated and approaches to inhibit these enzymes to treat disease. However, nearly 30 years since the identification of the first clinically beneficial small molecule protein kinase inhibitor, there are only a few examples where these drugs provide sustained and durable patientresponses. The goal of this book is to provide biomedical scientists, graduate, and professional degree students insight into different approaches using small molecules to block specific protein kinase functions that promote disease.

Published
2020

265. Immunotherapy

Author

Aung Naing, Joud Hajjar, Aung Naing, and Joud Hajjar

Subjects
Cancer, Immunology, Oncology
Abstract

Immunotherapy is a rapidly evolving field that mandates frequent revision of the book as new insights to fight cancer emerge. The third edition of Immunotherapy is an updated overview of immuno-oncology in different cancer types and toxicities associated with immunotherapy. It explores the breath of immunotherapeutic strategies available to treat a wide range of cancers, from melanoma and non-small cell lung cancer to gastrointestinal, genitourinary, gynecologic and nervous system malignancies. With increasing use of checkpoint inhibitors as standard of care and in clinical trials, the challenges associated with their use undoubtedly increase. As objective response is limited to a subset of patients and is often associated with distinct immune related side effects that are potentially life threatening, it is essential to identify patients who are likely to respond to immunotherapy and those who are at a risk for developing treatment-related side effects. In the absence of a validated predictive biomarker, innovative technologies and assays are being used to identify critical biomarkers that drive the immune response. Hence, a chapter to provide a basic understanding of the diagnostic procedures has been included besides the chapter on the cellular components of the human immune system. This new edition will also inform readers on use of novel microbiome and imaging approaches. Finally, the book includes a chapter on patient-reported outcomes in patients treated with immunotherapies as the authors recognize the importance of including missing patient voice in clinical trials and longitudinal assessment of symptom reports. In short, the third edition of this book provides a comprehensive overview of the latest developments in the field of immune-oncology that will help health care professionals make informed treatment decisions. The book's chapters are written by a diverse cast of experts conducting cutting-edge research,providing the reader with the most up-to-date science.

Published
2020

266. DeVita, Hellman, and Rosenberg's Cancer

Author

Vincent T. DeVita, Steven A. Rosenberg, Theodore S. Lawrence, Vincent T. DeVita, Steven A. Rosenberg, and Theodore S. Lawrence

Subjects
Oncology, Cancer
Abstract

Publisher's Note: Products purchased from 3rd Party sellers are not guaranteed by the Publisher for quality, authenticity, or access to any online entitlements included with the product. Now updated online for the life of the edition, DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology, 11th Edition keeps you up to date in this fast-changing field. Every quarter, your eBook will be updated with late-breaking developments in oncology, including new drugs, clinical trials, and more.

Published
2020

267. Central Nervous System Metastases

Author

Manmeet Ahluwalia, Philippe Metellus, Riccardo Soffietti, Manmeet Ahluwalia, Philippe Metellus, and Riccardo Soffietti

Subjects
Nervous system—Surgery, Radiology, Oncology, Cancer, Quality of life
Abstract

This book provides a comprehensive overview of brain metastases, from the molecular biology aspects to therapeutic management and perspectives.Due to the increasing incidence of these tumors and the urgent need to effectively control brain metastatic diseases in these patients, new therapeutic strategies have emerged in recent years. The volume discusses all these innovative approaches combined with new surgical techniques (fluorescence, functional mapping, integrated navigation), novel radiation therapy techniques (stereotactic radiosurgery) and new systemic treatment approaches such as targeted- and immunotherapy. These combination strategies represent a new therapeutic model in brain metastatic patients in which each medical practitioner (neurosurgeon, neurologist, medical oncologist, radiation oncologist) plays a pivotal role in defining the optimal treatment in a multidisciplinary approach.Written by recognized experts in the field, this book is a valuable tool for neurosurgeons, neuro-oncologists, neuroradiologists, medical oncologists, radiation oncologists, cognitive therapists, basic scientists and students working in the area of brain tumors.

Published
2019

268. Targeted Therapies for Lung Cancer

Author

Ravi Salgia and Ravi Salgia

Subjects
Cancer, Medicine—Research, Biology—Research
Abstract

This book contextualizes translational research and provides an up to date progress report on therapies that are currently being targeted in lung cancer. It is now well established that there is tremendous heterogeneity among cancer cells both at the inter- and intra-tumoral level. Further, a growing body of work highlights the importance of targeted therapies and personalized medicine in treating cancer patients. In contrast to conventional therapies that are typically administered to the average patient regardless of the patient's genotype, targeted therapies are tailored to patients with specific traits. Nonetheless, such genetic changes can be disease-specific and/or target specific; thus, the book addresses these issues manifested in the somatically acquired genetic changes of the targeted gene. Each chapter is written by a leading medical oncologist who specializes in thoracic oncology and is devoted to a particular target in a specific indication. Contributors provide an in-depth review of the literature covering the mechanisms underlying signaling, potential cross talk between the target and downstream signaling, and potential emergence of drug resistance.

Published
2019

269. Cancer of the Thoracic Cavity : Cancer: Principles & Practice of Oncology, 10th Edition

Author

Vincent DeVita, Theodore S. Lawrence, Steven A. Rosenberg, Vincent DeVita, Theodore S. Lawrence, and Steven A. Rosenberg

Subjects
Peritoneum--Cancer, Cancer, Chest--Cancer, Lungs--Cancer, Oncology
Abstract

Selected from the world's leading comprehensive cancer textbook, this tightly focused resource provides you with the practical, cutting-edge information you need to provide the best cancer care to each patient. Cancer of the Thoracic Cavity: From Cancer: Principles & Practice of Oncology, 10th Edition, offers a comprehensive and balanced view of this rapidly changing field, meeting the needs of oncology/hematology practitioners, fellows, and others who need an in-depth understanding of cancer of the lung and mediastinum. The print reference gives you the solid, dependable guidance you have come to expect from this outstanding title, and the Inkling version features new quarterly updates written by a team of experts selected by the authors. Delivers focused, comprehensive information on cancer of the thoracic cavity drawn from the world's leading cancer textbook, DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Covers the molecular biology of lung cancer, non-small cell lung cancer, small cell and neuroendocrine tumors of the lung, and neoplasms of the mediastinum. Discusses in detail the growing importance of prevention and screening, giving you the understanding you need to improve your patients'chances for a healthier, cancer-free life. Explains how the latest developments in biologic therapy applies to cancer of the thoracic cavity. Provides exhaustive coverage of combined modality cancer treatment, helping you determine when and how to integrate modalities in patient treatment. Ensures that you are fully up to date thanks to easy, mobile access to quarterly updates.

Published
2016

270. Cancer of the Skin : Cancer: Principles & Practice of Oncology, 10th Edition

Author

Vincent T. DeVita, Theodore S. Lawrence, Steven A. Rosenberg, Vincent T. DeVita, Theodore S. Lawrence, and Steven A. Rosenberg

Subjects
Oncology, Cancer, Skin--Cancer
Abstract

Selected from the world's leading comprehensive cancer textbook, this tightly focused resource provides you with the practical, cutting-edge information you need to provide the best cancer care to each patient. Cancer of the Skin: From Cancer: Principles & Practice of Oncology, 10th Edition, offers a comprehensive and balanced view of this rapidly changing field, meeting the needs of oncology/hematology practitioners, fellows, and others who need an in-depth understanding of skin cancers. The print reference gives you the solid, dependable guidance you have come to expect from this outstanding title, and the Inkling version features new quarterly updates written by a team of experts selected by the authors. Delivers focused, comprehensive information on cancer of the skin drawn from the world's leading cancer textbook, DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Covers the full range of skin cancers, including nonmelanoma skin cancer, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, angiosarcoma, microcystic adnexal carcinoma, and more; as well as cutaneous melanoma, including molecular biology; and genetic testing in skin cancer. Discusses in detail the growing importance of prevention and screening, giving you the understanding you need to improve your patients'chances for a healthier, cancer-free life. Explains how the latest developments in biologic therapy applies to skin cancer. Provides exhaustive coverage of combined modality cancer treatment, helping you determine when and how to integrate modalities in patient treatment. Ensures that you are fully up to date thanks to easy, mobile access to quarterly updates.

Published
2016

272. What the Oncologist Needs From the Pathologist for Tyrosine Kinase Inhibitor Therapies

Author

Bernicker, Eric H.

Subjects
Precision medicine, Lung cancer, Osimertinib, Atezolizumab, Bevacizumab, Nivolumab, Tyrosine, Carboplatin, Pembrolizumab, Antineoplastic agents, Alectinib, Ipilimumab, Motor vehicle drivers, Crizotinib, Cancer, Phenols (Class of compounds), Cetuximab, Cancer patients, Health
Abstract

Although the debate continues on whether the promises of precision medicine in oncology have arrived or still tarry, there is little question that in the management of patients with advanced [...]

Published
2019
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273. International Manual of Oncology Practice : (iMOP) - Principles of Medical Oncology

Author

Ramon Andrade de Mello, Álvaro Tavares, Giannis Mountzios, Ramon Andrade de Mello, Álvaro Tavares, and Giannis Mountzios

Subjects
Cancer, Oncology, Hematology, Cytology, Pharmacy
Abstract

This textbook addresses themes ranging from the molecular issues of cancer sciences to clinical practice in medical oncology. It clarifies many topics, including molecular oncology, chemotherapy pharmacology and practical issues for clinicians. Systemic treatments in many areas of oncology feature, such as breast cancer, gastrointestinal, thoracic, urological oncology, head and neck tumors, bone tumors, sarcomas and palliative care.An excellent source for young physicians and researchers in the field of oncology, this book furthers understanding of medical oncology practice and facilitates professionals'treatment of cancer patients. It sets the direction for future research in the field, and will become the readers'regular working tool.

Published
2015

276. Codon-specific translation reprogramming promotes resistance to targeted therapy

Author

Rapino, Francesca, Delaunay, Sylvain, Rambow, Florian, Zhou, Zhaoli, Tharun, Lars, De Tullio, Pascal, and Sin, Olga

Subjects
Cancer treatment -- Research, Cancer research, Translation (Genetics) -- Research, Melanoma -- Research, Codons -- Research, Messenger RNA, Glucose metabolism, Protein synthesis, Cancer, RNA, Enzymes, Transfer RNA, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Reprogramming of mRNA translation has a key role in cancer development and drug resistance.sup.1. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation.sup.2,3. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U.sub.34) tRNA (U.sub.34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF.sup.V600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAF.sup.V600E-expressing melanoma cells are dependent on U.sub.34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U.sub.34 enzymes. Mechanistically, U.sub.34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1[alpha] protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U.sub.34 enzymes and HIF1[alpha]. Together, these results demonstrate that U.sub.34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. Enzymes that catalyse modifications of wobble uridine 34 tRNA are essential for the survival of melanoma cells that rely on HIF1[alpha]-dependent metabolism through codon-dependent regulation of the translation of HIF1A mRNA., Author(s): Francesca Rapino [sup.1] [sup.2] , Sylvain Delaunay [sup.1] [sup.2] , Florian Rambow [sup.3] [sup.4] , Zhaoli Zhou [sup.1] [sup.2] , Lars Tharun [sup.5] , Pascal De Tullio [sup.6] , [...]

Published
2018
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277. Abeloff's Clinical Oncology E-Book

Author

John E. Niederhuber, James O. Armitage, James H Doroshow, Michael B. Kastan, Joel E. Tepper, John E. Niederhuber, James O. Armitage, James H Doroshow, Michael B. Kastan, and Joel E. Tepper

Subjects
Cancer, Oncology
Abstract

Practical and clinically focused, Abeloff's Clinical Oncology is a trusted medical reference book designed to capture the latest scientific discoveries and their implications for cancer diagnosis and management of cancer in the most accessible manner possible. Abeloff's equips everyone involved - from radiologists and oncologists to surgeons and nurses - to collaborate effectively and provide the best possible cancer care.Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability. Select the most appropriate tests and imaging studies for cancer diagnosis and staging of each type of cancer, and manage your patients in the most effective way possible by using all of the latest techniques and approaches in oncology.Enhance your understanding of complex concepts with a color art program that highlights key points and illustrates relevant scientific and clinical problems. Stay at the forefront of the latest developments in cancer pharmacology, oncology and healthcare policy, survivorship in cancer, and many other timely topics.See how the most recent cancer research applies to practice through an increased emphasis on the relevance of new scientific discoveries and modalities within disease chapters.Streamline clinical decision making with abundant new treatment and diagnostic algorithms as well as concrete management recommendations.Take advantage of the collective wisdom of preeminent multidisciplinary experts in the field of oncology, including previous Abeloff's editors John E. Niederhuber, James O. Armitage, and Michael B. Kastan as well as new editors James H. Doroshow from the National Cancer Institute and Joel E. Tepper of Gunderson & Tepper: Clinical Radiation Oncology.Quickly and effortlessly access the key information you need with the help of an even more user-friendly, streamlined format.Access the complete contents anytime, anywhere at Expert Consult, and test your mastery of the latest knowledge with 500 online multiple-choice review questions.

Published
2013

278. Oncoyeasti: a web-based application to translate data obtained from Saccharomyces cerevisiae high-throughput drug screens into cancer therapeutics [version 1; referees: 1 approved with reservations, 2 not approved]

Author

Ruby Gupta, Samir Cayenne, Madhu Dyavaiah, Pragnya Srinivas, David Otohinoyi, Debjyoti Talukdar, Moheem Halari, Chidambra Halari, Ashok Ramani, Joshua Yusuf, Khushdeep Chahal, Rupinder Kaur, Ankit Patel, Avaniben Patel, Ravindrasingh Rajput, Harish Siddaiah, Shilpadevi Patil, Ashish Patil, and Nikhilesh Anand

Subjects
Software Tool Article, Articles, saccharomyces cerevisiae, Cancer, drug screening, toxicity screen, human homologs, cancer cell lines, TCGA, CCLE, translational research
Abstract

The budding yeast ( Saccharomyces cerevisiae) gene deletion library consists of a collection of more than 6,000 gene-deletion mutants and is useful for high-throughput screening of anti-cancer drugs. Because of the shorter doubling time and the significant homology the budding yeast shares with human cells, using a high-throughput chemical screen of budding yeast gene deletion library, one can rapidly identify various genetic targets of anti-cancer drugs. But analyzing the data derived from a yeast library screen to identify corresponding human homologs and their status in various cancers is a cumbersome process. We have developed a web-based app, Oncoyeasti, which enables the researcher to automatically identify the corresponding human homologs of S. cerevisiae and the status of these homologs genes in tumor samples from The Cancer Genome Atlas Database and cell line samples from the Cancer Cell Line Encyclopedia. This would enable the scientists to identify the tumors and choose cell lines to work on and thus serve as an indispensable tool to translate their research into human cancers.

Published
2018
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279. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology

Author

Vincent T. DeVita Jr, Theodore S. Lawrence, Steven A. Rosenberg, Vincent T. DeVita Jr, Theodore S. Lawrence, and Steven A. Rosenberg

Subjects
Cancer, Oncology
Abstract

DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology, 10th edition has garnered universal acclaim as the world's definitive, standard-setting oncology reference. More than 400 respected luminaries explore today's most effective strategies for managing every type of cancer by stage of presentation - discussing the role of all appropriate therapeutic modalities as well as combined-modality treatments. This multidisciplinary approach will help your cancer team collaboratively face the toughest clinical challenges and provide the best possible care for every cancer patient. Access the complete contents online or on your mobile device, with quarterly updates reflecting late-breaking developments in cancer care, free for the first year on LWW Health Library. Take full advantage of the latest advances with brand-new chapters on Hallmarks of Cancer, Molecular Methods in Cancer, Oncogenic Viruses, Cancer Screening, and new sections on Genetic testing and counseling for cancer, plus comprehensive updates throughout – including coverage of the newest biologic therapies. Make optimal, well-coordinated use of all appropriate therapies with balanced, multidisciplinary advice from a surgeon, a medical oncologist, and a radiation oncologist in each major treatment chapter. Review the latest molecular biology knowledge for each type of cancer and its implications for improved management. Make the best decisions on cancer screening and prevention, palliative care, supportive oncology, and quality-of-life issues

Published
2011

280. Using Genomic Sequencing to Improve Management in Melanoma

Author

Funchain, Pauline and Tarhini, Ahmad A.

Subjects
Melanoma -- Genetic aspects -- Development and progression -- Care and treatment, Precision medicine -- Innovations, Oncogenes -- Health aspects, Intelligence gathering, Cancer, Cancer diagnosis, Vemurafenib, Ipilimumab, Tumors, Bevacizumab, Gene expression, Genetic testing, Criminal investigation, Technology, Health
Abstract

Rapidly advancing genomic sequencing technologies are changing all areas of cancer, from diagnosis to surveillance, and prognostication to treatment. The role of genomic testing in melanoma is expanding, and multiple genomically based tests are available, including somatic tumor sequencing for actionable genetic alterations and tumor mutational burden, prognostic gene expression profiling from tumor tissue, and germline genetic testing from blood. The available testing options have varying levels of supporting data, from robust to preliminary. Here we summarize the available genomic and genetic tests for melanoma, and the level of evidence supporting each of these. We also discuss the current impact of genomic sequencing on the management of melanoma, as well as roles it may play in the near future., Introduction The last decade has seen rapid advances in the utilization and understanding of immunotherapy; these advances have been largely due to groundbreaking work in the immunobiology of melanoma, a [...]

Published
2018

282. Researchers from University of Verona Describe Research in Melanoma (Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-kB, STAT3, AP1 Transcription Factors and the Expression of Functional ...)

Subjects
Cancer, Melanoma, DNA binding proteins, Health
Abstract

2023 FEB 10 (NewsRx) -- By a News Reporter-Staff News Editor at Health & Medicine Week -- Fresh data on melanoma are presented in a new report. According to news [...]

Published
2023

283. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas

Author

Newman, Scott, Fan, Liying, Pribnow, Allison, Silkov, Antonina, Rice, Stephen V., Lee, Seungjae, and Shao, Ying

Subjects
RNA sequencing -- Usage, Melanoma -- Genetic aspects -- Risk factors -- Care and treatment, Gene expression -- Research, Medical schools, Resveratrol, Cancer, Data mining, Genomics, Serine, Tumors, Young adult literature, Genes, DNA sequencing, Genomes, RNA, Youth, Biological sciences, Health
Abstract

Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF.sup.1,2. However, in approximately 50% of cases no genetic driver has been established.sup.2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK.sup.3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements--uncovered by comprehensive clinical sequencing of a single case--are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition. Rearrangements in MAP3K8 respond to MEK inhibition and represent the most common genetic driver in pediatric spitzoid melanoma, and in some adult melanomas lacking other MAPK alterations and for which clinical testing is warranted., Author(s): Scott Newman [sup.1] , Liying Fan [sup.2] , Allison Pribnow [sup.3] [sup.4] , Antonina Silkov [sup.1] , Stephen V. Rice [sup.1] , Seungjae Lee [sup.5] , Ying Shao [sup.1] [...]

Published
2019
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285. Studies from University of Verona Further Understanding of Melanoma (Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins)

Subjects
Antineoplastic agents -- Research, Ribonuclease -- Research, MicroRNA -- Research, Cancer, Transfer RNA -- Research, Melanoma -- Research, Antimitotic agents -- Research, Health, Onconase (Medication) -- Research
Abstract

2022 MAR 4 (NewsRx) -- By a News Reporter-Staff News Editor at Health & Medicine Week -- Data detailed on melanoma have been presented. According to news reporting out of [...]

Published
2022

288. Linking brain tumors and epileptic seizures

Author

Mulcahy Levy, Jean M. and McMahon, Martin

Subjects
Epilepsy -- Genetic aspects -- Risk factors, Gene mutation -- Health aspects, Seizures (Medicine) -- Genetic aspects -- Risk factors, Brain tumors -- Genetic aspects -- Complications and side effects, Death, Neurophysiology, Cancer, Brain research, Universities and colleges, Tumors, Pediatrics, Plastics industry, Biological sciences, Health
Abstract

Mutationally activated BRAF-V600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic., Author(s): Jean M. Mulcahy Levy [sup.1] , Martin McMahon [sup.2] Author Affiliations: (1) Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado and University of Colorado, Denver, USA [...]

Published
2018
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290. Study identifies novel treatment resistance mechanism in BRAF-mutant melanoma

Subjects
Physical fitness, Cancer, Melanoma, Health, Massachusetts General Hospital
Abstract

2016 AUG 27 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A Massachusetts General Hospital (MGH) research team has identified an additional mechanism [...]

Published
2016

292. Study Results from Netherlands Cancer Institute Update Understanding of Melanoma (Switch to checkpoint inhibition after targeted therapy at time of progression or during on-going response: a retrospective single centre experience in patients ...)

Subjects
Cancer, Cancer research, T cells, Antigens, Editors, Health
Abstract

2019 NOV 8 (NewsRx) -- By a News Reporter-Staff News Editor at Health & Medicine Week -- Researchers detail new data in Oncology - Melanoma. According to news reporting out [...]

Published
2019

293. Reports Outline Melanoma Study Findings from Friedrich-Alexander-University [Inhibition of Peptidyl-prolyl Isomerase (Pin1) and Braf Signaling To Target Melanoma]

Subjects
Vemurafenib -- Research -- Reports, Melanoma -- Research -- Reports, Cancer research, Immunohistochemistry, Cancer, Medical law, Cancer metastasis, Editors, Business, Health, Health care industry
Abstract

2019 AUG 20 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Weekly -- New research on Oncology - Melanoma is the subject of a report. According to news [...]

Published
2019

294. Exelixis to Host Investor/Analyst Webcast During European Cancer Congress 2015

Subjects
Exelixis Inc., Cancer, Biotechnology industries, Business, Business, international
Abstract

- Briefing to Discuss Results from METEOR Phase 3 Pivotal Trial of Cabozantinib in Advanced Renal Cell Carcinoma Presented at the Meeting - - Cabozantinib and Exelixis-Discovered Cobimetinib to be [...]

Published
2015

295. Patent Application Titled 'Activities of Multiple Cancer-Related Pathways Are Associated with Braf Mutation and Predict the Resistance to Braf/Mek Inhibitors in Melanoma Cells' Published Online (USPTO 20160222466)

Subjects
Cancer genetics, Gene therapy, Cancer, Patents, Melanoma, Patent/copyright issue, Biotechnology industry, Health, Science and technology
Abstract

2016 AUG 22 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent [...]

Published
2016

296. Scientists at M.D. Anderson Cancer Center Target Melanomas

Subjects
Cancer, Scientists, Melanoma, Health
Abstract

By a News Reporter-Staff News Editor at Clinical Trials Week -- Researchers detail new data in Melanomas. According to news reporting from Houston, Texas, by NewsRx journalists, research stated, 'CDDO-Me [...]

Published
2013

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